Aewcqrca 32

Yvonne Bouwman-Boer
V‘Iain Fenton-May
Paul Le Brun Editors
Practical
Pharmaceutics
An International Guideline for the Preparation,
Care and Use of Medicinal Products
Practical Pharmaceutics
Yvonne Bouwman-Boer • V’Iain Fenton-May
Paul Le Brun
Editors
Practical Pharmaceutics
An International Guideline
for the Preparation, Care
and Use of Medicinal Products
Editors
Yvonne Bouwman-Boer V’Iain Fenton-May
Royal Dutch Pharmacists Association KNMP Former Quality Control Pharmacist to the Welsh
Laboratory of Dutch Pharmacists Hospitals
The Hague Cardiff
The Netherlands United Kingdom
Paul Le Brun
The Hague Hospital Pharmacy
The Hague
The Netherlands
ISBN 978-3-319-15813-6 ISBN 978-3-319-15814-3 (eBook)

DOI 10.1007/978-3-319-15814-3
Library of Congress Control Number: 2015933496
Springer Cham Heidelberg New York Dordrecht London

Translation and revision based on the Dutch language edition: Recepteerkunde:
Productzorg en bereiding van geneesmiddelen, 5th Ed, edited by Yvonne
Bouwman-Boer, Paul Le Brun, Christien Oussoren, Ria Tel and Herman
Woerdenbag Copyright # 2009 KNMP. All Rights Reserved
# KNMP and Springer International Publishing Switzerland 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic
adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
express or implied, with respect to the material contained herein or for any errors or omissions that may have been
made.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)

Preface
The core role of a pharmacist is and has always been to supply the patient with the most
appropriate medicines according to their needs. Patients have differing needs. Not all patients
fit the ‘normal profile’ upon which the efficiencies of scale allow the pharmaceutical industry
to mass produce medicines. A significant proportion of patients require medicines to be
specifically made to suit their needs.1
The pharmaceutical art of preparing medicines should be seen in the social context of
guaranteeing the availability of necessary medicines to patients. The Council of Europe
Resolution on pharmacy preparation2 considered the preparation of medicinal products in
pharmacies as indispensable for accommodating the special needs of individual patients
in Europe.
Another reason for preparing in pharmacies is the fact that the pharmaceutical industry has
become so international and many of the smaller national industries have been swallowed up
in the process that any small effect on the supply chain leads to the observed shortages now felt
in all countries around the world.
For several years pharmacists in many European countries have felt the need for knowl-
edge, information and guidelines on the practice of preparation in the pharmacy. This was
clearly put forward by experts from many European countries at the EDQM symposium on
European Cooperation and Synergy and at the BEAM compounding course.3 During this
course it was agreed that the knowledge for the preparative pharmacist were contained in
the Dutch book Recepteerkunde and that this book could be used as a base for a European
wide textbook on preparation in pharmacies.
The aim of Practical Pharmaceutics is to offer:
• Basic knowledge for undergraduate and graduate pharmacy students.
• Practical knowledge on the design and preparation of medicines for the pharmacists
responsible for preparations in community and hospital pharmacies.
• Basic knowledge for the Qualified Person (QP) in industry and all pharmacists involved in
quality assurance.
• Product knowledge for all pharmacists working directly with patients, to enable them to
make the appropriate medicine available, to store medicines properly, to adapt medicines if
necessary and to dispense medicines with the appropriate information to inform patients
and caregivers about product care and how to maintain their quality. This basic knowledge
will also be of help to industrial pharmacist to remind and focus them on the application of
the medicines manufactured.
1
Fenton May V. Preparation in the hospital pharmacy: from the past to the present and, hopefully, beyond.
Eur J Hosp Pharm 2012;19:465–6.
2
Resolution CM/ResAP (2011) 1 on quality and safety assurance requirements for medicinal products
prepared in pharmacies for the special needs of patients. Available from: https://wcd.coe.int/ViewDoc.jsp?
id¼1734101&
3
EAHP Academy third BEAM summit on Aspects of Compounding. 2010.
v
vi Preface
The first principal was that Recepteerkunde would form the basis of the book. Secondly we
agreed to retain the principal of using experienced practising pharmacists from hospital and
academia as authors to the chapters. In order to ensure that the book reflected the practice from
across Europe, experts in the specific fields were chosen from all quarters of Europe.
Practical Pharmaceutics covers such a vast area that the production of the book would have
taken many more years to complete if the Dutch starting reference work had not been there as a
basis. Its first edition, edited by Harry Cox, Gerad Bolhuis and Jan Zuidema, was published in
1992 as a gift of the Dutch Pharmacists’ Association KNMP to their members on the occasion
of the 150th anniversary. It has been used since at both universities in the Netherlands offering
the Pharmacy curriculum. The fifth edition from 2009 forms the basis of Practical
Pharmaceutics.
The book is generally written in GB English but liberties have been taken where it has been
considered that an adaption would make the sense easier to understand across Europe. Some of
those changes are explained in the Introduction.
We owe a debt of thanks to the authors and translators who were given extremely short
deadlines for their tasks, most of whom are practicing pharmacists with full time and often
stressful jobs. An editorial advisory group has dutifully answered many questions about the
actual situation in their countries.
The financing of such an enterprise is never easy, and we thank EAHP and both the Dutch
pharmacists associations KNMP and NVZA for the foresight to invest in the book without
which it would not have been produced.
Comments for improvement could be forwarded to [email protected]
The Hague, The Netherlands Yvonne Bouwman-Boer

Cardiff, United Kingdom V’Iain Fenton-May
The Hague, The Netherlands Paul Le Brun
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Yvonne Bouwman-Boer, V’Iain Fenton-May, and Paul Le Brun
2 Prescription Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Andrew Lowey and Stefanie Melhorn
3 Availability of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Helena Jenzer and V’Iain Fenton-May
4 Oral Solids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Minna Helin-Tanninen and João Pinto
5 Oral Liquids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Antje Lein and Shi Wai Ng
6 Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Anne de Boer and Ernst Eber
7 Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Suzy Dreijer - van der Glas
8 Nose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Suzy Dreijer - van der Glas and Anita Hafner
9 Ear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Suzy Dreijer - van der Glas and Monja Gantumur
10 Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Annick Ludwig and Holger Reimann
11 Rectal and Vaginal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Stineke Haas, Herman Woerdenbag, and Małgorzata Sznitowska
12 Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Antje Lein and Christien Oussoren
13 Parenteral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Marija Tubic-Grozdanis and Irene Krämer
14 Irrigations and Dialysis Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Daan Touw and Olga Mučicová
15 Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Rogier Lange, Marco Prins, and Adrie de Jong
16 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Erik Frijlink, Daan Touw, and Herman Woerdenbag
17 Product Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Herman Vromans and Giovanni Pauletti
vii
viii Contents
18 Physical Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Wouter Hinrichs and Suzy Dreijer - van der Glas
19 Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Hans van Doorne, David Roesti, and Alexandra Staerk
20 Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Herman Wijnne and Hans van Rooij
21 Quality Risk Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Yvonne Bouwman-Boer and Lilli Møller Andersen
22 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Daan Touw and Jean Vigneron
23 Raw Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Roel Bouwman and Richard Bateman
24 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Jan Dillingh and Julian Smith
25 Human Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Jan de Smidt and Hans van Rooij
26 Occupational Safety and Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Yvonne Bouwman-Boer, Shi Wai Ng, and Sylvie Crauste-Manciet
27 Premises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
Willem Boeke and Paul Le Brun
28 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Marco Prins and Willem Boeke
29 Basic Operations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Herman Woerdenbag, Małgorzata Sznitowska, and Yvonne Bouwman-Boer
30 Sterilisation Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
Marco Prins and Mattias Paulsson
31 Aseptic Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Frits Boom and Alison Beaney
32 Quality Requirements and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Oscar Smeets, Mark Santillo, and Hans van Rooij
33 Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Rik Wagenaar and Mark Santillo
34 Production, Quality Control and Validation . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Rogier Lange and Lilli Møller Andersen
35 Pharmaceutical Quality Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
36 Logistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
V’Iain Fenton-May and Hana Šnajdrová
37 Instructions for the Use of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Suzy Dreijer - van der Glas and Anthony Sinclair
Contents ix
38 Impact on Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829

Bengt Mattson and Tessa Brandsema
39 Information Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
Doerine Postma and Sin Ying Chuah
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Abbreviations
AAD Adaptive Aerosol Delivery

ACD Automated Compounding Devices
ADI Acceptable Daily Intake
ADS Automated Dispensing Systems
AIO All In One
ALARA As Low As Reasonably Achievable
APV Arbeitsgemeinschaft für pharmazeutische Verfahrenstechnik (Association
for Pharmaceutical Technology)
AQL Acceptable Quality Level
ART Advanced REACH Tool
AUC Area Under The Curve
AV Analytical Validation
BCS Biopharmaceutical Classification System
BPI Batch Preparation Instruction
BPR Batch Preparation Record
BSC Biological Safety Cabinet
CAN Critical Aggregation Number
CAPA Corrective And Preventive Action system
CAPD Continuous Ambulant Peritoneal Dialysis
CDC (U.S.) Centers for Disease Control and Prevention
CEDI Continuous Electro-deionisation
CFC ChloroFluoroCarbons
CFU Colony Forming Unit
c-GMP current Good Manufacturing Practice
CHMP Committee for Medicinal Products for Human Use
CIVAS Central Intra Venous Additives Service
CLP Classification, Labelling and Packaging Regulation
CMC Critical Micelle Concentration
CMR Carcinogenic, Mutagenic and Reprotoxic
COC Cyclic Olefin Copolymer
COMP Committee for Orphan Medicinal Products
COSHH Control of Substances Hazardous to Health (UK)
CPD Continuous Professional Development
CPMP Committee for Proprietary Medicinal Products
CT Computed Tomography
CTD Common Technical Document
CVC Central Venous Catheter
DEHP Di-2-EthylHexyl Phthalate
DHPC Direct Healthcare Professional Communication
DLVO-theory Deryagin-Landau-Verwey-Overbeek theory
DMEL Derived Minimal Effect Level
DNEL Derived No-Effect Level
xi
xii Abbreviations
DOP Dioctylphthalate
DPI Dry Powder Inhalers
DQ Design Qualification
DS Detail Specification
D-value Decimal reduction value
ECHA European Chemicals Agency
EDI Electro-deionisation
EDQM European Directorate for the Quality of Medicines
EFQM European Foundation for Quality Management
EMA European Medicines Agency
EPAR European Public Assessment Report
EPI Extemporaneous Preparation Instruction
EPR Extemporaneous Preparation Record
ERA Environmental Risk Assessment
EU-OSHA European Agency for Safety and Health at Work
Eu-US PFI European – United States Paediatric Formulation Initiative
FAT Factory Acceptance Test
FMEA Failure Mode Effect Analysis
FNA Formularium der Nederlandse Apothekers (Dutch Pharmacist’s Formulary)
FRC Functional Residual Capacity (pulmonary medicines)
FRCs Functionality-Related Characteristics
FRS Functional Requirements Specifications
FTU Finger Tip Unit
GAMP Good Automated Manufacturing Practice (Guides)
GDP Good Distribution Practices
GHS Global Harmonised Classification and Labelling System
GMP Good Manufacturing Practice
GPP Good Preparation Practices
GUM Guide to the Expression of Uncertainty in Measurement
HCP Health Care Professional
HDF Haemodiafiltration
HDPE High Density Polyethylene
HEPA High Efficiency Particulate Air
HFA Hydrofluoroalkanes
HLB Hydrophilic-Lipophilic Balance
HVAC Heating, Venting and Air Conditioning
IARC International Agency for Research on Cancer
ICER Incremental Cost-Effectiveness Ratio
ICH International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IED Industrial Emissions Directive
IMP Investigational Medicinal Products
IMPD Investigational Medicinal Product Dossier
IQ Installation Qualification
ISO International Standards Organisation
ISPE International Society of Pharmaceutical Engineering
LDPE Low Density Polyethylene
LEL Lower Explosion Level
LQL Limiting Quality Level
LTC Long Term Care
LVP Large Volume Parenterals
MAH Marketing Authorisation Holder
MDI Metered Dose Inhaler
Abbreviations xiii
MEC Minimal Effective Concentration

MICC Midline Inserted Central Catheters
MKT Mean Kinetic Temperature
MMAD Mass Median Aerodynamic Diameter
MPN Most Probable Number
MRI Magnetic Resonance Imaging
MSHG Manufacturers’ Safe Handling Guidance
MTC Maximal Tolerable Concentration
NIOSH National Institute of Occupational Safety and Health (US)
NOAEL No Observed Adverse Effect Level
NOEL No Observed Effect Level
NRF Neues Rezeptur-Formularium (German Formulary)
NSI Needlestick and Sharp Injuries
OEL Occupational Exposure Limit
OMCL Official Medicines Control Laboratories
OOS Out of Specification
OOT Out of Trend
OQ Operational Qualification
OSH Occupational Safety and Health
OSHA Occupational Safety and Health Administration (US)
P&IDs Piping & Instrumentation Diagrams
PAH Polycyclic Aromatic Hydrocarbons
PAT Process Analytical Technology
PCA Patient Controlled Analgesia
PDA Parenteral Drug Association
PDA Permitted Daily Exposure
PDCA Plan, Do, Check, Act
PEC Predicted Environmental Concentration
PEG Percutaneous Endoscopic Gastrostomic
PET Polyethylene Terephthalate
PET Positron Emission Tomography
PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection
Co-operation Scheme
PICC Peripheral Inserted Central Catheter
PIL Package Information Leaflet
PK/PD Pharmacokinetics and Pharmacodynamics
PLC Programmable Logic Controller
PNEC Predicted No-Effect Concentration
PP Polypropylene
PPE Personal Protective Equipment
PQ Performance Qualification
PQS Pharmaceutical Quality System
PTFE Polytetrafluorethene
PUR Polyurethane
PVC Polyvinylchloride
PVDC Polyvinylidene Chloride
QA Quality Assurance
QALY Quality-Adjusted Life Year
QbD Quality by Design
QC Quality Control
QMR Quality Management Review
QMS Quality Management System
QP Qualified Person
xiv Abbreviations
QPPV Qualified Person for PharmacoVigilance

QRM Quality Risk Management
RCA Root Cause Analysis
RDA Recommended Dietary Allowance
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
RI&E Risk Inventory and Evaluation
RMM Rapid Microbiological Methods
RO Reverse Osmosis
RODAC Replicate Organism Duplicate Agar Contact
RPN Risk Priority Number
rsd Relative standard deviation
RTA Ready To Administer
SAL Sterility Assurance Level
SAT Site Acceptance Test
SED Safety-Engineered Sharp Device
SLA Service Level Agreement
SMART Specific, Measurable, Acceptable, Realistic and Time bound
SmPC Summary of Product Characteristics
SOP Standard Operation Procedure
STEP Safety and Toxicity of Excipients for Paediatrics
SVP Small Volume Parenterals
TAMC Total Aerobic Microbial Count
TDM Therapeutic Drug Monitoring
TFBUT Tear Film Break Up Time
TGV Threshold Guidance Values
TLC Thin Layer Chromatography
TLC Total Lung Capacity
TPN Total Parenteral Nutrition
TRS Technical Requirement Specification
TTC Threshold of Toxicological Concern
TYMC Total combined Yeast and Mould Count
URS User Requirement Specification
VAD Vascular Access Device, Venous Access Device
VHC Valved Holding Chamber
VMAD Volume Median Aerodynamic Diameter
WFI Water For Injections
WHO World Health Organisation
WHPA World Health Professions Alliance
WI Work Instruction
The Structure of Practical Pharmaceutics
PATIENTS’ NEEDS
PATIENTS’ NEEDS
• Prescription assessment.
• Availability of medicines
PRODUCT DESIGN
PRODUCT DESIGN
• Oral solids
• Oral liquids
DISPENSING • Pulmonary
• Oropharynx
• Logistics • Nose
• Instructions for the use • Ear
of medicines • Eye
• Impact on environment • Rectal and vaginal
• Dermal
• Parenteral
• Irrigation and dialysis
• Radiopharmaceutics
Basics
• Biopharmaceutics
PRODUCTION
• Product design
PRODUCTION • Physical chemistry
• Microbiology
• Raw materials • Statistics
• Containers • Quality risk management
• Human resources • Stability
• Occupational safety and
health
• Premises
• Equipment
• Basic operations
• Sterilisation methods
• Aseptic handling
• Quality requirements
and analysis
In control
• Documentation
DISPENSING
• Production, Validation
and Quality Control
• Quality systems
xv
Introduction
1
Yvonne Bouwman-Boer, V’Iain Fenton-May, and Paul Le Brun
Contents Abstract
This chapter explains some of the principles that have
1.1 Structure of the Book . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
been followed during the production of this textbook. The
1.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 basic principal is that the structure follows the needs of
1.2.1 Types of Pharmacy Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.2 Aseptic Preparation, Aseptic Handling and Reconstitution . 4 the patient. Concepts such as preparation, manufacturing,
reconstitution, aseptic handling, hazardous substances are
1.3 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.1 Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
defined in order to avoid any ambiguity. Specific termi-
1.3.2 Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 nology on the technological operation of dispersing is
1.3.3 Hazardous Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 defined, which covers particle size reduction, mixing
1.3.4 Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 and de-agglomeration. Any spelling and notations used
1.3.5 Dispersion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
in the European Pharmacopoeia have been followed in
1.4 Spelling and Notation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 this book, in the absence of such guidance they are
1.4.1 Active Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
defined herein.
1.4.2 Spelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4.3 Gender Neutral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4.4 Greek Letters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Keywords
1.5 Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Terminology Definitions Spelling Notation
Formulations
1.6 Examples, Guidelines, Legislation, Ph. Eur. . . . . . . . . . . . . . . 6
1.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1 Structure of the Book
The focus of Practical Pharmaceutics is the medicine as a

product for the care of patients. The book focuses on its
preparation, control, logistics, dispensing and use.
Although the existence of medicines is almost taken for
granted, the design, description and control of this whole
process of availability is so wide-ranging that this book
easily became as large as it is.
Y. Bouwman-Boer (*)
Despite of the focus on the medicinal product, the struc-
Royal Dutch Pharmacists Association KNMP, Laboratory of Dutch ture of the book follows the patient, see Fig. 1.1. Product
Pharmacists, The Hague, The Netherlands care is a vital part of pharmaceutical care.
e-mail: [email protected] A patient may need medicines. In most countries they
V. Fenton-May need a prescription from a medical doctor who thereby
Former Quality Control Pharmacist to the Welsh Hospitals, Cardiff, shares responsibility with the patient. ‘The’ pharmacist
United Kingdom
e-mail: [email protected]
(community, hospital, industrial pharmacist, scientist,
teacher or competent authority) is responsible for the supply
P. Le Brun
The Hague Hospital Pharmacy, The Hague, The Netherlands
of the prescribed medicines, being professionally
Y. Bouwman-Boer et al. (eds.), Practical Pharmaceutics, 1

DOI 10.1007/978-3-319-15814-3_1, # KNMP and Springer International Publishing Switzerland 2015
2
PATIENTS’ NEEDS
• Prescription assessment. PRODUCT DESIGN
• Availability of medicines
• Oral solids
• Oral liquids
• Pulmonary
• Oropharynx
• Nose
• Ear
• Eye
• Rectal and vaginal
DISPENSING • Dermal
• Parenteral
• Logistics
• Irrigation and dialysis
• Instructions for the use of
• Radiopharmaceutics
medicines
• Impact on environment In control
PRODUCTION • Documentation
• Production, Validation
• Raw materials Basics
and Quality Control
• Containers • Biopharmaceutics
• Quality systems • Product design
• Human resources
• Occupational safety and • Physical chemistry
health • Microbiology
• Premises • Statistics
• Equipment • Quality risk management
• Basic operations • Stability
• Sterilisation methods
• Aseptic handling
• Quality requirements
and analysis
Fig. 1.1 The structure of the book.1
1
Y. Bouwman-Boer et al.
The authors thank Cathrien Dijken ([email protected]) for the concept.

1 Introduction 3
responsible for procurement, medicines design and prepara- When the patient has his medicine dispensed, he has
tion, storage and dispensing. to receive labelled or oral instructions, or both, not only
The pharmacist needs to assess the doctor’s prescription, for therapeutic reasons but also for keeping and taking
for therapy reasons, but within the focus of this book also for the medicine in the right way. Awareness on the impact of
availability and, in case of a pharmacy preparation, for medicines on the environment is growing but not
safety and quality as well. integrated yet.
The administration route and dosage form strongly influ- Although many references are in all chapters, the book
ence the design of the medicine and its method of preparation. ends with a list of super references: textbook and hints for
Chapters 4–14 are written according to the route of adminis- postgraduate education.
tration. These chapters make ample use of examples from
preparation in pharmacies, however the design in industrial
manufacturing is basically not different. If relevant and possi-
ble industrial approaches are touched upon. All design 1.2 Definitions
activities need basics independent of the route of administra-
tion. These basics are dealt with in the following 7 chapters in 1.2.1 Types of Pharmacy Preparations
a practical pharmaceutical context.
The actual production of medicines is a highly regulated The textbook started its life in the field of pharmacy prepa-
sector of society. The 10 chapters about the different aspects ration and although the focus of this edition is on mainstream
clearly reflect that. Although regulations are omnipresent, manufactured products as well, much attention goes to
the approach of these chapters stems from practice and logic. provisions that the hospital or community pharmacist has
This also applies to the 3 chapters that cover the control to offer because not every patient fits the mainstream. It
mechanisms of production. became obvious that official terminology for these periph-
Before the patient can take the prepared or manufactured eral activities is insufficiently discriminating. Therefore a
medicine it has to be stored, procured, and distributed. terminology was developed as pictured in Fig. 1.2.
Starting Material Process Legal status
No extra activity
Licensed
Reconstitution medicinal
Licensed product
medicinal
products
Repackaging or replenishing
Dispensing or
administration
to the patient
Reconstitution in excess of SPC instructions
Unlicensed
Pharmaceutical
Preparations
Licensed Preparation by adapting the dosage form of an
medicinal existing medicinal product
products
Or
Raw
materials Preparation from raw materials
Fig. 1.2 Terminology of preparation activities

4 Y. Bouwman-Boer et al.
The terminology and definition of the activities is as 1.3.1 Drug

follows:
Reconstitution: manipulation to enable the use or application The term ‘drug’ is not used. The reasons are because of its
of a medicinal product with a marketing authorisation in wider connotation in the area of abuse and because it is not
accordance with the instructions given in the summary of discriminating between the active substance and the medi-
product characteristics or the patient information leaflet cine. Instead of drug either the term ‘medicine’ is used or –
(Ph. Eur. Pharmaceutical Preparations). Often reconstitu- when appropriate – ‘active substance’. European legislation
tion is needed in excess of the instructions of the sum- is thereby followed as well as international harmonisation.
mary of product characteristics or the patient information Only in compounded, mainly biopharmaceutical, terminol-
leaflet, such as when a longer shelf life is assigned or ogy such as ‘drug release’ or ‘drug distribution’ the word
when a different dilution with an infusion solution takes ‘drug’ is used. The terms ‘orphan drug’ and ‘drug shortage’
place. This action is legally considered as preparation. are generally changed into orphan medicine and medicines’
When speaking about the actual work process, that is the shortage (which is sometimes caused by shortage of an
handling, it appears not sensible to distinguish between active substance).
the processes. Therefore this book uses the term ‘recon-
stitution’ for reconstitution in the strict sense as well as
for Reconstitution in excess of the summary of product 1.3.2 Preparation
characteristics or the patient information leaflet. If recon-
stitution is about parenteral medicines, as is often the The Ph. Eur. defines preparation (of an unlicensed pharma-
case, the term ‘aseptic handling’ may be used in order ceutical preparation) as: the ‘manufacture’ of unlicensed
to distinguish it from aseptic preparation or processing. pharmaceutical preparations by or at the request of
Preparation by adapting an existing product: reformulating pharmacies or other healthcare establishments (the term
a licensed product into a different dosage form suitable ‘preparation’ is used instead of ‘manufacture’ in order
for the intended use, presented in a suitable and appropri- clearly to distinguish it from the industrial manufacture of
ately labelled container (after Ph. Eur. Pharmaceutical licensed pharmaceutical preparations). As many situations
Preparations). apply to production of medicines in (hospital) pharmacies,
Preparation from raw materials: formulating active the term ‘preparation’ is used most in the book. Sometimes it
substances and excipients into a dosage form suitable is quite obvious that it concerns manufacturing.
for the intended use, presented in a suitable and appropri- ‘Compounding’, as a term for small-scale preparation often
ately labelled container (after Ph. Eur. Pharmaceutical used in the US, is not used in this book.
Preparations).
1.3.3 Hazardous Substance

1.2.2 Aseptic Preparation, Aseptic Handling
and Reconstitution The definition of ‘hazardous’ in combination with
substances follows the European Occupational Safety and
The reconstitution of parenteral medicines in the strict sense Health legislation i.e. every substance that has been assigned
as well in the extended sense (see Sect. 1.2.1) is very fre- a so-called H(azard)-statement. Carcinogenicity, Mutage-
quently performed in hospital pharmacies. The right perfor- nicity or Reprotoxicity (CMR) are reflected in specific
mance of this process requires extensive precautions on H-statements, but many other types of toxicity exist. This
procedures, premises, validation and control. However approach should diminish the confusion that arises when
these differ considerably, due to working with closed ‘hazardous’ is considered synonym with CMR or, in other
systems, from the generally accepted precautions for aseptic situations, even with CMR plus some specific types of tox-
processing from raw materials. The use of the term ‘aseptic icity. Let alone if ‘hazardous substances’ is considered syn-
handling’ therefore was felt justified. onym with the therapeutic class of antineoplastics.
1.3 Terminology 1.3.4 Terms
The Editors had to come to an agreement on a number of Dosage forms, administration routes and containers usually
aspects that required compromise in the usage of descriptive follow the Ph. Eur. or are named according to the EDQM
terms and spelling. (European Directorate of Quality of Medicines) lists of
1 Introduction 5
Table 1.1 Overview of the terminology used in relation to particle size reduction, mixing and de-agglomeration
Topic Term Description
Particles Primary particles Particles that consist of a single crystal
Secondary particles Particles are agglomerates
Particle size Milling Particle size reduction by (different) forces
reduction Grinding Milling a substance by hand
Wet grinding Grinding with an amount of liquid as small as possible for reasons of: preventing agglomeration,
augmenting milling efficiency (grease effect) or for occupational safety and health reasons
(to prevent the creation of dust particles)
Pulverising Smashing a material into a powder
Comminuting Reducing to powder (US)
Mixing and Dispersing Distributing primary particles into a medium; may bring about the breaking up of agglomerates
de-agglomeration (de-agglomeration)
Geometrically dilution Mixing using the ratio 1:1 repeatedly
(Triturating)
Mixing (¼ blending) Putting substances together to get a homogeneous distribution
Rubbing Intensely mixing (triturated) powders with a semisolid or liquid on a surface to obtain a smooth
mixture
Making into a (thick) paste
Levigating (US)
Triturating Mixing a solid with a solid, semisolid or liquid substance in such a ratio and intensity that
agglomerates are dispersed (de-agglomeration); de-agglomeration may take place if the right
medium is chosen
standard terms. In other areas terms of the International 1.4.2 Spelling

Committee on Harmonisation (ICH), GMP and ISO are
used where possible. The difference between industrial As in European legislation the GB English spelling is used.
scale production and preparation in pharmacies has led to Commas are used to separate thousands in numbers
the use of other terms but they are defined, where used. instead of a space as in the European Pharmacopoeia and
the stop sign that is common in many European Countries.
In some instances English words have been created, such
as hydrophilise as a verb (instead of the description: making
1.3.5 Dispersion
hydrophilic), considering that a French and German reader
for instance will immediately understand what is meant.
A main challenge of processing an active substance if it is
not dissolved is the dispersion of the particles. This affects
many dosage forms such as oral suspensions, cutaneous
1.4.3 Gender Neutral
preparations and suspension-type suppositories. It appeared
that this process could be performed in different ways on a
Any reference, in the text, to the word ‘he’ should be taken to
small scale, making a difference in the result. It was felt
be gender neutral and to include ‘she’.
justified to use different words for these different ways.
Table 1.1 (also as Table 29.4) shows the result.
1.4.4 Greek Letters
1.4 Spelling and Notation Greek letters are indispensable part of specific formulas or
equations. But in running text they better be changed into
1.4.1 Active Substances Latin. So: “α” becomes “alpha”. The reason behind is that
with moving and copying texts between different word
The quality of specified active substances and excipients processing programs, as happens in editing and with using
has to meet, in Europe, the European Pharmacopoeia electronic books, symbols easily get lost or disfigured. The
criteria and thus are named according to the English mono- only exception is the chapter Statistics that definitely needs
graph titles. If not included, another reference pharmaco- Greek letters as symbols, and μm that will not lead to
poeia is given. misunderstandings.
means that a single textbook for all will cover topics and
1.5 Formulations practices, which may be new to some, but old to others. The
main legislative starting point for this book is the Ph. Eur.
The book is not intended to be a formulary but many especially the monograph Pharmaceutical Preparations.
preparations’ formulas are included in order to exemplify Other basic legislation used is the EC legislation on
principles described in the texts. Some readers may wish to medicines, the EU-GMP (Good Manufacturing Practice)
use the formulas in practice, however for that purpose more and guidelines of ICH (International Conference on
information is necessary, such as the detailed method of Harmonisation).
preparation, stability data, appropriate containers, back- If the Ph. Eur. is referred to it is always the current edition
ground information and justification, etcetera. The original at time of closing the manuscript (September 2014) that is
source formulary, e.g. FNA (see Sect. 39.4.5) or NRF (see meant.
Sect. 39.4.2) should be consulted to meet that demand. Comments on the interpretation of regulation is always
The amounts in formula-tables are virtual amounts, that offered as a snapshot in time and is only valid as long as the
is: they are not meant as “to be weighed” or to provide a wording of the legal texts is unchanged compared to the
preparation instruction. They are used to illustrate the cited reference.
percentages of all substances.
1.6 Examples, Guidelines, Legislation, 1.7 References

Ph. Eur.
It was noted that scientific publications in this field are
Most information in the book is universally applicable in the sometimes lacking where practical experience, guidelines
field of preparation and manufacturing of medicines. Focus as well as procedures may be widespread. Therefore some
on specific items has been guided by European legislation literature quotes in the original Dutch book have been
and guidelines, and by country-specific examples put for- retained even though, as they are in Dutch, they cannot be
ward by the authors and an editorial advisory group. Most considered truly available to all. In cases where there is no
Countries in Europe have produced Guidelines, Publications literature we rely on a scientific base, sound thinking and
and Textbooks to cover aspects of pharmacy that is of explanation, then best practices and then regulations. The
particular interest to their unique practice. The emphasis in aim is to provide our colleagues with the systematic knowl-
each Country differs, usually as a result of some historic edge that gives them the tools to act professionally in what-
incident, which focused efforts in a particular direction. This ever situation they will find themselves.
Prescription Assessment
2
Andrew Lowey and Stefanie Melhorn
Contents Abstract
Upon receipt of a request from a prescriber for a phar-
2.1 Pharmacy Preparation: Way Out or Unjustified . . . . . . . . 7
macy preparation, the pharmacist must decide whether
2.2 Prescription Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 the request is appropriate and reasonable, and judge the
2.2.1 Alternative Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.2 Considerations Upon Receiving a Request . . . . . . . . . . . . . . . . . . 9 level of risk associated with proceeding with the request.
2.2.3 Structured Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 The pharmacist must also consider the risks of not sup-
2.3 The Prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
plying a medicine which may lead to the patient not
2.3.1 Legal Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 receiving treatment. Further discussion with the medical
2.3.2 Consultations with the Prescriber and the Patient . . . . . . . . . . . 16 team may be needed. This chapter approaches the risk
2.3.3 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 assessment of the prescription in a structured way, refer-
2.3.4 Contra Indications, Interactions and Intolerances . . . . . . . . . . . 19
2.3.5 Narcotic and Psychotropic Substances . . . . . . . . . . . . . . . . . . . . . . . 20
ring to procedures and forms from different countries.
2.3.6 Standard Amounts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 The assessment also includes the feasibility of producing
a preparation of appropriate pharmaceutical quality and
2.4 Special Categories of Prescriptions . . . . . . . . . . . . . . . . . . . . . . . . 20
2.4.1 Herbal Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 with all necessary clinical information.
2.4.2 Agents Used for Assisted Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Pharmacy legislation defines the framework in which
2.4.3 Homoeopathic and Anthroposophic Medicines . . . . . . . . . . . . . 21 pharmacists can prepare medicines, however there are
2.4.4 Veterinary Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
other legislative and quality frameworks that they must
2.4.5 Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.4.6 Biocides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 be aware of if other categories of products are requested,
2.4.7 Raw Materials (Chemicals) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 such as biocides, medical devices, or placebo’s, or agents
2.5 Essentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 used for euthanasia Veterinary and homeopathic
medicines are also dealt with, as are raw materials, espe-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
cially hazardous materials and precursors.
Keywords
Risk assessment Prescription Preparation Reasoned
assessment
2.1 Pharmacy Preparation: Way Out

or Unjustified
Based upon the chapter Beoordeling recept by André Wissenburg en
Frits Boom in the 2009 edition of Recepteerkunde.
A. Lowey (*)
Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire, England
Case Suppositories with Hydrocortisone
e-mail: [email protected] Prescription states: Hydrocortisone suppositories
S. Melhorn
240 mg, 6 units
Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium, Govi Dosage – Use 1 suppository when required as directed
Verlag Pharmazeutischer Verlag GmbH, Eschborn, Germany
e-mail: [email protected] (continued)

8 A. Lowey and S. Melhorn
pharmacovigilance or monitoring systems for pharmacy

The parents of a 2 month old girl Klaartje come to prepared products also means that the likelihood of detection
the pharmacy with this prescription. The suppositories for any errors that lead to side effects is low.
have been recommended by an endocrinologist at the Despite the relative lack of information about side effects
hospital. Upon inquiry it appears that Klaartje suffers related to pharmacy prepared products, there have been
from a condition known as Prader Willi syndrome, a reports of catastrophic errors associated with them, includ-
hereditary disorder which affects hypothalamic func- ing an error in the US that led to a 1,000-fold overdose of
tion; the adrenal cortex produces insufficient cortico- clonidine in a 5 year old child [1]. A high profile error also
steroid at times of stress. occurred in 1998 in the UK, when a baby died following a
An intramuscular injection with a licensed pharma- calculation error in preparing peppermint water in a commu-
ceutical preparation that contains hydrocortisone nity pharmacy [2].
sodium succinate would constitute a major treatment Therefore, upon receipt of a request from the doctor, the
option. However, the child’s parents do not want to pharmacist must examine the situation and decide whether
give an injection to their child. Klaartje drinks very the request is appropriate and judge the level of risk
reluctantly as all babies with the Prader Willi syn- associated with proceeding with the request. Before pro-
drome. The parents don’t consider administration ceeding, the pharmacist should review all other potential
with the feeding of the contents of a capsule or of treatment options. The use of a licensed product in line
crushed tablets as a reliable option. Therefore, the with its approved indication should be strongly advocated
doctor has suggested a rectal preparation. unless there is a specific reason not to use such a medicine.
This case is typical of requests for pharmacy However, the pharmacist must also consider the risks of not
preparations; in order to give tailor-made care, the supplying a medicine which may lead to the patient not
doctor has prescribed an individual preparation instead receiving treatment. In this context, it should be recognised
of a licensed pharmaceutical preparation. When the that some patients do have special clinical needs which
oral route would have been an option, licensed oral cannot be met by other viable options.
solid medicines had to be adapted anyway because of The pharmacist must make every effort to ensure that
the low dose required. the medicine produced is of appropriate pharmaceutical
Before the pharmacist starts preparing the quality and is fit for the intended purpose; an approved
suppositories, he needs to perform a risk assessment or authorised formula should be used wherever possible.
to establish the likely safety, quality and efficacy of the Where such formulae are not available, steps should be
product (in comparison with alternative treatment taken to minimize risk where possible e.g. restricted shelf
options). life, fridge storage (if applicable), use of licensed starting
materials etc.
The same principles apply for reviewing prescriptions
Pharmacy preparation allows the doctor and pharmacist to for pharmacy preparations as for licensed medicinal
provide individualised and tailor-made pharmaceutical care. products.
The preparation of a medicine in the pharmacy fulfils a need
when the licensed pharmaceutical preparation is not avail-
able (see also Sect. 3.2.2) or when a licensed pharmaceutical 2.2 Prescription Assessment
preparation does not satisfy a specific situation.
However, pharmacy prepared products are not subject to 2.2.1 Alternative Treatment Options
the same levels of scrutiny with respect to quality assurance
and efficacy as licensed medicines; therefore prescribers and Before a pharmacist decides to prepare a product, he must
pharmacists cannot make the same assumptions of quality, consider various alternative treatment options available.
safety and efficacy about these products as they do for Depending on legislative situation in the country and the
licensed medicines. relation between pharmacists and physicians, options may
This is due to the wide range of elevated risks associated include:
with pharmacy preparation, including calculation and • Use of a (licensed) medicine which is then administered
manipulation errors, formulation failures leading to over- by an alternative route or method e.g. use of a soluble or
dose or underdose, possible toxicity from raw materials dispersible product or indeed rectal product in patients
and microbiological contamination. The relative lack of who have difficulty swallowing whole tablets.
2 Prescription Assessment 9
• Use of an appropriate licensed formulation of an alterna- • Are the facilities and equipment appropriate and
tive medicine from the same therapeutic class (e.g. using calibrated?
PATIENTS’ NEEDS
a licensed liquid formulation of lisinopril rather than • Has a health & safety risk assessment been carried out?
preparing a captopril oral suspension). • Are there systems in place to monitor the efficacy and
• Manipulation of a licensed medicine prior to each dose safety of the product? Is the patient being monitored
e.g. dispersing a tablet in a small volume of water or closely (if appropriate)?
halving tablets (Note: the practice of dispersing a tablet
in water and then using an aliquot of the liquid is
associated with a high risk of inaccurate doses and is 2.2.3 Structured Assessments
generally not recommended except in extraordinary
circumstances). For the general approach of options Some pharmacists have suggested a structure approach to
when difficulties swallowing solid licensed medicines is the decision-making process: e.g. Leeds approach, German
the reason for the request, see Sect. 37.6.2. reason check, Risk-benefit Form.
• Use of a product intended for a different route e.g. use of
an injection orally.
• Use of an imported product which bears a product license 2.2.3.1 Leeds Approach
in its country of origin (a check should be made to ensure At Leeds Teaching Hospitals NHS Trust in England, the
that the absence of a local license is not due to a revoca- Pharmacy department has a ‘catalogue’ of authorised phar-
tion of a previous license). macy preparations, which is periodically reviewed to ensure
• Purchase of a batch-manufactured unlicensed product that other more suitable options are not available. Each
from an alternative supplier (e.g. ‘Specials of the approved preparations on the catalogue have been
Manufacturers’ in the UK). Note that this practice is not reviewed by a group of senior technicians and pharmacists
allowed or highly restricted in some countries in Europe to ensure that they have a sound evidence base and are
(see Sects. 3.9 and 3.12). backed by an authorised preparation instruction and
agreed label.
This means that the clinical pharmacist has some assur-
2.2.2 Considerations Upon Receiving ance of the likely quality of the end product. They must,
a Request however, still judge if the individual formulae is appropriate
for the intended patient. This is the difference between a
When faced with a request for individualised pharmacy product of high quality and one that is appropriate or ‘fit for
preparation, a pharmacist may find it helpful to consider purpose’.
the following questions in order to reduce or avoid risks: If a ‘non-catalogue’ (non-standard) preparation is
• Has a risk assessment been carried out that has requested, the requesting pharmacist must complete a form
established pharmacy preparation as the most appropriate (see Fig. 2.1) to acknowledge that other options have been
choice for this patient? considered, along with the possible risks associated with
• Are there other more suitable alternatives, is a licensed the preparation. High risk products can still be authorised
product available, could a licensed product be adapted for if the benefits outweigh the potential risks; however the
each dose, are there other batch-manufactured products authorisation must come from one of the senior management
available, could you use an imported product that has a team in the department.
licence in a mutually-recognised country? This process creates an appropriate barrier to pharmacists
• What is the risk of not treating the patient? who might otherwise decide to authorise ad hoc or unusual
• Does the active substance have a narrow therapeutic formulations without considering the associated risks.
index? The group of senior pharmacists and technicians then
• Can a peer-reviewed and evidence-based formula meet every few months to review the requests for non-
be used? If not, have the physico-chemical properties catalogue preparations, and review whether other options
of the active substance been considered, and have should be pursued e.g. purchase of a licensed product from
steps been taken to minimise risk and complexity (e.g. a foreign country, use of a batch-manufactured product
reduce shelf-life, store in fridge, prepare a solution rather than an extemporaneously-prepared product for an
instead of a suspension, use commercially available individual etc.
suspending agents which have been tested with the active As a guide to help the risk assessment, the department
substance in question and pharmaceutical-grade raw provides a risk assessment matrix to highlight potential
materials)? problems to the clinical pharmacist, see Fig. 2.2.
Leeds Teaching Hospitals NHS Trust Leeds Teaching Hospitals NHS Trust
10
Pharmacy Services Pharmacy Services

Document EXP01
Section C: Risk Assessment
Request Form for a Non-Catalogue Extemporaneous Product
Use the risk assessment matrix (EXP03) to assess risks for each category and overall risk. (Please attach
Section A: Request Details evidence to form)
• Risks to Quality (Formulation & Stability) Low / Medium / High (Please circle)
Patients Name:…………………………………… Consultant: ………………………………….
Comments:
Ward: ………………………………………….…. Weight: ………………………………………
Date of Birth: ….……………….…………….…... Hospital: …………………………………….. • Clinical Risks (Safety & Efficacy) Low / Medium / High (Please circle)
Pharmacist Name: …………………………………………….….…… Date: ……………………….…. Comments:

Print Name Signature
Requesting Doctor: ……………………………………………… Grade: ………………. Date: ………………. • Health & Safety Risks (COSHH) Low / Medium / High (Please circle)
Drug Requested: Comments:

Approximate Duration Inpatient/
Name Route Dose
of treatment Outpatient
Overall Risk Rating: Low / Medium / High (Please circle)
Clinical Reason for use: ……………………………………………………………………………….. Section D: Approval
Section B: Points to consider (please circle) Decision to make product: Yes / No Signed: Date:
Is an alternative formulation available? Yes/No For Low and Medium Risk products obtain approval from CPTL. PRINT NAME ……………………………
Is an alternative route available? Yes/No
Is an alternative licensed product available? Yes/No For High risk products obtain approval from LEVEL D PHARMACIST. PRINT NAME………………………
Can the product be sourced from a licensed specials manufacturer? Yes/No
Is an alternative method possible? Yes/No Section E: Preparation

(e.g. tablet crushing & dispersing in water / oral administration of injection)
Is the medicine licensed for the indication? Yes/No Notify dispensary and arrange for a blank worksheet and labels to be prepared. Authorize worksheet.
Could the prescription be changed to a catalogue presentation? Yes/No Note Worksheet authorization must occur before product is made.
Photocopy worksheet and retain copy in the dispensary. Attach form EXP01 to the original completed
Comments:……………………………………………………………………………………………………………… worksheet and leave in appropriate wallet in ‘Green Extemp File’ (found in LGIIP, LGIOP, CLA, SJIP, CDH,
………………………………………………………………………………………………………………….………… WGH, CKE, CAH dispensaries).
……………………………………………………………………………………………………………………………. If this item needs to be added to catalogue refer to the ‘Catalogue Request Pack’ (found in dispensary
……………………………………………………………………………………………………………………………. Extemporaneous Dispensing File) Also refer to the Extemporaneous Dispensing Policy.
……………………………………………………………………………………………………………………………. These documents will be reviewed periodically by the Extemporaneous Steering Group/Extemporaneous
……………………………………………………………………………………………………………………………. Review Group.
Fig. 2.1 Request form for a non-catalogue extemporaneous product

A. Lowey and S. Melhorn
2
DOCUMENT EXP03 EXTEMP PRODUCT RISK ASSESSMENT MATRIX
Assessment of Overall Risk
• Assess risk for each category: Quality; Safety & Efficacy; COSHH.
• The highest individual rating gives the overall risk category.
• For high and medium overall rating contact:
QC for quality issues

Clinical Lead for clinical issues (categorisation of drug toxicity/ TI; patient monitoring measures)
COSHH Team for COSHH issues
SCORE
Risks to Quality Validated formula and • Formula available, but not • Formula available, but not • Formula available, but No Formula available.
(Consider effect of supporting stability data validated. No supporting validated. not validated.
preparative available. stability data. • No supporting stability • No supporting stability
process on drug • Published papers • Evaluation of formula and data or evaluation. data or evaluation.
stability • Pharmacopoeia shelf life from first • Experience of safe and • No evidence of safe
and uniformity • Developed by licensed principles by suitably effective use in NHS. and effective use in
of dose ) manufacturer experienced staff. • Reduced shelf life (max 7 NHS.
• Experience of safe and days).
effective use in NHS.
Rating: Low Rating: Low Rating: Medium Rating: High Rating: High
Risks to Low Toxicity. Wide Therapeutic Index (TI) Wide Therapeutic Index Narrow Therapeutic Index Narrow Therapeutic Index
Safety/Efficacy Short term use Short term use Maintenance Therapy Short term use Maintenance Therapy
(Consider effect of Bioavailability could be Bio-availability could be
formulation on significantly changed by significantly changed by
drug bio- crushing tablet crushing tablet
availability)
Rating: Low Rating: Low Rating: Medium Rating: High Rating: High
H & S Risks Full supporting COSHH data Inadequate supporting COSHH data
(see extemp Control measures in place No control measures in place.
COSHH No COSHH assessment carried out.
Guidance)
Rating: Low Rating: High
Overall Risk Assessment: HIGH MEDIUM LOW
Low Risk: Prepare worksheet & make in accordance with local SOP’s. Use licensed or QC approved starting materials only.
Medium Risk: Make for short-term use only and monitor patient for clinical effect and ADRs. Consider outsourcing to a specials unit or alternative therapy for long term
use.
High Risk: Consider all alternatives before making - only make as last resort. Monitor patient closely for clinical effect, toxic effects and ADRs.
Document EXP03 Second Edition April 2009
Fig. 2.2 Extemporaneous product risk assessment matrix

11
PATIENTS’ NEEDS
2.2.3.2 German Reason Check 2.2.3.3 Risk-Benefit Form [4]

In Germany, pharmacists must perform ‘reason checks’ A risk-benefit form has been elaborated for extemporaneous
(Plausibilitätsprüfung) to establish the likely safety, quality, and for stock preparation (Figs. 2.4 and 2.5). They enable the
and efficacy of the product they want to prepare. The Phar- pharmacist to list and balance the benefits and risks of the
macy Practice Order (Apothekenbetriebsordnung, ApBetrO) clinical and pharmaceutical qualities of the required phar-
specifies parameters of the preparation formula that must be macy preparations. The form follows the process for
checked, whether it is a doctor’s prescription or self- handling of requests for preparation, and defines decisive
medication on patient’s request. Beyond that, the guideline steps, levels of evidence of decisions, individuals concerned
recommends that the pharmacist considers the overall ratio- and responsibilities.
nale for treatment. Possible benefits include:
A form has been developed (Fig. 2.3) for the performance • Unique therapeutic value if there is no comparable
and documentation of the reason check. Some parts will be authorised medicine available
dealt with. • Improved patient friendliness and therefore a better com-
Regarding “Qualitative and quantitative composition”: pliance with therapy
Substances used as active substance or as an excipient • Improved safety of health care processes (using
in pharmaceutical preparations have to be described in an preparations that don’t need any reconstitution steps on
individual monograph of the European Pharmacopoeia or the wards or in nursing homes)
comply with the requirements of the relevant general • Improved occupational safety and health (OSH) of health
monographs (see also Sect. 23.1). Cosmetics and medicinal care personnel (by diminishing exposure from hazardous
products may only be used if the required quality is active substances)
documented. In Germany it is not allowed to change or add • (Lower price)
any active substances without permission of the prescriber. Possible risks include:
This does not apply to excipients that have no pharmacolog- • Uncertainty about therapeutic safety and efficacy
ical effect. • Design failure causing quality defects, like poor bioavail-
Regarding “Compatibility”: if components of a prescribed ability or poor content uniformity
preparation are not compatible (or there is a lack of evidence), • Preparation risk: if the actual pharmaceutical quality sys-
it does not mean automatically that it should not be prepared. tem cannot guarantee that the preparation will fully meet
The preparation needs to show sufficient compatibility up to specifications
the in use expiry date; it may be possible to produce a • Discouraging the marketing of authorised of
preparation with a shortened but useful shelf life. Interactions medicines
between the active substances and excipients can however The forms for extemporaneous and stock preparation use the
make it impossible to produce a preparation of sufficient same benefits and risks. With extemporaneous preparations
quality. These incompatibilities can be visible or invisible the balance refers to an individual patient. With stock
during preparation. The attending pharmacist has to verify if preparations the balance results in the definition of the group
incompatibilities are apparent. More information about of (anonymous) patients for whom, or care situation in which,
incompatibilities is to be found in references such as Fiedler the benefits may outweigh the risks.
(Sect. 39.2.2), Handbook of Pharmaceutical Excipients Clinical benefits and risks are assessed on the front of the
(Sect. 39.2.3), Martindale (Sect. 39.2.4), Handbook of Extem- form by the attending pharmacist, who decides if the request
poraneous Preparation (Sect. 39.4.6), Kommentar zum adds enough value to be considered further. On the back the
Arzneibuch (Sect. 39.4.8) and Trissel’s Stability of preparatory pharmacist assesses the risks of design and prep-
Compounded Formulations (Sect. 39.4.14). aration. He also checks the feasibility: if necessary conditions
Regarding “Stability and shelf life”: These items are are met such as availability of starting materials or sufficient
amply discussed in Chap. 22 Stability. Stability is influenced control of the health and safety risk of the pharmacy person-
by the solubility of all substances in the preparation, pH of the nel. Over-all it is the preparatory pharmacist who decides:
base, pH at which the active substances are stable, and the • In case of an extemporaneous preparation if he accepts
influence of oxygen and light. Shelf life is restricted due to: the request(or not)
• Chemical, physical, physico-chemical reactions • In the case of a stock preparation on the conditions on
• Rheological changes which he will make this preparation available.
• Formations of toxic degradation products Balancing benefits and risks (see Fig. 2.6) is not a matter of
• Microbiological growth mathematics but of professionalism, responsibility and
• Decrease in concentration of the active substance transparency. The forms therefore are transparent about the
• Incompatibilities or issues caused by the container decisions and show who made them.
Actions
Checklist for Reason Check
Notes
PATIENTS’ NEEDS
1. Sufficiency and readability of the prescription
Is the prescription complete? yes no
Is everything readable? yes no
Are there any perceivable mistakes? yes no

2. Safety and treatment concept, dosage and dosage
instructions
Are there questionable ingredients? yes no
Is the treatment concept obvious? yes no
Is the dosage sensible? yes no
Are the dosage instructions sensible? yes no
3.Qualitative and quantitative composition
Is the concentration of the active substances higher

yes no
than the indicative concentration?
Is the concentration of the active substances within
yes no
the normal dosage range?
Are all ingredients available in the required
yes no
pharmaceutical quality?
Does the prescription conform to a standard
yes no
formulation?
If so, please specify the source:
Are there any similar standard formulations? yes no
If so, please specify the source:
4. Compatibility
Are the ingredients compatible? yes no
If no, please specify the incompatibilities:
5. Stability and shelf life
Is there a need for an added buffer? yes no
Is the microbiological stability sufficient for the

yes no
targeted shelf life?
Is the prescribed preparation stable enough for the
yes no
targeted shelf life?
Additional assessments
Date, Signature Responsible Pharmacist/Delegate
Fig. 2.3 Form for German reason check ([3] translated). Further explanation about items 3, 4 and 5 is given in Sect. 2.2.3.2
Design
14
Request for extemporaneous preparation

Design of formulation and Analogous to ……………………………………
Final formulation or action
of preparation process
From literature: ……………………………………
Own design, based on: ……………………………
Attachment(s): ………………………………………..
Availability as authorised medicine Is the design well- Yes / No∗)

considered enough if Comments:
checked
balanced with the added
Patient (name, details): value for the patient?
Discussion with attending pharmacist: ………

Name physician or GP, specialism, date, discussion: …………………………..
Indication: Feasibility
Raw materials available? yes/no∗) Comments:
Standard therapy: Sufficiently stable for clinical use? yes/no ∗)
Is the health and safety risk of the pharmacy

Reason of request
personnel controllable? yes/no∗)
Non-availability authorised medicine Comments / references / literature /
Other preconditions yes/no∗)
Unique therapeutic value attachments:
Another aspect: ……………………………
Improvement patient-friendliness
Improved health and safety health Conclusion: preparation is (not) ∗) feasible
care personnel
Decision about request
Different: ……………………
To prepare for this individual patient (p.t.o.)
No preparation: no well-considered design available
Level of consensus about evidence
No preparation: the request adds value for the patient indeed, the design is well-
National (authorisation, guidelines, consensus), that is: ……..
considered but the preparation is not feasible
Regional: ……………
Other . …………………………………………………………………………………
Local: ………………..
Result discussed Attending pharmacist (name, date): …………………………..
Individual physician, GP, pharmacist: ….……………………
with:
……………………………………………………………………..
Experience with this therapy: …………………………………………
Conclusion Assessed by attending pharmacist: Signature:

Request will (not) ∗) be
considered subsequently. ……………………………………. (name, initials) Preparatory pharmacist (name, date, signature): ……………………………………….
∗) ∗)
delete where not applicable delete where not applicable
Fig. 2.4 Form for balancing risks and benefits of an extemporaneous preparation; front and back side (see Sect. 2.2.3.3)
A. Lowey and S. Melhorn
2
Stock preparation Design

Design of formulation and Analogous to ……………………………………
(formula, strength, administration route, dosage form)
of preparation process
From literature: ……………………………………
Own design, based on: ……………………………
Attachment(s): ………………………………………..
Is the design well- Yes / No∗)

considered enough if Comments:
balanced with the added
value for the patient?
Indication:
Feasibility
Starting materials available? yes/no∗) Comments:
Patient population:
Sufficiently stable for clinical use? yes/no∗)
Standard therapy: Is the health and safety risk of the pharmacy

personnel controllable? yes/no∗)
Availability as authorised medicine checked Other preconditions yes/no∗)
Another aspect: ……………………………
Reasons for preparation Level of consensus about evidence
Conclusion: preparation is (not) ∗) feasible
Non-availability authorised medicine National (authorisation, guidelines,
Unique therapeutic value consensus), that is: …….. Decision about suitability for stock preparation
Improvement of patient-friendliness Regional: ……………
To prepare only for patients from the own pharmacy
Improved safety of health care Local: ………………..
To prepare for patients nationwide
processes Individual physician, GP, pharmacist:
No preparation: no well-considered design available
Improved health and safety of care ….……………………
No preparation: the preparation is valuable and the design is well-considered but
personnel Experience with this therapy:
the preparation is not feasible
Authorised medicine available but not …………………………………………
Other . …………………………………………………………………………………
reimbursed
Result discussed …………………………..
Different: ……………………
with:
……………………………………………………………………..
Comments / references / literature / attachments:
Signature:
Conclusion Assessed by pharmacist:
Risk/benefit assessment is Preparatory pharmacist (name, date, signature): ……………………………………….
in∗)/sufficiently founded to continue the …………………………………….
assessment. (name, initials)
∗) ∗)
delete where not applicable delete where not applicable
Fig. 2.5 Form for balancing risks and benefits of a stock preparation; front and back side (see Sect. 2.2.3.3)
15
PATIENTS’ NEEDS
between different countries; the validating pharmacist must

takes steps to assure themselves that the prescriber is appro-
friendliness
Process priately registered to prescribe.
Patient
safety Clinical The pharmacist should consult the prescriber if it is possible
Therapeutic Design unsafety/ or more appropriate to use a different medicine. A licensed
value failure inefficacy
medicinal product should be used in preference to a pharmacy
preparation, if an appropriate product is available.
When a pharmacist considers that the delivery of a medi-
cine carries an unacceptable level of risk, he can refuse to
dispense the medicine to the patient, as pharmacists have a
duty of care to the patient. In this situation, they must contact
Fig. 2.6 Balancing benefits and risks of specific pharmacy preparations the prescriber to discuss possible alternatives.
(see Sect. 2.2.3.3)
2.3 The Prescription 2.3.2 Consultations with the Prescriber

and the Patient
2.3.1 Legal Requirements
2.3.2.1 Consultation About a Prescription
A prescription is a request from a prescriber (usually a doctor) When there are doubts about the pharmaceutical options,
to a pharmacist to dispense a medicine in the stated amount, consultation between the pharmacist and the prescriber
strength and method of use. Each country has its own takes place. The pharmacist can advise on the options for
medicines law which will define the exact requirements of a treatment following consideration of the diagnosis and
prescription. However, there is a standard data set used with pathophysiology by the doctor.
the European Economic Area (European Union plus A discussion between the pharmacist and the patient (or
Lichtenstein, Norway and Switzerland) as given in Table 2.1. carer) may also be needed in order to make the most appro-
In some countries, the list of prescribers may include priate treatment decision. This is often the case in paediat-
‘non-medical prescribers’ such as nurses, pharmacists or rics, and the parent or carer may require some assurances
chiropodists. These other prescribers may have limited about the need for medication, especially if the treatment is
formularies in some countries. However, the law varies long term.
Table 2.1 Non-exhaustive list of elements to be included in medical prescriptions in the EEA [5]
Identification of the patient Surname(s)
First name(s) (written out in full, i.e. no initials)
Date of birth
Authentication of the Issue date
prescription
Identification of the Surname(s)
prescribing health First name(s) (written out in full, i.e. no initials)
professional Professional qualification
Details for direct contact (email and telephone or fax, the latter both with international prefix)
Work address (including the name of the relevant Member State)
Signature (written or digital, depending on the medium chosen for issuing the prescription)
Identification of the ‘Common name’ as defined by Article 1 of Directive 2001/83/EC of the European Parliament and of the Council of
prescribed product, 6 November 2001 on the Community code relating to medicinal products for human use
where applicable The brand name if:
(a) the prescribed product is a biological medicinal product, as defined in point 3.2.1.1.(b) of Annex I (Part I) to
Directive 2001/83; or
(b) the prescribing health professional deems it medically necessary; in that case the prescription shall shortly state
the reasons justifying the use of the brand name
Pharmaceutical formulation (tablet, solution, etc.)
Quantity
Strength, as defined in Article 1 of Directive 2001/83/EC
Dosage regimen
Adherence to treatment regimens is influenced by a of validated formulae then allows for the potential for batch
number of other factors, including the formulation (e.g. manufacture and suitable quality control testing.
PATIENTS’ NEEDS
solid or liquid), administration route (e.g. rectal or Another advantage of using a national formulary is that
oral), dosage size and frequency, and the organoleptic it is kept up to date, with obsolete formulations removed
qualities of the medicine chosen (e.g. smell, appearance, or replaced regularly. This may be due to a change in
flavour). By choosing a formulation that is easy to administer recommendations (e.g. an excipient is no longer considered
and by giving good information and instruction, the patient is appropriate) or when a suitable licensed formulation
more likely to comply with their treatment regimen. becomes available.
Case – Vitamin ADEK Mixture Ferrous chloride oral drops had been removed from
Pim is 14 years old and suffers from cystic fibrosis. Due the Dutch formulary as there are now sufficient
to his illness, he cannot absorb fat-soluble vitamins alternatives like Ferrous fumarate oral suspension
well. The paediatrician recommends that Pim needs 20 mg/ml as a licensed pharmaceutical preparation.
treatment with vitamin A, D, E and K in various oral That product however is so viscous that a small vol-
preparations. The licensed pharmaceutical preparation ume, which is necessary for young children, cannot be
consisting of 400 IU vitamin D is no longer available, measured accurately. In the FNA therefore a Ferrous
meaning Pim potentially has to take even more tablets chloride oral solution 45 mg/ml has been reintroduced.
than previously. This oral solution contains 20 mg iron (II) per ml
The parents express concern to the paediatrician which is suitable for children and it is not viscous.
that Pim is unlikely to comply with his treatment. So the necessary small amounts can be easily
Therefore, the paediatrician requests a pharmacy prep- measured.
aration in which all vitamins are combined.
The pharmacist designs an oral liquid based on a
standard formulation for an oral vitamin D solution. 2.3.3 Dose
The mixture contains, per millilitre, 750 IU vitamin A,
250 IU vitamin D, 50 mg vitamin E and 0,25 mg The doctor writes the dose on the prescription and the
vitamin K. pharmacist checks or ‘validates’ this dose. The validation
The pharmacist chooses an aqueous solution, process may take place with the help of a pharmacy com-
because of the better availability of fat-soluble puter system or electronic prescribing system. The usual
vitamins in patients with absorption disorders, such support offered by pharmacy computer systems is limited
as cystic fibrosis patients. Due to a lack of data about if local formulae are used, and the pharmacist may need to
the shelf life of the mixture and the absence of a consult a range of reference sources when considering the
stability-indicating analytical assay, a shelf life of 1 appropriate indications, doses, likely side effects and contra-
month in the refrigerator is assigned. indications. Extra care is required with some patient
Pim now only has to use daily 4 mL of the oral populations, such as children and the elderly.
solution that the pharmacy prepares for him every
month.
2.3.3.1 Dosage Expression
The way in which the prescriber writes the dose is dependent
on the administration form. Capsules and suppositories are
Various national formularies exist and may be useful to given in an amount (usually milligrams) per dose unit
consult during discussions with the relevant doctor e.g the followed by the number of units and the daily or weekly
Dutch national child formulary (www.kinderformularium.nl) dose. For example:
[6] contains various pharmacy preparations, which are R/ Folinic acid capsules 10 mg
included in the Dutch pharmacists Formulary (FNA, see x 10
Sect. 39.4.5). 1 capsule once a week
Such national formularies are good starting points for In the case of oral liquids, the doctor will write the
formulations as they may have been tested or supported by strength in milligrams per millilitre followed by the amount
published or validated formulae. A second example is and dose. In the case of electrolytes the strength is often
the German Formulary (Neues Rezeptur-Formularium, see written in millimol per millilitre because the dosages of
Sect. 39.4.2). In the UK, the Handbook of Extemporaneous electrolyte are based on blood concentrations. For example:
Preparation (see Sect. 39.4.6) also lists a selection of 50 R/ Magnesium gluconate oral solution 0,1 mmol/mL
commonly used formulae, and the British Pharmacopoeia 300 mL
has a small number of formulations detailed. The existence 1 mmol 3 times a day
For the preparation and the dose check, it may be neces-

sary to convert the strength to milligrams per millilitre. In
case of the oral solution in this prescription magnesium
gluconate dehydrate is used. Therefore, the equivalent
strength is 45 mg/mL. The above prescription can then be
read as:
R/ Magnesium gluconate oral solution 45 mg/mL (Mag-
nesium 2,43 mg/mL)
300 mL
10 mL 3 times a day
In the case of medicines for cutaneous use (e.g. dermatol-
ogy medicines), the concentration of the active substance is
usually written as a percentage. The prescriber writes the
amount and the frequency with which the dermatologic
medicine has to be applied. The doctor usually writes
the part of the body on which the patient should apply
the preparation. In this way the pharmacist can check
whether the prescribed amount is sufficient. Furthermore it
is also important to know whether the cutaneous medicine
has to be applied thickly (liberally) or thinly. A practical
device for dosing a cutaneous preparation is the fingertip
unit (FTU), see Table 12.3. In Germany, the Neues
Rezeptur-Formularium for doctors [7] contains a useful
outline figure for the prescriber to mark the area of applica-
tion (Fig. 2.7).
The pharmacist must look carefully at the chemical form
in which the active substance (see Sect. 23.1) of the prepa-
ration is prescribed (or meant to be prescribed), because the
active substance may be available in various forms such as a
base, ester or salt. Also the amount of water of crystallisation Fig. 2.7 Form for the instructions for use of dermatological
in the raw material may vary. E.g. folinic acid is dosed as the medicines, # GOVI-Verlag Pharmazeutischer Verlag
calcium salt. The doctor may use a brand name in the
prescription, in this case Leucovorine®. This contains
15 mg folinic acid in the form of calcium folinate. Research Network [8] has been established to investigate
formulation quality and the practice of manipulation of
dosage forms before administration e.g. cutting tablets,
2.3.3.2 Paediatric Population opening capsules etcetera It is preferable to use an active
Children regularly get prescribed medicines that are licensed substance that has been used previously in a pediatric popu-
only for adults or are licensed for use in other indications in lation, as information about the dose, pharmacological effect
children. This is called ‘off-label’ use and in this case the and side effects will already be available. Doses for
medicine is used in an ‘unlicensed’ manner. babies and children are commonly expressed in mg per kg
Unlicensed medicines used in children are usually body weight. For medicines with a large therapeutic win-
prepared by utilising raw materials or through adapting dow, this approach is satisfactory. However, it must be
a dosage form designed for an adult population. Often recognised that during the growth and development of a
there is limited data available about the dose and side child, the pharmacokinetic parameters change continuously.
effects in children. This means that consultation between Children are not small adults and neonates are not small
the prescriber and pharmacist may be necessary. children. When considering active substances with a narrow
In 2007 the Nederlands Kenniscentrum Farmacotherapie therapeutic window, a dose in m2 body surface may there-
bij Kinderen (NKFK) was founded. It was established to fore be a more accurate basis for dose calculation and
help improve information available about medicines use in adjustment. This is because some physiological parameters,
children. One of the activities of the NKFK is the compila- which are directly related to the elimination of medicines,
tion and publication of the national children formulary in the are better correlated to body surface e.g. hepatic and renal
Netherlands) [6]. In the UK, the Medicines for Children function.
Various formulae for calculating body surface area can be Due to the larger risk of adverse effects and toxicity,
found in literature [9]. For example, the Dutch kinderfor- certain medicines are not administered on the skin of young
PATIENTS’ NEEDS
mularium [6] uses the Mosteller formula as below: children. e.g. Salicylic acid is preferably not used on children
younger than 2 years old and certainly not on large surfaces.
Body surface ðin m2 Þ ¼ Less potent corticosteroids are preferred as they are associated
ð2:1Þ
½length ðin cmÞ weight ðin kgÞ=3, 6000:5 with a smaller risk of systemic adverse effects. Other options
include a decreased dosing frequency to limit adverse effects
Tables with length, weight and body surface of children of e.g. application every other day rather than every day.
different ages with normal proportions [6] are convenient
when one does not have the length and weight of the child.
The British National Formulary (BNF) for Children in the 2.3.3.4 Elderly Population
UK also has tables for guidance, using the Boyd equation Body composition, homeostasis, body tissues and organs
[10]. Finally the result has to be rounded to a practical change as people age. Therefore, this has consequences for
strength for the product to be prepared. the pharmacokinetic and pharmacodynamic processes
associated with the active substance. E.g. due to a larger
percentage fat tissue, the volume of distribution of lipophilic
Case Hydrocortisone Suppositories 240 mg substances such as diazepam increases in elderly patients.
X6 The decrease of blood flow through the liver also has an
1 suppository when required effect with substances that have a high level of hepatic
The pharmacist consults reference sources which elimination e.g. morphine. Furthermore, two thirds of the
suggest a rectal dose of 100 mg/m2 body surface for elderly population has some degree of renal impairment.
stress situations in children with adrenal cortex This has consequences for the dose of medicines with mainly
disorder. renal elimination and a small therapeutic window e.g.
Klaartje is 2 months old and a girl of that age has an digoxin, lithium. Skin also tends to be thin somewhat with
estimated body surface of 0.27 m2. This means that the advancing age.
prescribed dose is too high. Discussions with the pre- The pharmacokinetic and pharmacodynamic changes
scribing endocrinologist confirm that a prescribing usually become clinically more relevant over the 75th year
error has been made. Hydrocortisone suppositories of of life. There are however large intra- and interindividual
24 mg should have been prescribed. differences in aging of organ functions. Therefore, it is
difficult to predict the exact pharmacological response of a
given elderly patient. As with licensed medicines, it may be
necessary to adjust doses of pharmacy prepared medicines
In some cases, it may be necessary to estimate or derive a carefully and cautiously in elderly patients.
paediatric dose from a proportion of the adult dose, using a Elderly patients are more sensitive to certain medicines
comparison of relevant body surface areas. However, this is and often use more medicines at the same time (sometimes
a very approximate calculation, and further discussion with called polypharmacy). This means that elderly patients are
the prescriber will be needed to agree a final dose. more vulnerable to adverse effects [11]. To avoid overdose
Usually the frequency of administration is similar to that and subsequent adverse effects, a lower starting dose may
of adults. However, this does sometimes require amend- be used.
ment. E.g. fluconazole dosing frequency varies with age, However, lower strengths are not available for every
due to the changes in elimination. medicine and not every licensed pharmaceutical preparation
is available as a tablet that can be divided e.g. coated tablets.
In this situation, it might be necessary to produce a lower
2.3.3.3 Cutaneous (Dermal) Medicines Used
strength oral liquid that could be used for careful dose
in Children
titration (see Sect. 5.4).
Children and particularly babies have a large relative body
surface area. Premature babies also have a thinner skin than
adults, and lack the outer skin layer known as the horny layer
or stratum corneum. In a young child with eczema, the skin 2.3.4 Contra Indications, Interactions
may also be more damaged than in an adult with eczema. and Intolerances
Therefore, the skin functions less well as barrier. Further-
more, application of any creams or ointments under a nappy In addition to the validation of the dose, each preparation has
or diaper prevents trans-epidermal water loss and leads to an to be reviewed in terms of possible contraindications,
increased absorption of the active substance. interactions and intolerances or allergies.
2.3.5 Narcotic and Psychotropic Substances requirements varies with the category. The relevant national
regulations should be consulted before any such items are
Based on United Nations conventions [12] most European prepared.
countries have extra requirements or controls which are Depending upon the item in question, the pharmacist may
applied to medicines with narcotic and psychotropic be obliged to ensure that the product is suitable for use in
substances. Requirements vary between countries but may humans, for instance does not contain any material of animal
include: origin that may transmit any known diseases e.g. Transmis-
• Name, initials, full address and phone number of the sible Spongiform Encephalopathies (Creutzfeldt-Jacobs
prescriber Disease), see Sect. 19.3.1.
• Date of prescribing
• Name of the medicine and amount, written completely in
letters
2.4.1 Herbal Medicines
• Name, initials and full address of the patient or of the
owner of the animal
The regulation of herbal medicinal products is complicated
• Clear description of the use, among what the maximal
and differs between countries1. Roughly speaking, herbal
total drug use per 24 h, “use known” or “if necessary” is
products can be considered as medicinal products with
not correct
medicinal claims, but also as food or dietary supplements
• If necessary: the amount of repeat doses
without medicinal claims. The status will generally depend
A prescription on which one or more raw materials fall
on the level of scientific evidence supporting their use.
under these regulations has to comply with these
A detailed overview of the regulations concerning herbal
requirements.
medicinal products worldwide can be found in Herbal
In Germany the use of narcotic or psychotropic
Medicines [13].
substances is not appropriate if the intended purpose can be
Herbal medicinal products are not explicitly mentioned
achieved in other ways, e. g. with medicines with other
in the Ph. Eur. but herbal raw materials are included.
active substances.
The reason is that any pharmacist should be able to judge
Some active substances falling under these regulations
the safety of herbal medicines but not the efficacy of the
are exempted from the requirements associated with admin-
products. According to EC legislation [14], “a herbal
istration and prescribing, such as for preparations with
medicinal product is any medicinal product, exclusively
codeine. However, for the raw material codeine, the admin-
containing as active ingredients one or more herbal
istrative obligations mentioned in the law do apply in
substances or one or more herbal preparations, or one or
Germany.
more such herbal substances in combination with one
or more such herbal preparations.” Herbal medicinal
products are also referred to in the international literature
2.3.6 Standard Amounts
as herbal medicines, herbal remedies, herbal products,
phytomedicines, phytotherapeutic agents or phytopharma-
The amount of a pharmacy preparation requested can vary
ceuticals. The use of herbal medicinal products for the treat-
widely, depending on the indication and area for use. The
ment and prevention of disease is called phytotherapy [13].
pharmacist should assess whether the amount is right for the
Few herbal medicinal products are on the market as
use (see Fig. 2.7), the length of the treatment and the shelf
authorised medicines in the EU, fulfilling the same stringent
life. In some countries, there are systems for standardising
requirements that count for conventional medicinal
amounts used in order to improve consistency of products
products. This is largely due to the limited availability of
and maximise efficiency in the pharmacy setting. In addition
randomised controlled trials to support the quality, safety
in some countries the amounts are limited by the health
and efficacy of herbal medicinal products. More often
insurance.
they are licensed as traditional herbal medicinal products,
following an adapted and simplified registration wherein
efficacy is made plausible based on available scientific data
2.4 Special Categories of Prescriptions
(well-established use) or long-term historic use in the EU
(traditional use). Sufficient data to underpin the safety
Not every request for a pharmacy preparation is by definition
should be available in all cases and the quality of the herbal
a medicine. Examples include biocides, medical devices,
starting materials and chemicals. It is important to make
this distinction, because with that it becomes clear under
1
which regulation the pharmacy preparation falls. The legal Contribution by Herman Woerdenbag, Groningen, The Netherlands.
medicinal product must always be demonstrated. A vast preparation may be requested. A general pharmacist will
majority of herbal products however, are unlicensed (not not be able to assess the efficacy of a homeopathic or
PATIENTS’ NEEDS
medicinal products) despite the fact that they are frequently anthroposophic prescription but he will be able to judge
intended for health improving purposes [13, 15]. the safety, for instance following these recommendations:
• The pharmacist should only fulfill a request for a pharmacy
preparation when the prescription comes from a homeo-
2.4.2 Agents Used for Assisted Suicide pathic or anthroposophic doctor and relates to a single
medicine of a non-animal or non-microbiological source
In countries with legislation that allows for assisted suicide, and with dilution 1:10,000, for oral or external use.
pharmacists will be involved in preparing and dispensing the • When the medicine does not belong to these groups then
products. These pharmacists are then faced with ethical, moral, the preparation is outside the competence of the regularly
and practical questions. Is a pharmacist obliged to dispense educated pharmacist. If that is the case it is recommended
these agents or is he allowed or even obliged to refuse in to get in touch with a pharmacy that specialises in prepar-
specific situations, and if so, based on which moral and ethical ing homoeopathic or anthroposophic medicines.
principles? How is professional information about pharmaco- At all times, pharmacists should only practice within their
logically effective agents and preparations distributed among sphere of competence.
pharmacists? These and similar questions have to be discussed
in a social and legal context with the purpose of improving the
difficult situation of patients and caregivers. 2.4.4 Veterinary Medicines
In the Netherlands a “Guidance for the management In relation to the administration of medicines for animals,
of euthanasia and assisted suicide” was developed by the pharmacological differences and local laws have to be
doctors and pharmacists and it covers the path from the observed. The pharmacokinetics of every active substance is
patient’s request onto the arrival of the autopsist. The different in each species. For animals, especially cats, the
use of this Guidance is closely monitored [16]. This toxic concentration of many human medicines is lower than
Guidance demands that any decision on dispensing the the therapeutic dose in humans due to differences in metabo-
agents can only be made after oral consultation lism of medicines. For example, in cats, the administration of
between the doctor and the pharmacist. The pharma- acetaminophen (paracetamol) very quickly leads to intoxica-
cist must be ethically and morally independent in his tion with methemoglobin formation, anemia, hemoglobinuria
decisions, like the doctor, which may eventually lead and liver damage, as they may metabolise the medicine poorly.
to the pharmacist refusing to dispense. The pharmacist The European Commission (EC) has acknowledged that
has to be informed about all relevant backgrounds, in insufficient authorised veterinary medicinal products are
order to be able to make his decision and to be able to available for the treatment of every clinical case in every
give the doctor or the patient relevant pharmacologic species. Therefore, Directive 2001/82/EC allows, under
and practical information. The relevant products are Articles 10 and 11, veterinary surgeons to prescribe products
prepared by the pharmacist and he will dispense them that are not authorised for the relevant clinical case or for the
personally to the doctor, accompanied by oral or writ- relevant species, this provision is known as the Cascade. This
ten information about their practical and technical is a derogation from the main requirement in the EU legisla-
administration. The standard advises pharmacist and tion to use authorised veterinary medicines. Therefore the
doctor making general arrangements before an actual Cascade increases the range of medicines that a veterinary
patient’s request will occur. surgeon can use [17]. The Cascade allows the veterinary
surgeon to use medicines designed for other species, only if
there is no licensed medicine for the species and the indication
2.4.3 Homoeopathic and Anthroposophic and the animal is critically ill. The use of medicines as part of
Medicines the Cascade system has to be carried out in the order specified:
• Licensed Animal medicine, which has a different
The law regarding the supply of homoeopathic and indication
anthroposophic medicines varies between countries. In • Licensed Animal medicine, which is licensed for a dif-
some countries, a pharmacist can refuse to dispense such ferent species
an item and refer the patient to an alternative pharmacy. • Licensed human medicine or EU licensed animal
In Europe the German Homeopathic Pharmacopoeia is medicine
available for the regulation of the quality of these medicines. • Extemporaneous preparation
If prescribed it usually is a licensed medicine but occasion- There are further regulations for animals bred for human
ally – mainly in cases of non-availability – a pharmacy food.
2.4.5 Medical Devices 2.4.6 Biocides
As for the regulations which apply to medicines, the Biocides (also called disinfectants) are active substances and
regulations for medical devices include consideration of preparations containing one or more active substances, put
the following issues: diagnosis, prevention, surveillance, up in the form in which they are supplied to the user,
treatment or relief of illnesses. However, the set-up of the intended to destroy, deter, render harmless, prevent the
regulations for medical devices differs essentially from the action of, or otherwise exert a controlling effect on any
one for medicines. In the case of medicines licensing, harmful organism by chemical or biological means.
the government is responsible for managing medicines reg- A pharmacy may get a request for the preparation of a
ulation. However, in the case of medical devices, the com- disinfectant. This may be difficult to handle because differ-
pany itself is responsible for risk assessing the product ent laws are appropriate.
before it enters the market [18, 19]. Medical devices are Disinfectants for the skin of patients, such as chlorhexidine
classified in four different risk classes [18, 19]. in alcohol, are regarded as medicines for humans. When the
The manufacturer has to decide in which risk class the same preparation is used in the hospital for disinfection of the
device falls: I, IIa, IIb or III; the higher the class, the more hands of nurses and other staff, it is considered as a biocide
risks are associated with the use. Therefore devices in class and falls under the applicable EC legislation [22].
IIb or III have to be assessed in advance by a competent Disinfectants that are used in combination with specific med-
authority a so-called Notified Body. This is an independent ical devices fall under the regulation for medical devices and
organisation, designated by the national government. When should have a CE identification mark. Disinfectants for inani-
the device belongs to class I or IIa, the producer only has to mate surfaces fall under the legislation for biocides. When
inform that authority of the device. delivering such a disinfectant the pharmacist has to comply
with this regulation, that is with the following requirements.
1. Generally only registered products should be used. This is
How does one handle the request of a hospital ward for
indicated by a number or registration code on the packaging.
the preparation of sodium citrate solution 30 % in
2. Registered biocides products must be delivered in the
ampoules? Concentrated sodium citrate solutions are
original package with the approved legal instructions
used as catheter locks on dialysis wards of hospitals.
and with the relevant danger symbols and safety
By filling the lumen of the catheter with such a solu-
recommendations.
tion the formation of blood clots is prevented and the
3. A pharmacy preparation is allowed ‘if necessary’ but uses
flow is maintained. Sodium citrate solution is an alter-
an allowed disinfectant and excipients.
native for a concentrated heparin solution and should
4. Operations such as diluting, addition of a buffering agent
be preferred because of the anti-microbiological
or dispensing should be executed in accordance with the
effect [20]. Citra-Lock® is available as a medical
instructions and with due regard for the required
device. This product contains 46,7 % sodium citrate
precautions for preparation and labelling.
and is CE registered class IIb. Are there justifiable
reasons to prepare the solution? This could be for
example when the marketed product is associated Practice Example: Sodium Hypochlorite
with more side effects due to the higher concentration, When the pharmacist obtains a request for the prepa-
or is delivered in a container that is hard to use in ration of a sodium hypochlorite solution 2 %, the
practice. If those reasons are absent, then the marketed indication for use must be clear. A dentist may use
product is to be preferred. such a solution for root treatment as a disinfectant and
because of the tissue-dissolving effect. The prescrip-
tion is from a dentist and therefore it is a medicine, so
Information about medical devices is not as accessible as falling under Medicine law. When using a sodium
about licensed medicines. If a pharmacist has to decide about hypochlorite solution for the disinfection of the floor,
a medical device being used in a way that is not included in the biocides legislation applies. The pharmacist firstly
the instructions for use, he has to contact the manufacturer. has to examine whether there is a registered product
The European Commission has made proposals for new which could be used instead. If this is not the case, then
guidelines in September 2012. This means that all medical he is allowed to prepare the solution on the condition
devices will have to undergo thorough, independent assess- that there is a recognised use. That is to say that the use
ment of safety and performance before they can be sold on is described in guidelines or other reliable sources. In
the European market. Also new rules on traceability are case of doubt, consultation with the authorities is
proposed and public information on products available on recommended.
the EU market [21].
2.4.7 Raw Materials (Chemicals) information such as Hazard and Precautionary statements.
A Material Safety Data Sheet (MSDS) must accompany
PATIENTS’ NEEDS
2.4.7.1 General delivery.
Chemicals only become recognised as medicines if they
have been incorporated into a dosage form or when a medi- 2.4.7.3 Precursors
cal indication is claimed. Chemicals can, if handled inex- Precursors are raw materials that may be used at the synthe-
pertly, become dangerous to the health and in that case have sis of narcotics and psychotropic substances (‘drugs’). For
to be labelled as hazardous substances (see Sect. 26.3). It is this group of raw materials, the EC regulations [23], lay
the responsibility of the pharmacist to assess whether he will down measures to be taken to discourage the diversion of
supply raw materials. When delivering to members of the certain substances to the illicit manufacture of narcotic drugs
public (without a doctor’s request) he should know the and psychotropic substances. These regulations recognise
potential dangers, assess the intentions of the person who 3 categories of substances of which only category 1 has a
requests the item, and inform that person about the possible practical significance for pharmacy preparation. That cate-
dangerous qualities. It is recommended to document such gory contains ephedrine, ergotamine and ergometrine.
supplies via a request form. Data recorded on this form Pharmacies require special licences for ordering and
should comprise the identity of the person who makes the possessing these substances. This special licence is only
request, data about the delivered starting material (name and valid for the use of precursors “within the scope of the official
amount) and the indicated use. For the delivery of some raw duties of the operators”. A licence is not required to supply
materials separate legal regulations apply if the risk of abuse pharmacy preparations that contain such substances.
is considered to be substantial, such as with precursors. See
further down.
2.5 Essentials
Two Examples of Requests
Pharmacy preparation allows the doctor and pharmacist to
Strong hydrochloric acid provide individualised and tailor-made pharmaceutical care.
A request for a bottle of strong hydrochloric acid The preparation of a medicine in the pharmacy fills a need
for hobby purposes will raise doubt about the intended when the licensed pharmaceutical preparation is not avail-
use. When the use seems to be acceptable, this raw able or when a licensed pharmaceutical preparation does not
material may be delivered but robust documentation of satisfy a specific situation.
the request is strongly recommended, also to prevent Upon receipt of a request from the doctor, the pharmacist
problems in the context of the precursor legislation must examine the situation and decide whether the request is
(see further down). Furthermore, the legally obliged appropriate and judge the level of risk associated with pro-
safety information has to be present on the package ceeding with the request. However, the pharmacist must also
(see Sects. 26.3.2 and 26.6.3). By supplying consider the risks of not supplying a medicine which may
Concentrated Hydrochloric Acid Ph. Eur. the quality lead to the patient not receiving treatment. Further discus-
is guaranteed. sion with the medical team may be needed.
Sodium sulfate The pharmacist must make every effort to ensure that the
Sodium sulfate may be delivered on request of a medicine produced is of appropriate pharmaceutical quality
citizen. Delivery is analogous to the hydrochloric acid and is fit for the intended purpose. An approved or
example. The situation is different when sodium authorised formula should be used wherever possible.
sulfate is required on a doctor’s prescription. Supply- Where such formulae are not available, steps should be
ing a measured quantity of sodium sulfate in a bottle taken to minimise risk where possible e.g. restricted shelf-
on prescription renders this raw material into a medi- life, fridge storage (if applicable), use of licensed starting
cine and it has to be labelled as such. materials etc.
The usual support offered by pharmacy computer systems
is limited if local formulae are used, and the pharmacist may
need to consult a range of reference sources when consider-
2.4.7.2 Hazardous Substances ing the appropriate indications, doses, likely side effects and
Hazardous raw materials are chemicals that provide a hazard contra-indications.
to safety or health because of the chemical characteristics. Whether the request is for a medicine or other type of
Substances are defined as hazardous if at least one H(azard) preparation, the pharmacist is responsible for ensuring that
statement (see Sect. 26.3.2) is attributed. They must only be the final product supplied is of acceptable quality and backed
delivered in a container that is labelled with the legal safety by the best possible evidence base.
United Nations Convention against Illicit Traffic in Narcotic Drugs

References and Psychotropic Substances. 1988. https://www.unodc.org/pdf/
convention_1961_en.pdf. Accessed 18 Sept 2014
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Availability of Medicines
3
Helena Jenzer and V’Iain Fenton-May
Contents Abstract
Fundamental changes and new challenges have been
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
emerging in the last decades as a result of the globalisation
3.2 The Pharmacist’s Mandate to Provide Medicines . . . . . . 26 of markets and of production, new economic doctrines, tight
3.2.1 Mandate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.2.2 Medicines Shortages (Also Referred to as Drug Shortages) 29 budgets as well as the development of information technol-
3.2.3 Bioequivalence Considerations for Coping with Shortages 30 ogy. This has brought with it a shift in the security of supply,
3.3 Medicines with a Market Authorisation . . . . . . . . . . . . . . . . . 32
which now has to cope with drug shortages to prevent a
3.3.1 Market Authorisation (Formerly “Registration”) . . . . . . . . . . 32 decrease in safety and a worse outcome for the patients.
3.3.2 Reimbursement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Medicines are made available as authorised medicines,
3.4 Investigational Medicinal Products . . . . . . . . . . . . . . . . . . . . . . 35 pharmacy preparations, or investigational medicinal
products. For many diseases active substances are avail-
3.5 Unlicensed Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
able, and yet groups of ‘neglected’ patients or special
3.6 Orphan Medicines and Neglected Patients . . . . . . . . . . . . . . 36 patient groups will not receive the medicines they need.
3.6.1 Orphan Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
If a patient needs a medicine, which is not on the national
3.6.2 Neglected Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
market, it may be imported from abroad or prepared in a
3.7 Medicines Import . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 pharmacy. The complicated rules, which are nationally
3.8 Preparation of the Remaining Necessary Medicines . . . 40 determined, for reimbursement (in some Countries) and
3.9 Organisation of Pharmacy Preparation . . . . . . . . . . . . . . . . . 40 long procedures render importation a laborious way to
make medicines available for the patient. To be reimbursed
3.10 Importance of Pharmaceutical Production
in Hospitals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 40 some Countries require that medicines are to be shown to
be efficacious, appropriate and economic.
3.11 Legislation of Pharmacy Preparation . . . . . . . . . . . . . . . . . . . . 45
Specials (unlicensed medicines) are being produced
3.12 Preparations’ Categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 according to GMP and PIC/S guidelines to cover these
3.13 Feasibility of Pharmacy Preparation . . . . . . . . . . . . . . . . . . . . 47 shortages. The European Association of Hospital
Pharmacists (EAHP) has dedicated a big effort to
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
animating and harmonising pharmacy production. The
need for flexibility in preparation and manufacturing pro-
cesses and the added value of a broad range of pharmacy
production have been clearly underlined by the Council
Based upon the chapter ‘Apotheekbereiding in de
of Europe’s resolution CM/ResAP (2011)1.
geneesmiddelenvoorziening’ by Yvonne Bouwman-Boer and Reinout
Schellekens in the 2009 edition of Recepteerkunde.
Keywords
H. Jenzer (*)
Bern University of Applied Sciences BFH, Health Division, aR&D Globalisation of pharmaceuticals Security of
Nutrition & Dietetics, Murtenstrasse 10, CH-3008 Bern, Switzerland supply Medicines shortages Authorised
e-mail: [email protected] medicines Pharmacy preparations Investigational
V. Fenton-May medicines Medicines for orphan
Former Quality Control Pharmacist to the Welsh Hospitals, Cardiff, diseases Importation Unlicensed medicines Added

United Kingdom
value of polyvalent hospital pharmacy production

26 H. Jenzer and V. Fenton-May
[2]. For comparison see WHO model list [3]. The perfor-
3.1 Introduction mance of the hospital pharmacy has to be available all time
without any disruption.
Medicines are available for patients as authorised medicines As a rule, medicines used in bigger amounts in hospitals
or as pharmacy preparations (unlicensed medicines). Market are commercially supplied by industry, smaller amounts and
logic ensures that only medicines with sufficient return on ad hoc orders by wholesalers, see Chap. 36. Some tasks
investment will be marketed. However, health care logic delegated to the hospital pharmacist may be fulfilled by
requires pharmacists to provide their patients with necessary centralised services for allied partners due to economic or
medicines. There are regulations that cover medicines for effectiveness reasons. The frame for this duty has to be
clinical research, marketing authorisation and import, as flexible enough to attain a fast track distribution within the
well as traffic between European countries (parallel institution and thus a fast dispensing of medicines to the
imports). If medicines are not available as authorised patient. Thus, not only drug supply, but also the medication
medicines, various options such as compassionate use or process and consequently the prevention of medications
parallel trial programme can be considered. The errors, which are multidisciplinary processes within patient
authorisation of medicines for orphan diseases is promoted care, are to be considered as integral parts of the
by the orphan drug regulations. The system of reimburse- mandate [4].
ment will be discussed briefly due to its special situation at The mandate has not changed throughout decades. It has
the interface of both public health and social insurances. even become more challenging as new pharmacokinetic and
Preparations prepared in pharmacies may serve as the last pharmacodynamic knowledge has been emerging and as
choice to provide patients with their necessary medicines. biopharmaceutic relevant characteristics of highly active
The European Ministers have formally confirmed “that the ingredients and products can be better anticipated
preparation of medicinal products in pharmacies, which may (interactions, drug monitoring, adverse drug events). There-
be required as a consequence of the individual or medical fore, in addition to pure logistics, the hospital pharmacist has
condition of the patient in the absence or unavailability of to focus more and more on rational and economic drug use
appropriate medicinal products on the market, is indispens- and to participate in pharmacotherapy and pharmacov-
able for accommodating the special needs of individual igilance. Mainly in hospitals, medicines use is assessed
patients in Europe [1].” Mainly special patient groups need more and more critical and differentiated. The mandate is
pharmacy preparations. Another need for pharmacy prepa- even enlarged where suitable, according to special skills of
ration arises from drug shortages. the pharmacist.
The traditional role of the hospital pharmacist still covers
production, analysis and assessment of the quality and safety
3.2 The Pharmacist’s Mandate to Provide of medicines, which includes the whole supply chain from
Medicines purchase to pharmacotherapy, and even to disposal of wastes
of unused drugs. The complex environment of public health
3.2.1 Mandate is particularly evident in hospitals. Supply, reconstitution,
preparation from raw materials or through adapting products
Based on an acceptable cost-benefit and risk-benefit-assess- and correct use are a matter of multidisciplinary
ment for both public and individual health, a pharmacist is contributions of many professionals to the benefit of the
mandated for the legal provision of medicines used to treat patient. They require a specialisation as well as life-long
his patients. This scope is defined by Acts, Ordinances or learning to remain in a strong and competent position within
Decrees, national or regional needs, and, in hospitals, is a care team. Graduate pharmacists have to pass a post-
formalised in the formulary, normally defined by a graduate specialisation to get ready to cope with challenges
medicines committee. This formulary includes medicines, and tasks, which are inherent to the hospital domain (see
controlled medicines, devices, chemicals, disinfectants, and Sect. 25.4.2).
ethanol in various concentrations and presentations. Each Fundamental changes and new challenges have been
pharmacy should be responsible for ensuring that a locally emerging in the last three decades as a result of the
agreed list of products should be available to meet the needs globalisation of markets and of production, of new economic
of the business even in times of accidents and catastrophes doctrines as well as of the development of information
(Table 3.1). This list is adapted and recalculated from a list technology. This has brought with it a shift in the security
of a Swiss University Hospital, which has been agreed by of supply and in the hospital pharmacist’s requested and
emergency and ICU, anaesthesia, and hospital pharmacy mandatory tasks (Table 3.2).
3 Availability of Medicines 27
Table 3.1 Preparations recommended to be kept minimally on stock for provision in case of accidents and catastrophes (minimum amounts
stored for a 500,000 people region, varying depending on further regional resources and supply time)
PATIENTS’ NEEDS
Product Minimal amount stored
Acetaminophen/paracetamol 10 suppositories 600 mg 40
Acetaminophen/paracetamol 16 Tbl. 500 mg 400
Acetaminophen/paracetamol infusion solution 1 g 100 ml 9,600
Acetaminophen/paracetamol infusion solution 500 mg 50 ml 1,800
Albumin infusion solution 20 % 5 50 ml 10
Amoxicillin/clavulanic acid 1 g Ad 20 Tbl 180
Amoxicillin/clavulanic acid infusion solution 1.2 g 5 Ad Amp 750
Amoxicillin/clavulanic acid infusion solution 2.2 g 5 Ad Amp 350
Atracurium besylate injection solution 5 Amp 2.5 ml 100
Basic infusion solution G5-K PP 500 ml 600
Bupivacaine injection solution 0.25 % 5 Amp 20 ml 50
Bupivacaine injection solution 0.5 % 5 Amp 20 ml 30
Ceftazidime vial 2 g 250
Ceftriaxone 2 g vial 800
Cefuroxim injection solution 1.5 g i.v. vials 2,800
Ciprofloxacin infusion solution 0.2 g 100 ml 400
Clarithromycin injection solution 500 mg i.v. Amp 150
Clindamycin injection solution 600 mg 3 Amp 100
Desflurane 6 bottles 240 ml 8
Dihydralazine mesylate 25 mg 5 Amp 25
Diphtheria tetanus toxoid combination pre-filled syringe 300
Dobutamine concentrate infusion solution 250 mg 180
Epinephrine/adrenalin injection solution 1 mg/ml 10 Amp 1 ml 150
Epinephrine/adrenalin injection solution 1 mg/ml 10 Amp 10 ml 20
Etomidate injection solution 10 ml 10 Amp 40
Fentanyl injection solution 0.05 mg/ml 10 Amp 2 ml 300
Fentanyl injection solution 0.05 mg/ml 5 Amp 10 ml 600
Flucloxacillin injection solution 1 g 10 vials 150
Glucose 5 % NaCl 0.9 % 2:1 PP 1,000 ml 1,800
Glucose 5 % NaCl 0.9 % 2:1 PP 500 ml 1,800
Glucose 5 % PP 1,000 ml 350
Glucose 5 % PP 250 ml 500
Glucose 5 % PP 500 ml 800
Glucose infusion solution 5 % PP 100 ml 100
Haloperidol injection solution 5 mg i.m./i.v. 5 Amp 1 ml 100
Hydroxyethyl starch 6 % infusion solution 500 ml 2,000
Imipenem/cilastatin 500 mg 10 Amp 20 ml 60
Isoflurane inhalation solution 250 ml 80
iv Line set 15,000
Ketamine injection solution 10 mg/ml 5 vials 20 ml 20
Ketamine injection solution 50 mg/ml 5 vials 10 ml 15
Lactated Ringer’s solution infusion solution 1,000 ml 500
Lactated Ringer’s solution infusion solution 1,000 ml 1,800
Lactated Ringer’s solution infusion solution 500 ml 1,500
Lactated Ringer’s solution infusion solution w/o air 1 L 1,800
Lactated Ringer’s solution infusion solution w/o air 500 ml 600
Lidocaine CO2 injection solution 2 % 10 Amp 20 ml 30
Lidocaine injection solution 1 % 10 Amp 5 ml 400
Lidocaine injection solution 2 % 5 ml w/o cons 10 Amp 120
Lorazepam 20Tbl 1 mg 400
Lorazepam injection solution 4 mg/ml i.v. 10 Amp 75
Mefenamic acid 500 mg 100 Tbl 50
(continued)
Table 3.1 (continued)

Product Minimal amount stored
Mepivacaine HCl 10 mg/ml 100 ml 800
Metamizole sodium injection solution 50 % i.m./i.v. 10 Amp 2 ml 500
Metronidazole infusion solution 500 mg 100 ml 1,400
Midazolam injection solution 15 mg/3 ml i.m./i.v. 5 Amp 80
Midazolam injection solution 5 mg/ml i.m./i.v. 10 Amp 100
Midazolam injection solution 50 mg/10 ml i.m./i.v. 5 Amp 50
Morphine HCl 10 mg/ml 10 Amp 1 ml 500
NaCl 0.9 % irrigation 1,000 ml 600
NaCl 0.9 % irrigation 250 ml 1,400
NaCl 0.9 % infusion solution 1 L 1,800
NaCl 0.9 % infusion solution 100 ml 15,000
NaCl 0.9 % infusion solution 250 ml 300
NaCl 0.9 % infusion solution 500 ml 100
NaCl 0.9 % infusion solution w/o air 1 L 600
NaCl 0.9 % infusion solution w/o air 500 ml 1,000
Norepinephrine/noradrenaline injection solution 0.1 % 10 Amp 10 ml 10
Norepinephrine/noradrenaline injection solution 0.1 % 10 Amp 1 ml 80
Pancuronium bromide injection solution 2 mg/ml 50 Amp 2 ml 50
Pentothal sodium 2.5 g 12 vials 8
Piperacillin/tazobactam 2.25 g vial 120
Propofol injection solution 1 % 5 vials 20 ml 300
Propofol injection solution 1 % vial 50 ml 10
Propofol injection solution. 2 % vial 50 ml 1,500
PVP iodine 10 Gauze pads 7,5 22.5 cm 20
PVP iodine alcoholic solution 5 1,000 ml 75
PVP iodine solution standardised 500 ml 150
PVP iodine solution standardised120 ml 250
Ringer’s solution irrigation 1,000 ml 1,600
Rocuronium bromide injection solution 50 mg 12 vials 15
Ropivacaine injection solution 0.2 % 5 Bag 200 ml 25
Ropivacaine injection solution 0.75 % 5 Amp 20 ml 25
Sevoflurane liquid 250 ml 60
Silver sulfadiazine cream 50 g 100
Silver sulfadiazine cream 500 g 10
Succinolated Gelatine infusion solution 500 ml 80
Sulfamethoxazole/trimethoprim forte 10 Tbl. 150
Sulfamethoxazole/trimethoprim injection solution i.v. 10 Amp 5 ml 80
Suxamethonium 100 mg 2 Amp 2 ml 80
Tetanus hyper gamma globulin 250 units syringe 1 ml (or corresponding amount of gamma globulin) 15
Table 3.2 Weighting over time of hospital pharmacists’ contributions to shared responsibility and improved outcomes
1960 1980 2000 2020
Clinical pharmacy + ++ +++ +++
Production, quality control, quality assurance +++ ++ ++ +++
Provision and supply chain ++ + ++ +++
Special tasks according to individual skills + ++ +(+) ++
In the past 20 years, investments have often been called Classic alkylating, anti-metabolic or topoisomerase-
off in favour of outsourcing to keep fixed costs small and to inhibiting antineoplastics with a long time market presence
PATIENTS’ NEEDS
optimise balances. From the 1990s, financial interests and vaccines are the products for which there is the most
dominated more and more the patient-centred outcome concern on the steadily growing list. Pharmaceutical exper-
objectives defended by physicians, pharmacists, other health tise succeeded in finding a suitable solution in 90 % of all
care professionals and the patient himself. The freedom of cases [13, 14]. To bridge a gap arising from a case of
action for the hospital pharmacist had been redefined and medicines shortage will take 1–7 h [15]. In any case, as a
became more restricted. medicine from the hospital formulary has been selected due
Today, the hospital pharmacist is still mandated to control to a favourable cost – benefit ratio, alternatives are in general
the supply chain, however there are challenges from supply cost-intensive compared to the standard product. A simple
chain professionals supported by those who consider intermediate substitution of a medicine on the formulary
medicines to be no different from any other commodity. costs 1,800 €, a definite substitution between 3,800 € and
Procurement now has to take place in an environment that 4,690 € (figures from Germany) [16].
has more and more budget restraints and external paralysing Small markets are particularly sensitive to shortages.
constraints induced by unwanted dependencies of third party High registration and regulation affairs cost for market
suppliers and sometimes even drug shortages. If the skills admission may tempt suppliers to economise in countries
are lost, important financial resources would be needed to with low volumes of sales. This is a major problem in a small
reactivate lost know-how related to neglected technical country. Withdrawal from the market in a country such as
equipment or outsourced activities. However, such time is Switzerland may be an alert for an upcoming critical situa-
not available in situations such as medicines shortages. Con- tion in the European Union.
sequently, re-adaption may cost more than ever could have In 2011, the situation prompted authorities to intervene in
been saved. the market and remind manufacturers and suppliers on their
responsibility. US President Obama signed the Executive
Order 13,588 instructing the FDA to require from
3.2.2 Medicines Shortages (Also Referred manufacturers adequately advanced notices of discontinua-
to as Drug Shortages) tion of certain prescription medicines and to review more
quickly modifications of the production processes of these
Shortages as a global phenomenon grew steadily and medicines [17]. These requirements comprised an obligation
increased sharply in the USA within a few years from 2006 to notify and inform on medicines shortages, but do not
(70 shortages) to 2011 (267 shortages) [5–10]. It is a phe- include a disclosure of the reasons nor of the decisions
nomenon that if left alone threatens to become a crisis in which lead to a withdrawal of products from the market.
terms of delivering patient care. In 2012, 99 % of over An adequate announcement is requested in cases where only
300 respondents from 27 European countries had to cope one provider for a medically necessary active ingredient is
with medicines shortage problems according to a survey of available. The FDA has created a task force for a strategic
the EAHP. Sixty three percent of hospital pharmacists expe- planning [18] and the EMA reflects particularly on shortages
rienced it weekly, sometimes even daily. Seventy seven caused by GMP compliance problems [19]. As a result,
percent report a worsening of the problem. In Belgium, 38 shortages could be prevented in 2010, 195 in 2011, and
some 30 medicines are regularly in short supply 150 in 2012 (up to November), but more has to be done to
[11]. Today, in Europe not only isolated cases are in the obtain a sustainable troubleshooting [20].
focus, but examples representing all of the therapeutic
groups. In the Netherlands, they are monitored and Relief may arise from less restricted importation
published on a website. From 2004 to 2011, more than frames. Import options depend on the current national
1,400 products were published. The number increased from legislation and are always related to a lag time for
91 in 2004 to 242 in 2011. The duration of a shortage delivery, if substitution cannot be an option. For exam-
increased from 139 to 242 days in the same period. Substi- ple, Swissmedic, may temporarily approve imports of
tution (62 %), alternatives (25 %) and pharmacy preparation EMA-admitted medicines from another European
(2 %) have been the method of choice to cope with such country for an intermediate interval of time in which
situations [12]. One of the biggest Swiss university hospitals the local supply chain is interrupted. There are further
experienced 172 cases of medicines shortage in 2011, i.e. 3 disadvantages related to importation, in addition to the
cases per week, with the involvement of 51 suppliers, and
with multiple shortages for some products. An out of stock (continued)
medicines was not available between 21 and 335 days.
cost” countries, which have less or no experience in a reli-

extra administrative effort. The importing country may able industrial production free from major operational
be causing a shortage in the exporting country if they disruptions. From a delivery, security and ethical point of
are prepared to pay a higher price. In some countries, view, the economic pressure on medicines production has
an imported product can be excluded from reimburse- lead to a disastrous situation, which is to everyone’s disad-
ment, if the assurance company is not in agreement. vantage (clinical, financial and health outcomes). An option
for pharmacies to immediately cope with the vacuum caused
by a stop of industrial manufacturing is only possible if the
The most severe among a list of multifactorial reasons
equipment and quality assurance of its production is regu-
[21] which have induced a medicines shortage, were:
larly updated and the capacity of those still able to produce is
• Quality or availability problems related to active
sufficient to cover also the needs of non-producing
ingredients or to production processes or equipment
pharmacies.
(e.g. heparin contamination [22] and propofol case [23])
The role of pharmacists to cope with drug shortages is a
• Demand spikes (e.g. oseltamivir following flu pandemic
determining one if consequences such as decreased safety
scenarios [24])
and worse outcome is to be prevented. The Swiss Associa-
• Unintended consequences of contracting by large buyers
tion of Public Health Administration and Hospital
leading to the loss of small suppliers
Pharmacists (GSASA) has edited guidelines to cope with
• Overstocking due to panic buying (especially when
drug shortages [27] and, supported by the most important
alternatives are lacking)
Swiss Associations and Federations of pharmacists
• Parallel trade of medicines [25, 26]
(Swisspharma), physicians (FMH), and hospitals (H+), has
• Discontinuation decisions taken by industry, possibly
signed an agreement with the leading associations of phar-
related to pricing or other macro-economic factors (like
maceutical industry (ASSGP, Intergenerica, Interpharma,
high cost and low gain)
Scienceindustries, and Swiss Association of Importers of
• Globalisation of supply chains creating new
Proprietary Medicines (VIPS)) to readily provide
vulnerabilities
pharmacies with active ingredients for extemporaneous
• Lacking alternatives
individualised preparations and small scale stock production
The latter may be explained by the fact that capital bound
of commercially not available formulations or dosages
in a stock is considered as an important item with potential to
[28]. Whatever the reason for a shortage may be, adaptation
optimise a financial balance. The risk of losing capital is
from both sides is highly recommended, i.e. from the sup-
reinforced by the availability of new technologies and new
plier and from the supply chain responsible in a hospital.
products, which might diminish or degrade the stock’s value
All pharmacies should have an up to date, written policy
due to a loss of demand for old products. However,
for managing shortages [29, 30]. That policy should include
medicines are not comparable to electronic or technical
the need for a risk assessment, which will assess the impact
devices with short half-lives. There is no doubt that general
of the shortage and the actions that should be taken to limit
economic rules are hardly applicable, one to one, for
those effects. Pharmacists have a responsibility not to do
medicines and in no way for special product groups such
anything that will exacerbate a shortage situation. They have
as antidotes, narcotics, antineoplastics, total parenteral nutri-
a responsibility to co-operate with any nationally agreed
tion, and anti-infectives, if no equivalent and equally expen-
scheme to reduce the effect of such shortages.
sive medicine is available. Thus, commercial items and lean
production are not convincing arguments for small stocks.
It is obvious that most drugs in short supply represent
highly active ingredients and the shortage is linked to safety 3.2.3 Bioequivalence Considerations
and quality issues. Deviations from GMP uncovered on for Coping with Shortages
inspections requiring improvements and investments in a
manufacturing plant may play an important role in decision Substitution or alternatives, which may be required in the
making about maintaining production or not. The risk and absence or unavailability of appropriate medicinal products
the consequences for the supply chain, which arises from on the market, are indispensable to cover the need arising
cases of a major quality problem and paralysis of a big from medicine shortages.1
manufacturing plant after a merger of several smaller sites,
is the more threatening as less alternatives will be available.
The risk of affecting a global market will be clearly higher in
1
case of one big facility affected instead of many smaller This section has been written by Wafa Jama, Royal Dutch
Pharmacists’ Association KNMP, The Hague, The Netherlands.
ones. It is even worse, if production is relocated into “low-
e-mail: [email protected].
Generic substitution is defined as the mutual substitution Medicines with a different dosage form are not tested for
of medicinal products having the same active ingredient, the bioequivalence. These medicines have different kinetic
PATIENTS’ NEEDS
same strength, and the same dosage form. Different salt properties and they are not bioequivalent by itself. From
forms of the same medicinal product are considered to be that viewpoint, these products cannot be substituted and
the same active substance, unless the salt forms in question caution is needed. The consequences for non-adherence
exhibit substantial differences in terms of efficacy and activ- and non-efficacy should be considered.
ity. Generic substitution usually involves replacing the pro- The main consideration where generic substitution is
prietary brand or reference medicinal product with a generic concerned with is that the efficacy and safety of substituted
or parallel-imported product. medicinal products should be equivalent to one another. As
The term pharmaceutical alternative is used to define the this is tested during the approval of generic medicinal
medicinal product with the same active ingredient, although products, on the basis of bioequivalence studies, it can be
the dosage form, salt form or strength may vary, such as assumed that the approved generic products are just as
substitution from a tablet with immediate release to effective and safe as the reference product. However, in
controlled-release, or from capsule to oral solution. Thera- conjunction with certain active substances or certain
peutic substitution is the mutual substitution of medicinal situations, it may be preferable to avoid even the slightest
products with different active ingredients, both of which risk (e.g. ciclosporine).
may or may not belong to the same therapeutic group. In addition, there is a range of other issues – unrelated to
In general, medicines, which passed bioequivalence test- bioequivalence – which can cause problems following sub-
ing, should be substitutable with their generically equiva- stitution. Accordingly, there is still a need to determine the
lent, when needed. The European Medicines Agency (EMA) advisability of substitution on a medicine-by-medicine and
and the Food and Drug Administration (FDA) consider patient-by-patient basis. The flow chart in Fig. 3.1 and the
products to be bio-equivalent if, based on the same molar following directions may be helpful in this regard:
dose, a generic substitute or pharmaceutical alternative (a) On first dispensing, the problems relating to efficacy,
exhibits a similar rate and degree of availability at the site safety and convenience for the patient are not an issue.
of action, and can thus be said to have a similar efficacy and This is not the case if the patient has already received the
degree of safety. medicine from another pharmacy (e.g. hospital
pharmacy).
(b) A precise dose titration is important. Small differences
Market approval of generic medicines requires phar-
in bioavailability can have large consequences. In
macokinetic bioequivalence studies. In
disorders such as psychosis or mania, patients can be
bio-equivalence studies, the product to be investigated
distrustful of medication. Changes can damage patient
is compared to an innovator product. Products are
adherence to the treatment.
regarded as bio-equivalent if the 90 % confidence
(c) Substances with which, for reasons of safety and effi-
interval of the AUC-ratio and Cmax are within
cacy, it is preferable that no risks be taken are
80–125 % of the reference product. If the confidence
biologicals, those with a narrow therapeutic index and
interval is within these limits, this means that the
those with non-linear kinetics. Although substances with
average will deviate far less from the corresponding
a narrow therapeutic index or non-linear kinetics meet
value found for the innovator product.
the requirements for bioequivalence, and are therefore
For medicinal products with a narrow therapeutic
theoretically interchangeable, patient-related factors that
index the 90 % confidence interval of the AUC ratio
adversely affect interchangeability may be involved.
must lie between 90.00 % and 111.11 %, and if Cmax
(d) Substitution can cause safety problems when the medic-
is important then this too must lie between 90.00 %
inal products contains an excipient to which the patient
and 111.11 %. The significance of this, in terms of
is allergic or intolerant.
interchangeability, is not known.
(e) The packaging of the medicinal product in question, or
For medicinal products with large intra-individual var-
an associated device, significantly affects its ease of use,
iation (i.e. if the variation of a kinetic parameter
or compliance.
exceeds 30 %) the 90 % confidence interval of Cmax
(f) Legally, there can be no substitution without the
should be between 69.84 % and 143.19 %, while the
physician’s consent, unless prescribed generically. In
AUC-ratio should be within normal limits. Classical
practice, this usually means that agreements have been
bioequivalence studies have limited value in
made on this point.
indicating equivalent efficacy and safety for
biosimilars (generic version of biological medicines).
Fig. 3.1 Flowchart with decision

points for substitution. Adapted No problems with substitution
from [31] by the same author. Is this a first dispensing? Yes Do not proceed with substition if the patient is
For substitution bioequivalence already set to the drug by another pharmacy (e.g.
hospital pharmacy).
and additional factors are
considered, especially if repeat
dispensing is required. No
Bioequivalent proven medicinal
products should be substitutable. Do not proceed with substitution
However, for a variety of reasons Is it a complex condition? A precise dose titration is important. Small
this may not be the case and • Epilepsy differences in bioavailability can have large
caution needs to be warranted • Psychosis or mania Yes consequences. In disorders such as psychosis or
• Parkinson’s disease mania, patients can be distrustful of medication.
• Post-organ transplantation Changes can damage patient adherence to the
treatment.
No
Do not proceed with substitution
Narrow therapeutic drugs, non-linear For reasons of safety and efficacy, it is preferable
Yes that no risks be taken with substances with a
kinetics or biologicals? narrow therapeutic index, non-linear kinetics or
biologicals.
No

Are there patient-related factors? Yes Substitution can cause safety problems when an
allergy or intolerance for a certain excipient is
involved.
No

Are there product-related factors? Yes Substitution can cause problems when the
packaging or an associated device significantly
affects its ease of use or compliance.
No
Physician disagrees with Consult the physician

Yes Legally, there can be no substitution without the
substitution? physician’s consent.
No
No problems with
Patient agrees with substitution? Yes
substitution
No
Explain the situation clearly
a marketing authorisation at the European Medicines

3.3 Medicines with a Market Authorisation Agency for the European Union [35] or at the Medicines
Agency of a country. The Medicines Agencies scientifically
3.3.1 Market Authorisation (Formerly evaluate the medicine and grant an application if they have
“Registration”) safety, quality and efficacy assessed positively. The process,
which formerly was called registration of medicines, now is
In Europe as in many other parts of the world, medicines can to be spoken of as granting of a Marketing Authorisation.
only be marketed if they are authorised [32–34]. A company, And the company is the Marketing Authorisation Holder
which wants to market a medicinal product, has to apply for (MAH).
The applicant has to be authorised for manufacture, National pricing and financing policies are guided by a
import, wholesaling, export or trading in foreign countries, WHO policy [41].
PATIENTS’ NEEDS
according to the activities and the locations of the business. Regulations for reimbursement are still nationally deter-
The applicant has to submit a product dossier with all neces- mined. In many countries the approaches are more or less the
sary data defined in a guideline [36]. Such an authorisation is same: the type of health insurance system,
limited in time. It is renewed after an inspection. It pharmacoeconomic data, the effectiveness of the medicine,
nominates the Qualified Persons and specifies limitations and the need in relation to similar medicines are determi-
or conditions. To be allowed to produce a medicinal product nant. The cost of a medicine for hospital patients may be
the manufacturer or the importer needs a Manufacturing regulated differently from the community situation. The
License, which is bound to compliance to GMP (see Sect. inclusion in clinical guidelines of a specific medicine is of
35.5.2). If the Medicines Agency judges positively, the major importance in order to obtain reimbursement.
European Commission or the National Authorities grant a The key questions by the assessor are about an added
Marketing Authorisation for the entire European economic benefit and about the medical value. In the Netherlands, the
area (EEA; EU Member States plus Switzerland, Norway, medical value is assessed unofficially by means of the
Iceland and Liechtenstein) or just for the country itself. Dunnings Funnel, which evaluates the candidates by defined
Conversely, local authority’s approval does not grant any criteria, e.g. necessity, effectiveness, safety, cost-
authorisation for other EU member states. Non Member effectiveness commonly calculated as incremental cost-
States ratify EU legislation such as on the pharmacopoeia effectiveness ratio (ICER), and social arguments such as
to adapt national legislation and may have treaties with the budget impact or own responsibility [42]. The societies’
EU, USA, Australia or Singapore [37, 38] European regis- willingness to pay for an additional quality-adjusted life
tration is possible for all medicines which meet certain year gained (QALY) is as follows [43–45]:
requirements [39]. It is however compulsory for specific • Canada: $ 20,000 – $ 100,000
medicinal products such as biotechnologicals, orphan • United States: $ 50,000 – $ 100,000
medicinal products, anti-neoplastics or medicines for auto- • The Netherlands: € 20,000 – € 50,000
immune diseases. The product is recognisable by a • Belgium: € 50,000
EU-authorised medicinal product registration number (for • United Kingdom: £ 20,000 – £ 30,000
example: EU/1/04/276/001). • WHO standard: 3 * GDP (gross domestic product) per
Product information on European authorised medicines capita
can be found at the EMA Regulatory and procedural guid- The added medical benefit may be assessed in compari-
ance index [40]. This information comprises: son with existing therapies in terms of effectiveness, adverse
• A list of authorised presentations of the medicinal effects, experience, applicability and ease of use. In France,
product the first step of reimbursement decision and price fixing
• The summary of product characteristics (SmPC) process is confirming the medical benefit obtained (SMR,
• The patient leaflet and labelling of the product service medical rendu) which determines the reimbursement
• The European Public Assessment Report (EPAR) percentage, whereas the second step evaluates the improve-
A medicinal product with a national marketing authorisa- ment of the medical benefit over existing medicines (ASMR,
tion has a national registration number, e.g. RVG 11,985 in amélioration du service médical rendu), which is used for
the Netherlands. Product information about nationally price negotiations [46]. In contrast to the methods of
authorised medicines can normally be found on national healthcare evaluation in other countries, the UK National
websites. National Medicinal Agencies refer to the website Institute for Health and Care Excellence (NICE) does not
of the EMA if the product has obtained a European Market- evaluate all interventions as they reach the market. NICE has
ing Authorisation. published guidelines on how it will select interventions for
review. This includes the following key questions [47–49]:
• Is the technology likely to result in a significant health
3.3.2 Reimbursement benefit, taken across the National Health Service (NHS)
as a whole, if given to all patients for whom it is
The manufacturer is allowed to market a product with a indicated?
Marketing Authorisation. The company sets the price of • Is the technology likely to result in a significant impact on
the medicine. This is done either by a calculation which other health related government policies (e.g. reduction in
takes into account the manufacturing and marketing costs, health inequalities)?
including a profit allowance, or it is set in comparison to • Is the technology likely to have a significant impact on
competing products of the same kind, especially, if the NHS resources (financial or other) if given to all patients
authorities negotiate with the company about that price. for whom it is indicated?
• Is the institute likely to be able to add value by issuing

national guidance? unlicensed medicines will be handled differently in
most European Countries. There may also be
differences between the reimbursement for hospital
Many countries, e.g. Switzerland, have compulsory
and public pharmacies.
social accident and health insurance systems for
every citizen. The choice of the insurance company
is free. The insurer has to accept every request and is Within the patient access and reimbursement schemes,
not allowed to reject applicants with increased risks in risk sharing is fixed as outcome-based or financial-based
the basic part. Rejection is only possible for coverage agreement between the payer and the manufacturer.
by complementary insurances. Physicians, Financial-based agreements are possible on a fixed price,
pharmacists, midwives, chiropractors, laboratories, on a price-volume ratio, on a price by diagnosis, on capita-
hospitals, several institutions for acute or chronic tion fee, or on dose-quantity limits. Outcome-based
care for in- or outpatients, policlinics, or ambulance agreements can be divided into evidence-development-
transporters are care providers approved from the con- based, conditional treatment continuation-based, or
cordat of insurers. Care providers are licensed to bill performance-based schemes. Most of these schemes are
the insurer for approved services at prefixed rates applied in Europe and Australia, followed by Canada and
according to lists such as TARMED and SwissDRG the United States [54, 55]:
(German modification) issued by the Federal Office of • Evidence development schemes (34 schemes in use,
Public Health (FOPH) [50, 51]. To be put on the list of regrouped into coverage-with-study or coverage-with-
pharmaceutical specialties, a request has to be appropriateness determination approaches)
addressed to the Swiss Federal Social Insurance – Example taxanes: In 2000 in the UK, the use of
Office, which is advised by the Swiss Federal Drug taxanes for adjuvant treatment of early breast cancer
Commission. Applicants have to follow a manual and was limited to randomised clinical trials.
submit several documents, e.g. a summary of product – Example temozolomide: In 2001 in the UK, this active
characteristics, the grant of marketing authorisation, ingredient was only recommended as an initial chemo-
key facts, clinical overview, non-clinical overview, therapy for patients with brain cancer included in a
most relevant clinical studies, epidemiologic data of clinical trial.
the disease to be treated, clinical guidelines, and – Example risperidone: In 2003 in France, costs were
pharmacoeconomic studies [52]. It is stipulated in the covered, if evaluation studies on whether it helps
Swiss federal act on health insurances, that medicines patients stay on the medications were performed. In
and care are required to be efficacious, appropriate and case of failure the manufacturer was to refund costs to
economic to be reimbursed [53]. The latter require- the French ministry of health.
ment is checked by means of price comparisons – Example human papilloma virus quadrivalent vaccine:
between the requested Swiss price and those applied In 2007 in Sweden, the manufacturer was asked to
in Denmark, Germany, the Netherland, Great Britain, provide every 6 months additional data on ongoing
France, and Austria [52]. and planned studies in order to determinate the cost-
The costs of materials, duration of preparation, quality effectiveness from a long-term perspective.
control, investment in premises, training, quality • Conditional treatment continuation schemes (10 schemes
assurance et cetera determine the basic cost of phar- in use)
macy preparation. As with the reimbursement of – Example bortezomib: For the multiple myeloma indi-
licensed medicines there is a distinction between cation, in the UK the manufacturer agreed in 2007 to
in-patient and out-patient supply. Pharmacy reimburse the NHS in either cash or product for
preparations used in hospitals could be considered to patients who did not respond, i.e. those who do not
be part of the reimbursement for the therapy as a show a 50 % decrease in serum M protein, after four
whole. Anyhow, the hospital pharmacist normally cycles. Responding patients received additional four
has to find his payment within the hospital cycles. In 2009, the same agreement was fixed with the
organisation. In community pharmacy most pharmacy Scottish Medicines Consortium.
preparations are reimbursed by the health insurer, – Examples sunitinib and sorafenib: A hospital discount
according to the Tax price with a surcharge according of 50 % applies in Italy to the first 3 months of treat-
to the performance cost system. Reimbursement for ment. For responding patients the treatment is then
reimbursed and the discount dropped.
(continued)
– Examples Alzheimer’s disease medicines: In Italy, dur- 15 years may pass until a new chemical entity reaches the
ing the first 3 months, patients starting Alzheimer’s market.
PATIENTS’ NEEDS
disease medicines are assessed for short-term effective- In the clinical phase of development of new chemical
ness. The medicines are provided free of charge by the entities, medicines are developed by hospitals, universities,
manufacturer. If treatment goals are met after 3 months, or pharmaceutical companies and administered to humans
treatment is continued for a maximum of 2 years and the as “Investigational Medicinal Products (IMP)”. In Europe,
costs reimbursed by the Italian Drugs Agency (AIFA). the administration of IMPs to human beings is regulated by
• Performance-linked reimbursement schemes (14 schemes Directive 2001/20/EC (which has been replaced on the
in use, regrouped into pricing review, try-before-you- 16 April 2014 by the new Regulation No 536/2014 which
buy, or no cure – no pay principles) is to come into force no earlier than 28th May 2016), which
– Example statins: In 1998 in the US and in 2000 in the deals with the implementation of good clinical practice in
UK, rebates were agreed and refunds were promised if the conduct of clinical trials on medicinal products for
LDL cholesterol could not be lowered. human use [56]. Each specific investigation has to be
– Example bosentan: In 2004 in Australia, the price of approved by an Ethics Committee. In the Netherlands, a
bosentan for pulmonary arterial hypertension was national committee for clinical research has to assign a
linked to the survival of patients followed in an obser- certificate of incorporation. Research with a non-licensed
vational study. medicine without such an approval is not allowed. In
– Example risedronate sodium: In the US in 2009, the Switzerland, a new act on human research entered into
manufacturer agreed to reimburse for the costs of force as from 2014. It inserts an article into the Swiss Federal
treating-related fractures. Constitution, recently voted and approved by the Swiss
nation in 2010 [57].
The dossier of an IMP is called the Investigational Medi-
cal Product Dossier (IMPD). It describes the technological,
3.4 Investigational Medicinal Products pharmacological and toxicological properties of the product
as well as the method of preparation. Importing or preparing
The manufacturing of investigational medicines goes IMPs by a manufacturer or a pharmacist requires a license/
together with phases I – III of the Clinical Trial Investiga- authorisation [58]. An authorisation as a wholesale trader in
tion, where pharmacokinetics and toxicology at different medicinal products is required, if the IMP originates from
dosages is investigated and compared with the standard another ERA state (European Research Area). A
treatment or placebo treatment in a small group of healthy Manufacturing Authorisation is requested, if the medicine
volunteers first, in a limited group of patients afterwards, and is imported from a country outside the ERA. These
finally in a large group of patients. After completing these authorisations are specific for a dosage form or for a prepa-
investigations the new medicine can be offered for approval ration process. Preparation and quality control should be
and admission to the market (market authorisation). In phase performed according to the IMPD. A Qualified Person
IV Authorised Medicines are evaluated for the authorised (QP, see Sect. 25.3.4) has to release the product after import,
indications, side effects and long term value and will be preparation and quality control and to guarantee that all
monitored in clinical practice. This may occur by quality requirements are met. Pharmacies don’t need a
pharmacovigilance or by outcomes research in specific Manufacturing License if the preparation of an IMP is lim-
patient populations. As described in Table 3.3, currently ited to operations such as reconstitution, dilution and
Table 3.3 Phases of clinical research

Discovery Clinical trials Launching
Preclinical testing Phase I Phase II Phase III Drug agency Phase IV
Years 6.5 1.5 2 3.5 1.5
approximately
Test Laboratory and 20–100 healthy 100–500 patient 1,000–5,000 patient Review process, Additional
population animal studies volunteers volunteers volunteers approval post-marketing
Purpose Assess safety, Determine safety Evaluate Confirm testing
biological activity and dosage effectiveness, effectiveness,
and formulations look for side monitor adverse
effects reactions from
long-term use
Yield 5,000 compounds 5 enter trials 1 approved
evaluated
labelling, which have to be performed for the purpose of scale [60], or if it is produced according to an own formula
administration to the patient and are defined in the IMPD. in small scale for own clients. Medicines from foreign
These activities however have to be carried out within the countries made available to tourists from the same country
institution where this clinical trial is carried out and by a to continue an existing treatment, is free from authorisation
pharmacist who is employed within this institution [59]. See request as well. In case of life-threatening urgencies, health
also Sect. 35.5.10. professionals have the obligation to assist the affected per-
son. If procedures will not resolve a problem in time, the use
of unlicensed medicines may be approved by phone or mail
contacts of inspectorates or of another direct supervising
3.5 Unlicensed Medicines authority [61].
Off-label use of a licensed medicine and unlicensed use
Unlicensed medicines are medicines, including pharmacy of not-admitted or not-marketed medicines have several
preparation, that don’t have a Marketing Authorisation. uncertainties in common. For neither one of them the
Patients who suffer from a disease, for which no licensed intended use is described nor approved by the authorities
medicinal product is available, may exceptionally get unli- (different indication, different dose, different application
censed medicines from a manufacturer. This happens on the mode, different patient population, different pharmaceutical
legal basis of a compassionate use program either on a items, e.g. expiry date, solvent, etc). Thus, the responsibility
named patient basis or to cohorts of patients. This regulation is attributed to the treating physician and to the producing
applies to patients with a chronically or seriously debilitating pharmacist, if he is or can be aware of the indication for
disease or whose disease is considered to be life threatening. which the medicine is given. They act under the obligation
Reimbursement has to be clarified from case to case (see and duty of care and have to consider the state of the art.
Sect. 3.3.2 Reimbursement). Adverse events have to be notified to the authorities. The
Compassionate use is a treatment option that allows the legitimation of having acted the selected way must be
use of an unlicensed medicine. Compassionate use justified. Informed consent of the patient must be available.
programmes are for patients in the European Union Information about reimbursement granting or rejection must
(EU) who have a disease with no satisfactory authorised have been given. The pharmacist’s duty is to validate the
therapies or cannot enter a clinical trial. They are intended prescription, to consult the prescriber, to produce according
to facilitate the availability to patients of new treatment to GMP, PIC/S or approved quality guidelines, and be
options under development. To qualify for a compassionate responsible for the formula (Table 3.4), in the case of a
use programme, the manufacturer calls on the national prepared medicine [62].
authorities for permission. The manufacturer must submit a
request for the granting of a marketing authorisation or he
must perform research in the context of a research 3.6 Orphan Medicines and Neglected
programme with a cohort. Compassionate use procedures Patients
are also applicable for unlicensed medicines withdrawn
from the market or for off-label use of licensed medicines. The pharmaceutical industry decides on the basis of a cost-
Several options to get authorisations for named patients benefit analysis, if the development and placing on the
have been applied in the past and still are in practice in order market of a medicinal product is profitable. The develop-
to maintain the supply chain with the most important ment of medicines for rare illnesses or for minority special
medicines. As long as they are classified as IMPs and thus patient populations (“neglected patients”), therefore gener-
not allowed on the market, patients may be treated in some ally does not get funded. Industrial providers however offer
countries, e.g. Switzerland, in a parallel trial programme or innovations for very small groups of patients at very high
within an extended access. Procedures follow those for prices, e.g. products from recombinant technologies
compassionate use and requests have to be submitted to the e.g. coagulation factor VII, monoclonal antibodies, and
ethical committee as well. A parallel trial programme will many more. Governments have designed programs to stim-
always require Ethical Approval and would therefore be a ulate the development of these medicines.
Clinical trial in the UK. Single cases different from compas-
sionate use have to be authorised but do not need an ethical
committee approval. 3.6.1 Orphan Medicines
No marketing authorisation is needed, if the required
medicine is a part of an approved formulary (formula Disorders which are rare, are called orphan diseases and the
magistralis or formula officinalis) produced on a small medicines intended for these diseases are called orphan
Table 3.4 General requirements for off label and unlicensed use of medicines. Authorisations may differ according to national and local
ordinances
PATIENTS’ NEEDS
Type Authorisation status Legal basis Requirements
Off label use
I Medicine with a market authorisation in the own No special authorisation needed Responsibility of treating
country (Market Admission covering local use) Prescription and dispensing according physician
to approved state of the art of Obligation and duty of care
pharmaceutical and medical sciences Information of the patient
II Medicine with market authorisation in a foreign country Special authorisation needed Liability
Authorisation for import needed Notification
Unlicensed use (compassionate use, parallel trial, extended access, individual case, medicines withdrawn from market)
I Medicine not admitted to own market, but admitted No special authorisation needed Small amounts
in an extra-European country (USA, Canada, Authorisation for import needed Responsibility of treating
Australia, New Zealand) To be used within the approved indications physician
II Medicine not admitted to own market, but admitted Physicians and pharmacist with allowance Obligation and duty of care
in an extra-European country (other than USA, for retail trade Information of the patient
Canada, Australia, New Zealand) Liability
III Medicine without market authorisation worldwide Notification
Market authorisation not needed
Formula magistralis medicine according to prescription for individual patient or patient group
Formula officinalis medicine according to an approved monograph
Own formula medicine produced in small amounts for own clients or patients
I Active ingredient known, used according to Authorisation to produce needed Strictly small scale
scientifically approved indication Manufacturing according to
c-GMP/PIC/S guidelines
Responsibility, obligation and
duty of care attributed to
physician and pharmacist
Liability
Notification
II Active ingredient known, used in an indication beyond Documentation of scientific
scientifically approved knowledge knowledge on the active
ingredient
Strictly small scale
Manufacturing according to c-
GMP/PIC/s guidelines
Liability
Notification
III Active ingredient not yet rated “for human use” Notification to ethical committee
Documentation of scientific
knowledge on the active
ingredient
Strictly small scale
Manufacturing according to
c-GMP/PIC guidelines
Liability
Notification
medicines. An orphan disease is a serious, life-threatening or legislation on orphan medicines. It was hoped that this
chronically debilitating condition which affects less than stimulant would encourage the market. However, the market
5,000–10,000 patients in the 750 million inhabitants in the is failing in this respect [64]. In trade, sellers get paid for
EU [63]. Governments try to stimulate the development of what they sell. In care, providers get paid for what they
orphan medicines with economic incentives through do. No orphan medicinal product will be available without
economic encouragement, at least the coverage of develop- authorisation has been granted due to the small number of
ment and production costs. The European legislation is patients. National incentives may be provided,
based on the economic motivation to put a medicinal product e.g. reimbursement options. In Portugal, France and
on the market. Public health arguments are secondary. If the Belgium, all orphan medicinal products are reimbursed, in
market fails, health care and tax payers should take over and the Netherlands most of them (95 %) [69].
care for the patient in another way, e.g. by attribution Designated orphan products, indications and more than
opportunities and flexibility to prepare medicines in a phar- 1,224 active substances are registered. Sixty are authorised
macy. Many case studies support a simplified handling for for 52 rare diseases, 25 are withdrawn or suspended,
pharmacy prepared compounded medicines with a long his- 9 expired. Oncological products dominate. Within this
tory of effective use [65]. class, no orphan medicinal product authorisation has been
In some countries, enterprises can be commanded to attributed to axitinib, crizotinib, erlotinib, gefitinib, lapatinib,
provide a medicine. This had been the case in the nineties pazopanib, vandetanib, vemurafenib. An orphan medicinal
with cladribine (2-CdA, 2-chlorodesoxy-adenosine), which product authorisation has been assigned to dasatinib,
was provided first by a current industrial supplier in the USA imatinib, nolotinib, sorafenib [70].
to treat hairy cell leukaemia as an alternative to interferon-
alfa. Cladribine was not available in Europe at that time,
neither as a product nor as an active substance. It took
3.6.2 Neglected Patients
several weeks until the six-step synthesis was developed
and a hospital pharmacy product could be made available.
For many diseases active substances are available, and yet
The US-price of the marketed syringe was some 20 times as
groups of patients will not receive the medicines they need.
much as could be attained later by hospital pharmacy pro-
This refers not only to patients who cannot pay for the
duction with the specially synthesised substance [66].
medicines, but also to various special patient groups,
Today, the EU encourages the development of orphan
e.g. children and elderly. They need doses or dosage forms
medicines [67] with:
which differ from the available licensed medicines. In the
• Advice and support on research protocols
wake of the WHO and DNDi, following the World Health
• EU-funded research
Assembly in 2012 [71–73], the EU, national Governments
• Free pre-submission meetings with persons or companies
and universities call for attention to be given to the develop-
(“sponsors”) on authorisation applications
ment of appropriate medicines for these neglected patients.
• Reduction on the registration fee
For the development of more medicines for children funding
• Centralised EU procedure
programmes have been started such as ERA-NET
• Market exclusivity for 10 years
PRIOMEDCHILD in the EU [74] and in the Medicines for
• After-designation support
Children Research Network (MCRN) in the Netherlands and
To be eligible for these incentives, products should be
the UK [75].
designated through the orphan designation procedure. The
From the WHO-report Priority Medicines for Europe and
EMA through its Committee for Orphan Medicinal Products
the World [76, 77]:
(COMP) assesses at request by the manufacturer, if a sub-
stance might be designated as an orphan drug for a specified . . . There is a wide range of existing evidence-based, very often
off-patent, technologies that are heavily underutilised. Such
orphan disease. The whole orphan designation procedure technologies could be used to improve the ‘patient-friendly’
comprises the following steps [68]: performance of a number of existing medicines, the use of
• Sponsor notifies the Agency of intent to file. medicines in paediatrics and geriatrics, and other areas where
• Pre-submission meeting/ teleconference. individualised time-dosing of medicines is required, e.g.,
patients with impaired liver or kidney functions, or patients
• Submission of application; validation by the Agency with compromised immune systems. . .
(day 1).
• Assessment/COMP meeting/ possible hearing/COMP Whereas agreements on patents and authorised produc-
opinion adopted (by day 60 or 90). tion can be negotiated in cases of shortages (see section on
• Opinion sent to the European Commission. shortages), this has so far not yet been possible in cases of
• Commission decision granted (within 30 days). national versus pharmaceutical industry interests on behalf
• Publication in EU Register on the Commission’s website; of neglected patients. Patented medicines block the produc-
publication of public summary of opinion on the tion of more affordable generic versions while more and
Agency’s website. more patients become sick or die because the medicines
After a positive assessment the manufacturer must follow they need to stay alive are simply too expensive. Recently,
the normal registration procedure, albeit that the clinical much attention has been attracted by India’s efforts to
studies normally will be continued after the market increase access to medicines and implement a patent system
in line with its public health needs. India is a critical pro-

ducer of affordable medicines. Competition among generic • Adrenaline injection various strengths (several
PATIENTS’ NEEDS
producers in India has brought the price of medicines to treat manufacturers)
diseases such as HIV, tuberculosis and cancer down by more • Phentolamine injection 10 mg/ml (Regitine®)
than 90 %. The majority of the antiretroviral medicines • Hyaluronidase injection (Hylase®)
purchased by the U.S. government’s global AIDS program • Biperidene injection 5 mg/ml (Akineton®)
come from India, and more than 80 % of the HIV medicines • Tinidazole tablets (Fasigyn®)
non-profit aid organisations use to treat more than 280,000 • Bismuth oxide tablets (De-nol®)
people with HIV in 21 countries are generics from India. • Fluphenazine coated tablets (Moditen®)
The policies and decisions by India’s patent offices and • Dihydralazine injection solution (Nepresol powder
courts to limit abusive patenting practices and increase for injection®)
access to affordable generic medicines are subject to
increased political pressure from the US government and
From those medicines prepared in one of a selection of
pharmaceutical industry. Among the critical decisions can
European hospital pharmacies, half to three-quarters are
be found a 7-year-battle to claim a patent on the salt form of
available in the market in another EU country, North Amer-
the cancer medicine imatinib, judged by the Indian Supreme
ica or Australia [80]. Although the European legislation has
Court as non-patentable, and a generic version of a kidney
been aimed at decreasing trade barriers since 2001, the
cancer medicine, which was made available for 97 % less
purchase of medicines from other countries is anything but
than the patented version. India’s health ministry has set up
simple. A patient is allowed to travel abroad and buy an
an independent expert committee to identify exorbitantly-
authorised medicine for personal use and import it into
priced medicines for which further compulsory licenses may
Europe, however, a pharmacist can only import a medicinal
be issued, relying on the Agreement on Trade Related
product if he has a wholesale import authorisation. The
Aspects of Intellectual Property (TRIPS) and the Doha Dec-
complicated rules for reimbursement (in some Countries)
laration on TRIPS and Public Health, both of which defend
and the amount of time the whole process takes, renders
access to existing medicines by allowing countries to use
import a laborious way to make medicines available for the
flexibilities such as patent oppositions and compulsory
patient.
licenses to overcome intellectual property barriers.
If an imported medicinal product has been granted a
The country must now deal with pressure from the multi-
Marketing Authorisation, the pharmacy can purchase it
national pharmaceutical industry trying to sue India in a
from a wholesaler established in the country or from the
foreign tribunal. The US Government has a policy of
manufacturer. The packaging must meet the labelling
negotiating and exerting pressure on governments to give
requirements in the subject country, and the patient leaflet
foreign investors the right to sue governments ’known as
has to be written in one of the country’s languages. In a
Investor-State Dispute Settlement’ for high amounts of
hospital, the patient leaflet and/or usage information are less
damages if a law or policy harms their investment [78].
important if information and skill is more readily available
from a permanent pharmaceutical assistance and documen-
tation than outside of a hospital. The pharmacist will then
3.7 Medicines Import dispense the product to the patient. As a second option, a
pharmacist or a wholesaler or a manufacturer can ask per-
If a patient needs a medicine, which is not on the national mission to import from the Competent Authority under the
market, it may be imported from abroad or prepared in a terms of the named patient regulation and on the following
pharmacy. conditions:
• The physician considers it necessary that the patient
In 2013 the following medicines had to be made belonging to his medical practice is treated with the
available in the Netherlands in 2013 by import [79]: medicinal product.
• Isoniazide tablets 200 mg (Isozid®) • There is no adequate alternative medication for the
• Sucralfat oral suspension 200 mg/ml (Ulcogant®) medicinal product on the market.
• Chinidine sulphate 200 mg tablets (Kiniduron • The physician has requested a pharmacist to deliver the
Depot®) medicine in writing using the national model form.
• Mitoxantron injection various strengths • The pharmacist has presented the written request of the
(Onkotrone®) physician to the Competent Authority.
• Riboflavine 10 mg tablets (Beflavine®) • The quantity of the medicinal product and the period
during which it may be delivered to the doctor, has been
(continued) determined by the Competent Authority.
• The manufacturer, wholesaler or pharmacist keeps track ward or in patient’s homes. Circumstances such as legisla-
of the quantity of the medicinal product, the name of the tion, logistics, regulation, and reimbursement have caused
physician, the number of patients for whom it is intended, the development of several types of preparing pharmacies,
and on the medicinal side effects observed. which differ in organisation, size, types, and batches. The
The costs of medicines purchased from abroad have to be organisation of pharmacy preparation should guarantee good
borne by the budget of the institution. In some Countries product and patient care. This is the scope of the legal basis
these imported medicines are not reimbursed from a social of pharmacy preparation.
health insurance, unless the patient has an allowance or is
covered by an extra private insurance, specifically for that
medicinal product. 3.10 Importance of Pharmaceutical Production
in Hospitals
All those hospitals, which have decided to run a hospital

3.8 Preparation of the Remaining Necessary
pharmacy without access to production, are deprived of an
Medicines
important scope for action to overcome shortages. If own
manufacturing has not been spectacular enough in the past to
A patient may need medicines which are not commercially
underline its importance and justification to exist, it should
available, neither in the country nor abroad, or which are
be recognised by now that flexibility counts and is one of the
temporarily not available, although a Marketing
determinant element for hospital pharmacists to fulfil their
Authorisation is granted. To provide the necessary care to
duty (Table 3.6). Grouping of geographically closely
the patient, these medicines may be prepared by the pharma-
situated production units may be an option to economise.
cist, either from raw materials or through adapting a licensed
In the 1990s, the justification of hospital pharmacy pro-
product. The need for this combined production-and-care
duction has been reassessed due to economic reasons and
task of the pharmacist is endorsed worldwide. Various
due to the severe GMP-requirements requiring important
references and lists from hospital pharmacy production
investments. Economic reflections have dominated rational
units are published online [81]. The Formularium der
ones and anticipation of supply problems. Administrators
Nederlandse Apothekers (FNA, see Sect. 39.4.5) contains
did not realise that only a few pharmacy-issued products
formulations for 200 medicines, which are prepared in the
were commercially available. In-house products have been
pharmacy because they are frequently needed but not on the
compared to standard industry-derived products as far as
market. It does not contain all the required pharmacy
comparisons existed. Some infusion solutions were commer-
preparations. The total number of required, rational
cially available at low prices due to the large numbers
medicines which pharmacies have to prepare out of raw
produced by scaling up. Some of these infusions were pro-
materials is estimated at 50 to more than 500. The estimate
duced in medium or low numbers by hospitals to put pres-
depends on the concepts ‘required’ and ‘rational’ (see
sure on prices, to keep installations running, and to
Table 3.5 for examples of the vast variety of medicines
continuously exercise technical staff. Their contribution to
provided by a Swiss University hospital pharmacy). Specials
coverage was judged as being insufficient. Intermediate and
(unlicensed medicines) are being produced according to
small-scale production of not commercially available
GMP and PIC/S guidelines and are becoming more and
products has not been included in the economists’ figures,
more important to produce, whereas extemporaneous
as there were no commercially available products to be
preparations, prepared according to less strict standards,
compared to.
are becoming less common. There is a need for consensual
In 1996, in one of the biggest hospital pharmacies of a
standards of preparation practices and common monographs
Swiss University Hospital, an internal cost assessment of
for preparations [82, 83]. The development of standard
hospital production revealed that there was no financial
formulations is costly, but considerably cheaper than devel-
loss, but rather an income of around 165,000 CHF had
oping a medicine with a Marketing Authorisation
been achieved with internally prepared stock products, if
(Table 3.4).
every product including small scale serial stock production
and extemporaneous production had been included in the
calculation. As a result of own figures, around 15 % only of
3.9 Organisation of Pharmacy Preparation the assortment of pharmacy products could be compared to
marketed brands and 85 % not. Outsourcing of the latter
Pharmacy preparation not only covers preparation from raw would have cost 2.9 times the amount of the cost billed to
materials, but also the adaptation of licensed medicines and internal users. These considerations and the mandate to
reconstitution in excess of the instructions of the SPC. Such provide medicines have helped to prevent the closure of
preparation also happens outside the pharmacy, e.g. on the hospital pharmacy production [84].
Table 3.5 Examples from a Swiss University Hospital of the vast variety of medicines provided by pharmacy preparations only. Some may be
prepared by contract manufacturing depending on the amounts used
PATIENTS’ NEEDS
Sterile products (large volume liquids 100 ml, aseptic
process) Indication, use
Alumen irrigation Astringent for hemorrhagic bladder
Cardioplex injection solution Cardioplegia for open heart surgery with cardiopulmonary bypass
Ethanol 70 % irrigation Irrigation
Hydration infusion solution standard bag EVA Pretreatments to carboplatin treatments
Hydrogen peroxide 2 % irrigation Irrigation
PCA Fentanyl 20 mcg/ml injection solution PCA
Total Parenteral nutrition all-in-one solution TPN
Sterile products (large volume liquids 100 ml, autoclaved) Indication, use
Aluminium acetotartrate irrigation Irrigation
Basic infusion solution G5-K Perf PP 500 ml Basic infusion
BSS irrigation Irrigation
Calciumchloride 170 mmol/l infusion solution Infusion by pump
Chlorhexidine 2 % irrigation Irrigation
Glucose 40 % with Ethanol 10 % (V/V) irrigation Irrigation
Glucose 7.5 %, 10 %, 12.5 %, 15 %, 30 % infusion solution Infusion volume and concentration adapted
Glycerol 85 % solution sterile Urethral use at extra-corporal shock-waves lithotripsy; Osmotic dehydration of
oedematous cornea
Hank w/o Ca/Mg solution sterile Not injectable, in vitro use
Mepivacaine HCl 0.5 %, 1 % injection solution Local anesthesia
Mixed infusion for neonates Infusion volume and concentration adapted
NaCl 2.5 % infusion solution Infusion volume and concentration adapted
NaCl 20 % irrigation Irrigation
Neomycin 0.5 % irrigation Irrigation
Novesin 1 % irrigation Irrigation
PCA Ketamin 5 mg/ml infusion solution PCA
PCA Ketamin 2 mg/ml/MORPHIN 2 mg/ml infusion solution PCA
PCA Morphine HCl 2 mg/ml infusion solution PCA
PDA forte (or standard) infusion solution Epidural analgesia
Polyelectrolyte infusion concentrate Component for TPN compounding
Ringer lactate infusion solution Infusion volume and concentration adapted
Sterile products (small volume liquids < 100 ml, aseptic
N-Acetylcysteine 1 % eye drops monodoses Ocular mucolytic eye drops
Alteplase 12.5 mcg/0.1 ml syringe Ready-to-use syringes or vials made from commercial product, plasminogen
activator for fibrinolysis
Amphotericin B 0.15 % eye drops Eye drops
Bevacizumab 25 mg/ml injection solution Anti-angiogenetic agent for intravitreal application
Bleomycin injection solution 1,000 I.U./ml syringe Therapy-resistant warts
Carbicarb injection solution concentrate Injection concentrate
Cefazolin 33 mg/ml eye drops Eye drops
Cefuroxime injection solution 10 mg/ml Intracameral injection solution
Ciclosporin 2 % eye drops Eye drops
Cocaine HCl 2 %, 10 % eye drops monodoses Eye drops
Cysteamine HCl eye drops 1.5 mg/ml Cystinosis
Ethanol 96 % infusion solution Antidote at methanol or ethylene glycol intoxication
Ethanol water free 99 % Antimicrobially filtrated, not for direct injection
FITC-Dextrane 25 % injection solution syringe Diagnostic agent, for microlymphography, subepidermal injection
Glucose 30 % solution oral sterile 10 MD Calmative for neonates
Lidocaine 2 % eye drops Eye drops
Methacholine HCl 2 mg/ml or 10 mg/ml inhalation solution Diagnostic for lung diseases
Mitomycin C 0.2 mg/ml eye drops or syringe Eye drops or syringe for ophthalmic use
Mixed eye drops tropicamide 0.5 %, phenylephrine HCl 2.5 % Eye drops
Novesin 0.2 % eye drops Eye drops
Paraffin liquid sterile solution Dipping bath for sutures
(continued)

Sterile products (small volume liquids < 100 ml, aseptic
Phenol 6 % injection solution syringe Intra-articular injection solution at neurolysis
Phenol orthopedic kit sterile solution Instillation at bone tumors
Pilocarpin 0.125 % pH 6.5 Eye drops monodoses Glaucoma (less irritating than commercially available products)
Polyhexanide 0.02 % eye drops Eye drops
Tobramycin 6.6 mg/ml eye drops monodoses Eye drops
Sterile products (small volume liquids 100 ml, autoclaved) Indication, use
Adenosine 3 mg/ml injection solution Test for blockages in the coronary arteries after adenosin exposition at
scintigraphy
Buffer pH 7.0 injection solution additive/amphotericin B Stabilization of amphotericin B infusion solution
stabiliser
Carbachol 2.5 mg/ml inhalation Diagnostic at lung function test
Clonidin HCl 6 mg/mL infusion solution concentrate Beta2-Sympatholytic to treat high blood pressure, anxiety disorders, panic
disorders, withdrawal symptoms
Cocaine HCl 5 %, 10 % sterile solution At local application for anesthesia and vasoconstriction
Dextrane T70 20 % sterile solution Additive to Hank w/o Ca/Mg at cryoconservation of stem cells
Dextran riboflavin kit Keratoconus therapy: Corneal collagen cross-linkage with riboflavin and UV-A
Glycerol 85 % eye drops Eye drops
Histamin injection solution 1:10’000 Diagnostic for intradermal and inhalation provocation
Komplexon III 3 % eye drops Eye drops at local ophthalmic use
Mepivacaine HCl 1 %, 2 % injection solution in sterile package Local infiltration anesthesia, epidural block
Morphine HCl 2 mg/ml // 4 mg/ml // 40 mg/ml injection solution Analgesia
Zinc 7.6 μmol/ml infusion solution concentrate Concentrate for infusion solution or component of TPN
Sterile products (semisolids) Indication, use
Lubricant for catheter syringe, bottle Lubricant various presentations
Methocel 2 % gel sterile Lubricant, various indications
Sterile products (solids) Indication, use
Talcum (sterile powder) Pleurodesis
Non-sterile products (liquids) Indication, use
Chlorhexidine tincture (or 0.02 % in glycerol) Irrigation
Codeine phosphate 2 % oral solution(1 ml ¼ 19 gtt ¼ 20 mg) Antitussive
Copper sulfate 20 mg/ml oral solution Oral copper supplement
Dessicating ear drops Ear drops
Ethanol 30 % Dermatological use for wetting dressings and cooling
Fuchsine ethanolic solution Dye
Hydrogen peroxide 3 %, 10 % solution Disinfectant, oxidiser
Individualised oral liquids from solids (active ingredient in Patients with swallowing difficulties or dose determining with children
ora-sweet® or ora-blend® or ora-blend® vehicle) [83]
Joulie solution (5 ml ¼ 337 mg phosphate ¼ 110 mg Oral phosphate supplement
P ¼ 3.55 mmol P)
KCl 1 mmol/ml solution Oral potassium supplement
Ketamine 25 mg/ml nasal spray Analgesia and bronchodilatation
Lugol solution 2 % Oral iodine supplement
Methoxsalen 0.15 % solution (10 gtt ¼ 0.3 mg) PUVA therapy
Midazolam 5 mg/ml nasal spray Sedative in pediatrics at short interventions
Morphine HCl 0.1 % oral solution (1 ml ¼ 20 gtt ¼ 1 mg) Analgesia
Morphine HCl 1 % oral solution (1 ml ¼ 20 gtt ¼ 10 mg) Analgesia
Morphine HCl 2 % oral solution (1 ml ¼ 20 gtt ¼ 20 mg) Analgesia
Oral thrush prevention solution Thrush prevention
Pepsin wine 2.5 mg/ml Pepsin supplement at achlorhydria
Phenobarbital 10 mg/ml 15 ml oral solution (1 ml ¼ 15 Anticonvulsive
gtt ¼ 10 mg)
Phenol 80 % solution Topic solution
Potassium permanganate 5 % solution Dermatologic use: to dilute 0.5 ml 1 ml in 1 L water
Resorcin ear drops Ear drops
(continued)

Non-sterile products (liquids) Indication, use
PATIENTS’ NEEDS
Salicylic acid Oil 5 %, 10 % or petroleum Jelly 20 % Dermatologic use as keratolytic
Silver nitrate 1 % solution Cutaneous solution at therapy-resistant warts
Trichloroacetic acid 40 % solution Cutaneous solution at therapy-resistant warts
Non-sterile products (semisolids) Indication, use
Aqua dalibouri solution Disinfectant, adstringent
Calciumgluconate 2.5 % Gel Antidote: cutaneous gel, HF burns
Capsaicin cream 0.075 % Pain relief at peripheral neuropathy e.g. post-herpetic neuralgia or shingles,
reduction of itching and inflammation at psoriasis
Chloral hydrate suppository Sedative at CT scans
Coal tar in pasta leniens 10 % Treatment of dandruff, psoriasis, head lice
Duret ointment Psoriasis on the scalp
Esophagus paste Diagnostic for CT images of the gastrointestinal tract
Hydrocortison oxytetracyclin paste Local anti-infective
Lubricant with chlorhexidine 0.05 % Non-sterile lubricant
Nasal ointment own formula Nasal ointment
Urea (carbamide) 20 % fatty cream Dermatologic use at rehydration and further indications
Wart ointment NRF Ointment at therapy-resistant warts
Non-sterile products (solids) Indication, use
Dexamethason 20 mg, 40 mg capsules Corticosteroid therapy
DHEA 10 mg, 25 mg, 100 mg capsules Supplement for many indications (schizophrenia, improving skin appearance,
systemic lupus erythematosus, sexual dysfunction, muscle ache, mouth ulcers,
osteoporosis)
Hydrochlorothiazide 0.5 mg, 1 mg, 3 mg, 5 mg capsules Pediatric cardiology
Estradiol 0.4 mg 100 capsules Physiologic induction of puberty with very low-dose, e.g. in Turner syndrome
Fordtran solution and aromatiser powder Osmotic laxative, pretreatment of diagnostic or surgical intestinal intervention
Gentamicin/Polymyxin 20 capsules Selective intestinal decontamination
Hydroxycarbamide 100 mg, 300 mg, 500 mg capsules Non-marketed dosage
Maltodextrin powder 0.5 g, 1 g, 2 g, or 5 g Pediatric use
Misoprostol 25 mcg vaginal capsules Medical abortion, treatment of miscarriage
Paracetamol 30 mg suppositories Non-marketed dosage
Spironolactone 0.5 mg, 1 mg, 3 mg, 5 mg capsules Pediatric cardiology
Thalidomide 50 mg 30 capsules Multiple myeloma
Repacked products (liquids) Indication, use
HIV-PEP-Set Post-exposition prophylaxis HIV infection after accidental injection
Spinal-Set Bupivacain long acting Spinal anesthesia
Spinal-Set hyperbar Spinal anesthesia at Caesarean section
Suxamethonium HCl (Succinylcholine) 5 % Depolarising neuromuscular blocker
Closing scenarios are influenced by the lack of financial advertising (4 %), distribution (9 %), medical information
resources needed for investments, typically calculated for a (11 %), research and development (15 %).
pay-back-time of 10–15 years. Generally, hospitals do not It is generally recognised that production should be taken
have such sums at their disposal to match those of industry, over and scaled-up by industry as soon as a hospital’s capac-
where 10–15 % reinvestments of the annual volumes of ity is exhausted. The contrary is seen today as well. Hospital
sales are current. Benchmarking with industrial production should be able to provide products made in house as soon as
cannot be more than a virtual cost comparison, because the the industrial scale is not reached any more and withdrawal
two markets differ fundamentally and most of the products from the market is imminent. In times of good economic
of hospital production do not compete with industrial ones. prosperity and when medicine shortages were exceptional
In trade, sellers get paid for what they sell. In care, providers occurrences, and in order to reduce the risks arising from
get paid for what they do. As a result, it is even not important non-industrial production, some countries and governments
to analyse and compare cost structures. Some components of favoured limiting hospital pharmacy production and support
cost are only, or mainly, found in industry but not in hospital industrial production. Another approach was to limit the
pharmacies, e.g. gains (around 10 % of the ex-factory price), number of units producing on a small-scale depending on a
Table 3.6 Arguments for pharmaceutical production in hospitals

High added value for public health from a global point of view
Traditional role as a central item of public health
Favourable cost-benefit-ratio
Mandate to provide medicines
Independence from unreliable suppliers
Preservation of know-how, returns and employment in the region
Responsibility for the patient mix from the region
Reasons for various kinds of logistics of medicines
Indispensable logistic resource
Active substances either not commercially available or not available in the required dose or patient friendly form
Individual pharmacotherapy (paediatrics, ICU, etc)
Choice of most suitable container
Option to adapt formula or container or both
Unstable medicines: short shelf lives
Emergency situations following accidents, crises, catastrophes
Local clinical trials
Medicine safety items
Know-how in times of medicines shortages
Know-how for medicine selection and formulary definition of industrial standard products
Know-how for extemporaneous preparation and magistral formulations
Individual pharmacotherapy (paediatrics, ICU, etc)
Quality assurance (high quota of professional staff)
Multidisciplinary shared responsibility and assistance of pharmacotherapy
Protection from hazardous influences and incidences (antineoplastics)
Small patient population, e.g. suffering from hypersensitivity or contraindication to substances
Direct dispensing and application to personally known patients, to promote patient adherence
Optimal stocks (no intermediate stocks)
Economic values
Adapted and polyvalent intermediate chain production
Low transport cost
No setting aside of reserves for risks
No cost for intermediate trade margin
No advertising and marketing cost
Low cost for storage of standard products
No or low cost for research and development
Ecologic values
Recycling
Reduction of waste volume
Simplified disposal of waste
No unnecessary transports
Different objectives of industry (returns) and hospital (public health service)
Ad hoc production not for stock, but adapted to needs
Assortment of many products in small amounts rather than of few products in big amounts
Physicians as initiator of orders (patient-oriented), not management or shareholder (yield on shares)
Mandate for provision is also applicable for unviable products
risk assessment estimated from application, amount pro- products produced according to a formula published in pro-
duced per year, active ingredient, production process, and fessional literature, and products not equally available on the
client or patient respectively. No flexibility based on the market and distributed to the own patient or client.
number of beds or on the number of allied institutions was The EAHP has dedicated big efforts for animating and
planned. Above this quota, a market admission would be preventing hospital pharmacy production from decline. The
requested [85, 86]. Excepted from the need for a market need for flexible unimpeded preparation processes, the
admission are still the magistral or officinal formulations, option to bridge gaps between pharmacy and industry
preparation, and the added value of polyvalent hospital the triangle patient-physician-pharmacist. The supply of
pharmacy production have been clearly underlined at the pharmacy preparations from a preparing pharmacy to other
PATIENTS’ NEEDS
17th EAHP Congress in a seminar on the harmonisation of pharmacies therefore is usually not allowed unless they are
quality requirements according to the EC resolution part of the same business and unless the ordering pharmacist,
CM/ResAP (2011)1 [1, 87]. obtaining a preparation from elsewhere, is considered as the
manufacturing pharmacist in terms of responsibility. How-
ever, the centralisation of manufacturing facilities may
3.11 Legislation of Pharmacy Preparation ensure more control over the product quality and lead to
economic advantages. This awareness actually has led, in
Local laws may define preparation in a pharmacy as the many countries, to the situation that not every pharmacy is
complete or partial manufacture of medicinal products or able, any more, to prepare all medicines. In the Netherlands,
the packaging or labelling of them. As a result, a pharmacy the Health Care Inspectorate allows pharmacies to supply
comprises premises in which medicines are prepared, stored, other pharmacies with pharmacy preparations, on condition
and dispensed, or just stored to be dispensed. that these preparations are efficient, effective and safe
The allowance of preparation of medicines in the phar- according to professional standards. In the UK such
macy is not self-evident. The main aim of EU legislation is centralised units are licensed as manufacturing facilities by
to ensure that medicinal products have a license. This the Competent Authority (see Sect. 3.12). These centralised
requirement results in a comprehensive external control of pharmacies need to fulfil further quality requirements. Only
the efficacy, effectiveness and safety of the pharmaceutical the own pharmacy is allowed to prepare the pharmacy
quality. Medicines prepared in the pharmacy don’t have a preparations that do not need to have an equally highly
license and but pharmacy preparation is an allowed excep- documented level of quality control.
tion to this rule. The reason for this exception is the need for
some medicines which are not available with a license. The
exception is only applicable to the patients of the pharma- 3.12 Preparations’ Categories
cist, which should have a prescription from the treating
physician. The essence of the exception is limiting the Preparation in the pharmacy involves more activities than
patient’s risk of getting an ineffective, inefficient and unsafe preparation from raw materials only. It comprises (see
medicine by: Fig. 3.2):
• Restricting the medicines to patients the physicians and • Preparation from raw materials
the pharmacist actually care for • Preparation through adapting a medicinal product
• Putting the responsibility on physician and pharmacist • Reconstitution (in the strict sense as well as in excess of
Laws covering patient’s rights adds the patient’s own the SPC)
involvement to the responsibilities of physician and pharma- • Repackaging/Replenishing of medicines
cist. A physician has to exercise due care in prescribing and The definitions are as follows:
act according to the professional standard and to inform the Reconstitution: manipulation to enable the use or application
patient about the nature and purpose of the treatment and of a medicinal product with a marketing authorisation in
about possible side effects. The pharmacist is liable for the accordance with the instructions given in the summary of
quality of pharmaceutical products prepared in the pharmacy product characteristics or the patient information leaflet
in accordance with national laws and guidance on quality of (Ph. Eur. Pharmaceutical Preparations). Often reconstitution
care and for checking the reasonableness of the prescription. is needed in excess of the instructions of the summary of
Informing the patient about the nature of pharmacy product characteristics or the patient information leaflet,
preparations is not yet common practice in many countries. such as when a longer shelf life is assigned or when a
In the UK patient leaflets on this topic are available different dilution with an infusion solution takes place.
[88]. They explain both the preparation in the pharmacy This action is legally considered as preparation. When
and off label prescribing of licensed medicinal products. speaking about the actual work process, that is the handling,
Both situations have in common that physician and pharma- it makes no sense to distinguish between the processes.
cist will of course act according to disease-specific profes- Therefore this book uses the term ‘reconstitution’ for recon-
sional guidelines or following a documented risk stitution in the strict sense as well as for reconstitution in
assessment. excess of the summary of product characteristics or the
The legal limitation of the risks of pharmacy preparations patient information leaflet. If reconstitution is about paren-
to the patient focuses mainly on pharmacotherapeutic teral medicines, as is often the case, the term ‘aseptic
aspects. The government manages this risk by limiting the handling’ may be used in order to distinguish it from aseptic
application and responsibility of pharmacy preparations to preparation or processing.
Starting Material Process Legal status
No extra activity
Licensed
Reconstitution medicinal
Licensed product
medicinal
products Repackaging or replenishing
Dispensing or
administration
Reconstitution in excess of SPC instructions to the patient
Unlicensed
Pharmaceutical
Licensed Preparation by adapting the dosage form of an Preparations
medicinal existing medicinal product
products
Or
Raw
materials Preparation from raw materials
Fig. 3.2 Preparation types
Preparation through adapting a product: reformulating a inspected for compliance with GMP by the Competent
licensed product into a different dosage form suitable for the Authority, but the efficacy and safety of the products are
intended use, presented in a suitable and appropriately under the responsibility of the Pharmacist/Physician.
labelled container (after Ph. Eur. Pharmaceutical From the preparation point of view, the following types of
Preparations). pharmacies have evolved:
Preparation from raw materials: formulating active • Non-preparing pharmacies with the ability to perform
substances and excipients into a dosage form suitable for non-sterile reconstitution, and to counsel patients and
the intended use, presented in a suitable and appropriately carers on this process as well on the right way to handle
labelled container (after Ph. Eur. Pharmaceutical their medicines
Preparations). Apart from raw materials also concentrates • Pharmacies which prepare for their own patients and
or intermediate products may be used. often for other pharmacies with which they have a care-
Preparation from raw materials is not performed in link (both community and hospital pharmacies)
every community pharmacy any more. Not every hospital • Nationwide supplying pharmacies under special terms:
pharmacy prepares in full extent either. The community these pharmacies could be hospital pharmacies as well
pharmacist who is not preparing himself could think of as manufacturing sites which have the legal status of
referring the patient with a prescription which demands public pharmacies as in the Netherlands or commercial
preparation to a preparing pharmacy. Referring seems unde- organisations as in the UK
sirable, however, because pharmacotherapeutic assessment • Pharmacies with a distribution or packaging machine,
of the prescription, any potentially necessary adaptations of which supply on demand from other pharmacies
the dosage form, dispensing and instructions is best to be repackaged licensed medicines in units per administra-
performed by the pharmacist who is in contact with both the tion for named patients
physician and the patient. Hospital pharmacies are often There are several special situations in some European
requested to supply products, which should be made avail- countries. In the United Kingdom and in the Scandinavian
able for patients after discharge. In the UK, there are a countries, most preparations are prepared at and supplied by
number of hospital units and commercial companies prepar- central pharmacies. In Belgium, Germany and Portugal,
ing medicines under Manufacturers (Specials) Licence such a supply is prohibited, so pharmacies have to prepare
(MS) which allows the preparation of medicines according for their own patients. In France, a large hospital pharmacy
to a prescription or order from a pharmacy. The facilities are in Paris provides many other pharmacies with preparations.
In the US and in Brazil preparing pharmacies have been Spitalapotheke der Universitäts-Kinderklinik Zürich im Rahmen
established. Patients have to refer themselves with their des Neubauprojekts KISPI 2000, Diplomarbeit
Nachdiplomstudium Wirtschaft, Süddeutsche Hochschule Lahr
PATIENTS’ NEEDS
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Accessed 3 May 2013
Oral Solids
4
Minna Helin-Tanninen and João Pinto
Contents 4.9.1 Orientation and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

4.9.2 Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.9.3 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.9.4 Release Control and Quality Requirements . . . . . . . . . . . . . . . 70
4.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4.10 Modified-Release Tablets and Capsules . . . . . . . . . . . . . . . . 70

4.10.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.4 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.10.2 Physico-chemical Mechanisms on Active Substance
4.4.1 The Need for Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.2 Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.10.3 Desired Release Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.3 Dilution and Flowability of the Powder Mixture . . . . . . . . . 56 4.10.4 Dosage Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.4 Disintegration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 4.10.5 Matrix Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.4.5 Incompatibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.10.6 Reservoir Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.4.6 Colouring and Flavouring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.10.7 Adapting Modified-Release Preparations . . . . . . . . . . . . . . . . . 72
4.5 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 4.11 Herbal Oral Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.5.1 Homogeneous Powder Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.5.2 Colouring of Powder Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.12 Complementary Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.12.1 Containers and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.6 Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.12.2 Storage and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.6.1 Capsule Shells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.12.3 Advices on Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.6.2 Different Methods for Preparing the Powder Mass . . . . . . . 62
4.6.3 Filling of Capsule Shells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.6.4 Preparation of Coated Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.6.5 Release Control and Quality Requirements . . . . . . . . . . . . . . . 64
4.7 Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.7.1 Single-Dose Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Abstract
4.7.2 Multidose Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 This chapter provides the pharmaceutical basis of com-
4.8 Cachets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 mon solid dosage forms and discusses biopharmaceutical
4.8.1 Filling of Cachets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 aspects related to their formulation. There is a need for
4.8.2 Patient Instruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 customised capsules and powders, usually when the
4.8.3 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
required dose is not available as a licensed product and
4.9 Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 this dose cannot be obtained by splitting of tablets, as it is
in paediatrics. Swallowing problems may be another rea-
son. The aspects related to the excipients to be used and
Based upon the chapter Oral Solids by Christien Oussoren and Gerad factors affecting the processing of materials, and thus, the
Bolhuis in the 2009 edition of Recepteerkunde. performance of the final product are discussed in this
M. Helin-Tanninen (*) chapter. The design of formulations and quality control
Department of Pharmacy, Kuopio University Hospital, of powders and capsules are presented in detail. Attention
PO Box 100, KYS FI-70029 Kuopio, Finland is also given to a specific area of solid dosage forms
e-mail: minna.helin-tanninen@kuh.fi
namely, cachets and herbal teas.
J.F. Pinto The pharmacist can prepare capsules or powders from
Department of Pharmaceutics and Pharmaceutical Technology,
the pure active substance or, when this is not available, from
University of Lisbon, Av. Prof. Gama Pinto, 1640–003 Lisbon,
Portugal pulverised tablets and the contents of higher dosed capsules.
e-mail: [email protected] Non-coated tablets can usually be pulverised. Modified-

52 M. Helin-Tanninen and J.F. Pinto
release tablets or enteric-coated tablets can be processed and powders present unit dosage forms, which diminish the
in only a limited number of cases. Critical steps in the risk of giving wrong doses to patients.
preparation of solid oral dosage forms are discussed which Normally hard capsules are swallowed whole, but when
are the preparation of a homogeneous powder mixture and they need to be administered to infants, pharmacy-prepared
evenly dividing the powder mixture over the dosage units. capsules may be opened before administration and the
contents mixed with a small amount of suitable liquid or
soft food. However, solid dosage forms that provide flexible
Keywords dosing, such as fast dissolving granules (sprinkles) and
Cachet Capsule Herbal tea Powder Formulation uncoated mini-tablets may be preferable for paediatric
Preparation Solid dosage form Tablet Content patients because taste and smell can be masked and therefore
uniformity Excipients Adapting oral dosage forms compliance may improve [3].
Most industrially manufactured herbal medicinal
products are oral dosage forms. Liquid preparations (fluid
4.1 Orientation extracts, tinctures) have advantages as to dose flexibility but
an unacceptable taste can be a problem in clinical practice.
Solid oral dosage forms are dosage forms that are usually The latter can be circumvented by using solid oral dosage
swallowed to release the active substance at one or more forms containing a dry extract of the herbal medicine.
sites of the digestive tract mainly for a systemic effect Tablets and capsules with pulverized herbal active
[1]. Solid dosage forms can be a powder or a mixture of substances are also available commercially. Some herbal
powders, often further processed into tablets or hard medicines have to be taken as loose powders. A tea can be
capsules. The latter are the most common dosage forms prepared from pulverized herbal medicines, either loose or
delivered to patients [2]. in teabags, or from an instant herbal tea [4, 5].
The structure of this chapter is such that after orientation Further details on the characteristics and use, advantages
on the application of oral dosage forms and their definitions, and disadvantages of the respective oral dosage forms will
at first the general aspects of formulation and preparation of be given in the separate Sects. 4.6 (capsules), 4.7 (powders)
powder mixtures are dealt with. Specific information about and 4.8 (cachets).
the respective dosage forms are then given in separate
sections on capsules and powders (single dose, multidose
and cachets). 4.2 Definitions
This chapter discusses the formulation and methods of
preparation of the most used solid dosage forms that can be Solid oral dosage forms are described in the Ph. Eur. as oral
prepared in hospital or community pharmacies. The formula- powders, granules, capsules and tablets.
tion of licensed medicines, particularly tablets and capsules, is Oral powders are “preparations consisting of solid, loose,
discussed to such an extent as it is necessary to understand dry particles of varying degrees of fineness. They contain
how they are made in case they may have to be adapted for the one or more active substances, with or without excipients
preparation of other oral preparations in pharmacies. and, if necessary, colouring matter (. . .) and flavouring
Powders as such or encapsulated into hard shells substances. They are generally administered in or with
(capsules) are alternatives to tablets. They are needed for water or another suitable liquid. They are presented as
example to obtain appropriately sized dosage units for chil- single-dose or multidose preparations” [6].
dren. Both powders and capsules are relatively easy to pre- Similarly, granules are solid, dry agglomerates of powder
pare on a small scale. Often, pharmacists use commercially particles [6]. The Ph. Eur. distinguishes effervescent
available medicines as a starting point to prepare the dosage granules, coated granules, gastro-resistant granules, and
forms, rather than starting ab initio from the active pharma- modified-release granules, according to the stability of the
ceutical substance with selected excipients. Pulverised medicine and purpose of administration.
tablets (if possible) can be used for the preparation of Capsules are solid preparations with hard or soft shells of
capsules with a lower dose than the one present in tablets various shapes and sizes, which contain a single dose of one
intended for adults. Alternatively, the contents of capsules or more active substances, with or without excipients
can be diluted to provide the dose required by the patient. [6]. The Ph. Eur. describes hard capsules, soft capsules,
Stability is one of the main advantages of solid dosage gastro-resistant capsules, modified-release capsules and
forms compared to liquid ones. There is no need for cachets.
preservatives or other excipients (e.g. antioxidants) to Cachets consist of a hard shell containing a single dose of
enhance stability. Capsules, cachets and powders can be one or more active substances with excipients. The cachet
prepared with few and safe excipients. Tablets, capsules shell is made of unleavened bread usually from rice flour and
4 Oral Solids 53
consists of two prefabricated flat cylindrical sections. The Capsules release their contents when at least a part of the
Ph. Eur. considers cachets to be a category of capsules [6]. capsule shell is dissolved. The Ph. Eur. requires that capsules
Tablets are defined in the Ph. Eur. as “solid preparations disintegrate within 30 min [6]. However, the shell of gelatine
each containing a single dose of one or more active capsules usually dissolves within 3–15 min in the aqueous,
substances” [6]. Tablets are prepared by compressing acidic gastric lumen. The powder in capsules prepared in the
uniform volumes of particles or by another suitable pharmacy has not been subjected to a compression stage,
manufacturing technique, such as extrusion, moulding or as is the case of most industrially manufactured capsules.
freeze-drying (lyophilisation). The Ph. Eur. distinguishes Therefore, the content of pharmacy prepared capsules is
various types of tablets; the most important being uncoated usually released more quickly than industrial prepared
tablets, coated tablets, effervescent tablets, dispersible capsules.
tablets, gastro-resistant tablets and modified-release tablets. Oral powders (single-dose or multidose) and the contents
Modified-release tablets are defined in the Ph. Eur. as of opened capsules do not require the release of the active
preparations with a modified drug release rate, place, or substance from the dosage form. Therefore, only the disso-
time at which the active substance is released compared to lution rate of the active substance itself is important,
standard tablets [6]. Modified-release tablets include provided no agglomeration is observed and the crystalline
PRODUCT DESIGN
prolonged-release, delayed-release and pulsatile-release structure of the active substance has not changed during
tablets. manipulation and exposure to air. Consequently, pharma-
ceutical availability and absorption rate of sparingly soluble
or slowly dissolving powders are comparable to those of oral
4.3 Biopharmaceutics suspensions. Effervescent powders and powders that dis-
solve well in water (preferably dissolved prior to ingestion)
Active substances are only absorbed from the gastro- have a bioavailability which is (almost) equal to oral
intestinal tract in the dissolved state (see Sect. 16.1.5). Dis- solutions.
solution of the active substance should occur as fast as Tablets are compressed preparations, and therefore,
possible after administration if an immediate effect is require a disintegrating agent to promote their disintegration
intended. When an active substance is administered as a by swelling, dissolving or becoming effervescent in contact
capsule or tablet, it will not be immediately in contact with with water. Furthermore, the hardness of a tablet is impor-
the surrounding fluid. Thus, rapid dissolution of an active tant. The Ph. Eur. requires that non-coated tablets disinte-
substance from a capsule or tablet requires the rapid disintegrate within 15 min in water. Currently available
gration of the dosage form. The disintegration rate depends disintegrating agents allow the preparation of tablets which
on the quantity and type of excipients and the processing disintegrate within a few minutes.
conditions, as well as on the active substance itself, particu- In addition to the disintegration of a capsule or tablet,
larly when present in high fractions. Hydrophilic excipients absorption rate is determined by the dissolution rate of the
improve the penetration of water into the powder bed, hence active substance. The dissolution rate of the active substance
the wetting of the preparation (Fig. 4.1). depends on various factors, for example the solubility, the
Problems may arise in the presence of hydrophobic active particle size and shape, the crystal morphology, and wetting
substances or excipients that are not wetted easily. In these ability. Section 18.1 discusses the effects of these factors on
cases it may be necessary to add a disintegrating agent to the the absorption of the active substance.
formulation. Ingestion of a tablet should not always lead to a rapid
release. In a number of cases it may be preferred that the
active substance is not released directly, for example [10]:
The choice of a diluent may influence the absorption • The active substance degrades in gastric juice, or irritates
of an active substance, which was seen in the 1960s in the stomach wall (e.g. valproic acid).
Australia. The diluent of phenytoin sodium capsules • The active substance should exert its effect in a specific
was changed from calcium sulfate dihydrate to lactose, part of the intestine or should reach undamaged a specific
which strongly enhanced the bioavailability of phenyt- part of the intestine for absorption (e.g. mesalazine).
oin sodium. Plasma levels of phenytoin increased up to • Absorption of the active substance should be spread out
fourfold, which led to an increased reporting of evenly over a period of time to reach an appropriate
adverse events [8, 9]. This case drew worldwide atten- plasma concentration (e.g. morphine, theophylline).
tion and resulted in an increased awareness of the • The therapeutic benefits from a specific release pattern
importance of pharmaceutical availability and bio- over time (e.g. methylphenidate, for which it may be
availability of active substances in the development therapeutically relevant to have an immediate release of
of solid oral dosage forms. a small fraction of the dose whereas the largest fraction is
controlled released).
a d
Gelatine capsule with only hydrophobic active Gelatine capsules with hydrophobic active
substance particles ( ) substance particles ( )and a hydrophilic, in
water-soluble diluent ( )
b e
The content of the capsule remains in the The hydrophilic diluent particles dissolve in
gastro-intestinal tract as a solid mass. The the gastro-intestinal juices, resulting in a
hydrophobic nature of the particles hinders porous mass.
the penetration of gastro-intestinal juices.
c f
Gastro-intestinal juices penetrate the

porous mass.
The active substance can only dissolve from
the surface of the solid mass, resulting in a
low dissolution rate. g
The relatively large surface area results

in a relatively high dissolution rate of the
active substance.
Fig. 4.1 The effect of a hydrophilic diluent on the dissolution rate of a a–c: Gelatine capsule with only hydrophobic active substance particles.
sparingly soluble, hydrophobic active substance in a gelatine capsule d–g: Gelatine capsules with hydrophobic active substance particles and
(from McConell and Basit [7], with permission). a hydrophilic, in water-soluble diluent
4 Oral Solids 55
• The patient benefits from a less frequent dosing regimen, discuss these functions in relation to the required properties
i.e. the release occurs over an extended period of time of solid oral dosage forms.
(e.g. clomipramine). Modified-release tablets or enteric- The intrinsic properties of the active substance are diffi-
coating tablets do not release the active substance cult to change, but the pharmacist can choose the right
directly, but do so in a specific part of the gastro-intestinal excipients and preparation techniques to overcome or
tract, either delayed or with a specific release pattern. The decrease the impact of limitations. Although excipients
release of these tablets is adjusted to therapeutic needs of should be pharmacologically inactive, they may cause
the patient. adverse effects. The European Paediatric Formulation Initia-
tive (EuPFI) project is considering the suitability of
excipients for paediatric formulations. The results have
Pentasa® microgranules are an example of a dosage
been published in the STEP database [13]. For example
form designed to release the active substance
many colouring agents have been associated with hypersen-
(mesalazine) in a specific part of the intestines.
sitivity and other adverse reactions.
Pentasa® tablets disintegrate into microgranules fol-
lowing oral administration, whilst Pentasa® sachets
contain the microgranules as such. The release rate
PRODUCT DESIGN
4.4.2 Active Substance
of mesalazine from the microcapsules is pH dependent
(faster release at higher pH), which results in a contin-
Solid oral dosage forms are preferably prepared with the
uous release of mesalazine in the small and large
active substance as such. The particle size of active
intestines at all enteral pH conditions. After one
substances in fast-release preparations should preferably be
1,500 mg dose, approximately 60 % is released in
not larger than 180 μm to reach a compromise between
the small intestine, and 40 % is released in the large
dissolution rate and flowability. If the raw material consists
intestine. Mesalazine is partly metabolised by the
of particles that are too large, the particles should be reduced
intestinal mucosa to acetylmesalazine. About 30 %
in size (see Sect. 29.2).
of the ingested dose is absorbed in the small intestine,
When the active substance is not available as raw mate-
and 25 % in the colon (predominantly as
rial, tablets containing the active substance may be used,
acetylmesalazine) [11].
providing that both the tablet and the active substance are
suitable for processing into a capsule. Sometimes the active
substance is extracted by dissolution into a liquid but unfor-
tunately these solutions (especially aqueous liquids) cannot
4.4 Product Formulation be further used in the preparation of capsules because they
affect the gelatine shell. However, there are exceptions such
The design of the formulation of capsules and oral powders as macrogols of small chain lengths [14], which do not affect
and that of tablets are similar in some respects, but there are the gelatine.
also some important differences. In this section, the general Any processing of the active substances (e.g. milling,
aspects of formulation design are discussed. hydration), which may occur during preparation, can modify
their physical properties. This is probably not being noticed
by the pharmacist as he will not have methods at his disposal
4.4.1 The Need for Excipients to confirm changes of the active substances [15]. For this
reason, preparation of dosage forms should preferably be
It is usually not possible to prepare a capsule, oral powder or carried out starting from the raw material of which the
tablet from an active substance without the addition of any quality meets the requirements. Thus, the availability of
excipients. Firstly, the volume of the active substance is pure qualified active substances is advantageous for the
often very small; a diluent is necessary in order to handle preparation of adapted doses and reduces the risk of
the powder mixture. Secondly, the active substance may not manipulations of licensed products.
have good flow properties; these can be improved by addi- Highly soluble salts (for example sodium fluoride, potas-
tion of a glidant. Another reason to use excipients is that a sium chloride, potassium citrate) are preferably not prepared
preparation, consisting only of an active substance, may not in a capsule at all, since rapid dissolution can result in a high
disintegrate well in the gastro-intestinal tract; a local concentration that may be harmful to the mucosa of the
disintegrating agent can improve this. Many excipients com- gastro-intestinal tract. An enteric coating on capsules and
bine a number of such functions so the number of different tablets can protect the gastric mucosa from irritating active
excipients can be limited and the potential interactions substances. But the preparation of an oral solution of the
between materials can be minimised [12]. The next sections active substance may be a better alternative.
4.4.3 Dilution and Flowability it is insoluble in water forming a suspension. Secondly, the
of the Powder Mixture active substance may adsorb onto cellulose particles, which
may reduce both solubility and dissolution rates of sparingly
Solid oral divided dosage forms are prepared by dividing a water soluble active substances, and thereby the active
mixture of the active substance and excipients evenly over a substance’s relative pharmaceutical bioavailability. Micro-
dosing mould, so every unit corresponds to one dose. In the crystalline cellulose causes no systemic adverse effects,
case of capsules or oral powders, the powder is spread over because humans do not absorb it [12, 20].
the capsule shells or powder papers, respectively. Moulds Lactose (alfa-lactose monohydrate) (see also Sect.
should be filled evenly. Therefore, good flowability is 23.4.4) has somewhat less favourable flow properties than
required. microcrystalline cellulose PH102. A disadvantage of lactose
The flowability of a powder (mixture) can be tested in is its incompatibility with primary amines. An advantage
several ways but a relevant impression for small-scale prep- compared to microcrystalline cellulose is that it is water
aration is obtained from observation during mixing soluble, which makes lactose suitable for capsules where
[16]. When the mixture is dusty, sticky, or when segregation the contents have to be dissolved. Capsules containing lac-
of components occurs, other excipients should be used or a tose disintegrate as a result of the dissolution of lactose
glidant has to be added. Even if the mixture looks all right, (Fig. 4.1). Its use might be limited in patients with lactose
powder flow may not be good enough. Insufficient flow will intolerance [12].
lead to uneven filling of the separate capsules and tablet Dried (corn, rice or potato) starch (see also Sect. 23.4.1)
moulds, and ultimately result in too large a weight variation. has good flow and disintegrating properties. It is used occa-
By preparing trial batches with various filling agents and sionally as a diluent in capsules for the processing of hygro-
glidants, and comparing the weight distributions, the powder scopic substances. Starch is extracted from plant material
formulation with the best flow properties can be selected. and subsequently dried. The water content should be below
Flowability of powder can be measured directly (flow 5 %. During a few hours of exposure to air with a relative
through an orifice) or indirectly (angle of repose or tapped humidity of about 60 %, dried starch will take up 5 % of
and bulk densities) [17]. water.
Powder flowability is influenced by [18]:
• The particle size: powders consisting of many small
particles tend to show a poor flow. 4.4.3.2 Glidants
• The particle shape: a more regular shape promotes good If not enough diluent is present, or if the powder does not
flow properties, particularly the spherical shape. flow sufficiently despite the presence of a relatively large
• The surface of the particle: a smoother surface results in quantity of diluent, the addition of a glidant can be consid-
better flow properties. Furthermore, the surface of ered. When a glidant is required for the preparation of
particles can be modified to improve the flow properties. capsules, preferably colloidal anhydrous silica (Aerosil
• The moisture content of the powder (this can vary under 200 V) is used in a fraction of 0.5 %. However, it has a
ambient conditions): the powder flows better when the tendency to adsorb onto active substance particles, so the
moisture content is low, but too low will generate static application should be investigated beforehand. Magnesium
electricity. stearate can be used as an alternative, but it is not preferred
• Electrostatic charge: removing the charge improves the because its hydrophobic nature may negatively influence the
flow properties. wetting and dissolution rate of the active substance.
A glidant does not always improve the powder
4.4.3.1 Diluents flowability, for example when the active substance is
Addition of excipients such as a diluent with good flow micronised. The cohesion forces between the small particles
properties may improve the flow properties of a powder. may be too large to be overcome by a glidant. Moreover,
Diluents are added to powder mixtures also to increase the when the poor flow properties of the powder are due to
mass and volume of the active substance. Very small irregular particle shapes, a glidant will not have much effect
amounts of active substances often require a carrier to ensure either.
their uniform distribution in the dispensed product, and to Addition of a glidant could be counterproductive because
guarantee an accurate dose [19]. of [21]:
The most often used diluent for capsules and powders is • Segregation: glidants may displace the active substance
microcrystalline cellulose (Avicel PH 102 or Pharmacel particles that are bound to a carrier by ordered mixing
102, see also Sect. 23.4.1). Microcrystalline cellulose has (see Sect. 4.5.1). The small particles that are displaced
both proper flow and disintegrating properties. However, may decrease the flowability and the powder mixture may
microcrystalline cellulose has some drawbacks. For instance segregate.
4 Oral Solids 57
• Segregation and loss: a glidant may also increase the Table 4.1 Prednisolone Capsules 10–40 mg [22]
flowability too much. Small particles may move too eas- Prednisolone micronised 10–40 mg
ily between the large particles, which may lead to segre- Primojel capsule diluent (Table 4.2) >200 mg
gation of the powder with the large particles on top and Capsules size 2
the small particles at the bottom. Moreover, particles may
fall between the capsule shell and the capsule filling
apparatus, resulting in loss of active substance content.
Table 4.2 Primojel Capsule Diluent [22]
• Incompatibilities: glidants may cause degradation of
other substances. For example, magnesium stearate may Calcium hydrogen phosphate dihydrate, heavya 94 g
react with acids. Silica, colloidal anhydrous compressed 1g
• Reduced dissolution rate: magnesium stearate is hydro- Sodium starch glycolate (type A)b 5g
phobic and forms a hydrophobic layer on the surface of Total 100 g
the powder particles. Therefore, the dissolution rate of the a
Di-Cafos® DC 92–14
active substance may be reduced. b
Primojel®
• Reduced pharmaceutical availability: colloidal silicon
PRODUCT DESIGN
dioxide has a large surface area, which may facilitate
adsorption to the active substance. This may reduce the
pharmaceutical availability of the active substance. During an investigation into the optimal formulation of
a well flowing powder for the preparation of Predniso-
lone capsules, microcrystalline cellulose with anhy-
4.4.3.3 Binding Agents drous colloidal silica failed to give a mean content
Binding agents combine the diluent function – and thus meeting the requirements [22]. Apparently the electric
improve flowability – and the binding function mainly used charge was not neutralised and prednisolone was lost
in direct compression of tablets. These excipients increase through flying up and through the exhaust. Calcium
the mass and promote the bonds between particles of other monohydrogen phosphate dihydrate in combination
materials in the formulation, so in fact they lead to, desired, with colloidal silicon dioxide gave the best results.
agglomeration. In direct compression the powder mixture is However, due to the lack of disintegrating properties
not granulated before compression. Therefore, binding of calcium monohydrogen phosphate dihydrate, a solid
agents should improve flowability without segregation of mass remained after dissolving of the capsule shell.
the mixture. Only capsules with prednisolone, calcium
In direct compression tablets, microcrystalline cellulose monohydrogen phosphate dihydrate, silicon dioxide
of various grades is used as a binding agent. Generally the and the disintegrating agent sodium starch glycolate
PH101 grade with a mean particle size of 50 μm and the disintegrated giving a desired dissolution rate.
PH102 grade with a mean particle size of 90 μm are used.
The PH101 grade flows poorly, not only because of the small
particle size, but also because of the needle like particle
shape. The PH102 quality flows better because half of the
particles are granulated. 4.4.4 Disintegration
Calcium monohydrogen phosphate dihydrate is used in
granulated grade as a binding agent in tablets prepared by Capsules disintegrate when the capsule shell dissolves and
direct compression. Since the binding properties are quite the powder mixture is wetted. Hydrophilic excipients pro-
poor, it is usually combined with another binding agent. In mote the wetting of the powder bed (Fig. 4.1). Due to the low
capsules calcium monohydrogen phosphate dihydrate is compaction of the encapsulated powder, and the easy disso-
used when none of the common diluents are suitable, for lution of most diluents for capsules, the addition of a
example for the processing of corticosteroids (Table 4.1). In disintegrating agent is often not needed for pharmacy
spite of its hydrophilic nature calcium monohydrogen phos- preparations. However, when excipients compact easily
phate dihydrate has neither disintegrating properties, nor it is (e.g. calcium monohydrogen phosphate dihydrate) a
water-soluble, therefore, addition of a disintegrating agent is disintegrant is recommended.
required. Primojel Capsule diluent FNA is a diluent for Disintegrating agents act through swelling or by promot-
capsules that contains, besides calcium monohydrogen phos- ing water penetration through capillary action or even by the
phate dihydrate, the disintegrating agent sodium starch production of a gas (e.g. effervescence) (see Fig. 4.1).
glycolate A (Primojel®) and the glidant silica colloidal Highly compressed powders or granulates in tablets are
anhydrous (Table 4.2). more difficult to disintegrate, thus, the addition of a
disintegrating agent is often required for immediate release 4.4.6 Colouring and Flavouring
of the active substance.
The diluents microcrystalline cellulose and lactose have A capsule or tablet that is swallowed as such is almost
some disintegrating properties. When these diluents are used tasteless, because only a small part of the active substance
in capsules, the addition of a separate disintegrating agent may comes into contact with the palate. Therefore taste masking
not be necessary, or it is used only in smaller fraction than in is generally not necessary. If taste masking is required for
tablets. However, when a diluent without disintegrating tablets, a coating can be applied. Patients who cannot swal-
properties is used, such as calcium monohydrogen phosphate low capsules receive either a powder or the contents of a
dihydrate, a disintegrating agent has to be added, particularly capsule. The direct contact between powder and palate
5 % of sodium starch glycolate [23]. For instance sodium results in a distinct taste sensation. Many active substances
starch glycolate exerts its disintegrating effect by strongly have an unpleasant taste and thus flavouring, sweetening and
swelling in the presence of water, which leads to the breaking even colouring of the powder are vital to patient compliance.
of bonds in the powder bed or tablet. Lactose disintegrates Taking the powder with food – e.g. yoghurt or custard – can
powder beds by dissolution in water. However, tablets for also be an adequate way to mask the taste, particularly for
immediate release of active substances always contain a children, which are very sensitive to organoleptic properties.
disintegrating agent. One of the scopes of a large European research project on
children’s medicines is to discover more about masking taste
and smell in oral dosage forms [26].
One cannot simply add a flavour to a dosage form
4.4.5 Incompatibilities
containing a unpleasent tasting active substance and expect
it to taste good because the strength of tastes are different or
The most important incompatibility in capsules is the
different receptors are sensitised. Flavours are complex
adsorption of active substances to excipients and vice
mixtures that are made up of many chemicals. Flavouring
versa. Sparingly water-soluble active substances may adsorb
agents can be natural (essential oil, derivatives from fruit
to non-water soluble excipients such as microcrystalline
vegetable juice) or artificial (see Sect. 5.4.10). In particu-
cellulose (diluent). On the other hand, the very fine glidant,
larly, natural flavours may have dozens of different types of
colloidal anhydrous silica, can adsorb onto active substance
molecules, which may interfere with the active substance.
particles. Especially for low dosed active substances, rela-
In some cases it may be desirable to colour the tablet or
tively large fractions may adsorb or be adsorbed. Such
capsule, for example to prevent a mix-up of medicines or to
adsorption may delay the dissolution of the active substance,
prepare placebos with an appearance identical to the original
resulting in a delayed or incomplete release of the substance.
tablets for use in clinical trials. In case of capsules, it is
This may lead to a reduced pharmaceutical availability and
possible to use coloured capsule shells, or to prepare a
ultimately a lower therapeutic activity. Substances known to
coloured powder mixture in transparent capsules. Colouring
adsorb to microcrystalline cellulose are ethinylestradiol and
agents should be used with caution, because they can cause
dexamethasone [24].
allergic reactions. The use of coloured capsule shells is
Due to the absence of water, which catalyses many chem-
preferred, but if it is necessary to colour the powder mixture,
ical reactions, chemical incompatibilities rarely occur in dry
a colouring agent can be added. Section 23.11 lists colouring
dosage forms. One exception is the incompatibility of the
agents for powder mixtures. Tablets can be coloured by
excipient lactose with primary amines, such as amphetamine
using soluble (for wet granulation) or insoluble (for direct
and lisinopril. The rate of the reaction (Maillard reaction) is
compression) colouring agents. Moreover, tablets are often
slow in absence of water, but may lead to yellow
coloured by processing of a colouring agent in the coating.
discolouration during storage [25].
Thus the pharmacist must be careful when choosing the
excipients. Pre-formulation studies to identify incompat- Patients with Addison’s disease or Cushing’s syn-
ibilities can be time-consuming but are required to prove drome take steroids two or three times a day in various
that no instability of the active substance will occur during doses, depending on the time of the day and the situa-
preparation and storage. In the case of the use of licensed tion. Commercially available tablets may not always
products to prepare capsules or powders, it might be difficult contain the dose they need. Moreover, tablets with
to obtain information from the manufacturer. Thus, it is different doses are not always easy to distinguish.
usually safe to dilute crushed tablet with the excipient that For these patients, capsules with a dose-related colour
is used in the tablet formulation, based on the market can be a solution [27].
authorisation holder who has ensured their compatibility.
4 Oral Solids 59
the ground mass; this dilution sometimes having to be quite

4.5 Method of Preparation considerable, even a 100-fold.
Coated tablets, such as enteric-coated tablets, and
The preparation of solid oral dosage forms consists of two modified-release tablets are better not split or pulverised,
steps. The first step is the preparation of a homogeneous because their specific features may be lost. If it is absolutely
powder mixture, and the second step is the even distribution necessary to break them then the pharmacist must know
of the powder mixture over the dose units. Mixing of solids beforehand the implications on the stability of the medicine
to obtain a homogeneous mixture is in principle the same and on its therapeutic effect (see Sect. 4.9). A controlled-
process whether capsules, powders or tablets are prepared. release tablet that has been split may overdose. Splitting may
However, the requirements regarding the filling of the dose also expose the taste of the medicine, which had originally
units are different for the three types of preparation. been masked in the coated tablet. Only standard, non-coated
Mass for oral powders is easy to prepare but time- tablets shall readily be processed into a powder mixture.
consuming to divide. The solids are mixed together and To obtain the required amount of active substance the
subsequently the powder mixture is divided evenly over equivalent amount of whole tablets are counted. It is preferable
the powder papers. The same applies to cachets. The prepa- to use several tablets to level out content differences between
ration of capsules is quick but somewhat more complex,
PRODUCT DESIGN
tablets. In principle there are two ways: take an exact, counted
because the powder mixture should have a fixed volume, number of tablets to pulverise, or to use an excess of tablets in
which is determined beforehand. Next, the powder mixture pulverising and then weighing the required quantity. If an exact
has to be divided evenly over the capsule shells. The prepa- number of tablets is used, the resulting mean content of active
ration of tablets is in this regard more complex. Tablets are substance in the final product has to be validated.
made with a tableting machine (see Sect. 28.7.3 for some A strict method of grinding is needed to avoid the loss of
brands), which imposes extra requirements to the flowability active substance for example due to static charges or to
of the powder mixture. To minimise flow and segregation sticking of tablet components to utensils such as mortar,
problems, powder mixtures are often granulated before pestle and tablet crusher device. This loss of active substance
compression. can be compensated beforehand by taking an excess of
tablets. Note, however, the risk of calculation errors in that
case. There is some loss of active substance also during
4.5.1 Homogeneous Powder Mixtures administration, i.e. taking the powder from folded paper or
emptying the capsule, and the loss seems to be higher in
4.5.1.1 Particle Size low-weight single-dose powders (Fig. 4.2).
Particle size of the constituents for powders range com- Tablets are crushed manually in a non-porous mortar with
monly from 10 μm up to 180 μm. For the preparation of a a pestle. After careful grinding the resulting powder may be
homogeneous mixture, the solids preferably have compara- more or less homogeneous (Fig. 4.3).
ble particle sizes, densities, shapes and equal mixing ratio The properties of all excipients present in the tablet must
(see Sect. 4.4.2). Particles with unequal sizes mix poorly and be considered for their possible effects on the final prepara-
may segregate easily. Segregation, for example during the tion, such as weight variation, disintegration time, dissolu-
filling of the capsules, may lead to a large weight variation tion characteristics and in vivo performance. The lower the
and a bad content uniformity. In practice, the maximum proportion of the active substance present in the mixture, the
particle size for the active substance is 180 μm, unless a more difficult it is to achieve a sufficient homogeneity. In
delayed release effect is envisaged. Larger particles have a Sects. 4.9 and 4.10, the formulation of tablets and the
relatively small surface area, which may result in a too low possibilities to process coated or modified-release tablets in
dissolution rate (see Sect. 18.1). When the particles of the capsules are discussed.
starting material are larger than 180 μm, the material should
be ground and, if necessary, sieved. However, grinding by 4.5.1.3 The Mixing Process
hand (triturating) of materials that are already fine enough Geometric dilution is used to ensure that small quantities of
should be avoided, because it may introduce agglomerates. ingredients are uniformly distributed in the powder mixture,
starting with the ingredient in the smallest quantity. Then a
4.5.1.2 Starting from Tablets or Capsules volume of powder equal to the volume of the powder mixture
Real challenges for the preparation of the powder mixture in the mortar is added and triturated with a pestle to a uniform
arise from the situation in which tablets or capsules are mixture. Then the mixture of the two components is mixed
needed to get access to the active substance. In the first again with an equal quantity of diluent. This process is repeated
place the pharmacist has to consider the suitability for grind- until all solids are mixed. Triturating and small-scale mixing is
ing or crushing of the tablets or capsules and then he has to performed in a mortar with pestle (Sect. 28.6.4). For larger
develop a reliable method to produce the required dilution of quantities a mixing apparatus needs to be used.
1.00
0.90
0.80
0.70
nifedipine (mg)
0.60
0.50
0.40
0.30
0.20
0.10
0.00
50 80 100 130 200 300 500
oral powder capsule oral powder capsule capsule oral powder oral powder
total weight (mg)
Fig. 4.2 Nifedipine contents in single-dose powders or capsules that powders weighing 50 mg, 100 mg, 300 mg and 500 mg. Mean values
were meant to contain nifedipine 1 mg as active substance (from are shown (n ¼ 10). The higher content of nifedipine can be observed
crushed tablets Adalat® 10 mg retard) and microcrystalline cellulose in all sizes of capsules compared to oral powders of 50 mg or 100 mg.
(MCC) as a diluent. The batch size was 50 single-dose powder or According to this study the use of different sizes of capsules would lead
capsules and no excess tablets were used. Capsules number 4 (80 mg to an acceptable content while oral powders should weigh at least
MCC), 3 (130 mg MCC) and 1 (200 mg MCC) are compared to oral 300 mg [28]
Mixing should be performed in such a way that the

following problems are avoided:
1. Adsorption of the active substance to the pestle, mortar,
measuring cylinder or the mixer. Adsorption of active
substances may be reduced by minimising direct contact
with utensils. Therefore, the active substance is best put
in between the utensils and the excipient (‘wrapping
method’, see Sect. 4.6.2). Mortars need to be
non-porous so that no active substance remains in the
pores to decrease the dose or to contaminate the next
product to be prepared.
2. Suctioning of the statically charged active substance with
the airflow, since mixing of powders is generally
performed in the presence of dust extraction. If it is
assumed that substances are selectively suctioned when
they become statically charged, this can be avoided by
selecting excipients (e.g. colloidal anhydrous silica) that
can neutralise the static charge, by reducing the mixing
time to the minimum, and by avoiding whipping too
much air into the mixture. A powder that is too fluffy
can be compacted slightly to change the surface
Fig. 4.3 Particle size variation in the manually (in a mortar with a
pestle) crushed Nifedipine tablet (Adalat® 10 mg retard). Scale bar in properties by the addition of a few drops of alcohol,
SEM is 100 μm [29] water or liquid paraffin.
4 Oral Solids 61
4.5.2 Colouring of Powder Mixtures

In the past, homogeneity of powder mixtures was
assessed by processing a colouring agent in the powder Capsule contents can be coloured by using a coloured
mixture. It was assumed that when the colour was powder mixture as diluent. Powders can be coloured with
spread homogeneously over the mixture, the entire water-soluble, or water insoluble colouring agents (see
mixture was homogeneous. However, this method Table 23.26). Water-soluble colouring agents should be
may not be suitable for two reasons. First, a homoge- dissolved in order to produce an even distribution over
neous distribution of a colouring agent is not a guaran- the diluent. The use of water to promote the dispersion of
tee that the active substance is distributed evenly over the water-soluble colouring agent may cause granulation
the mixture as well. The physical properties of solids, of particles. To prevent or minimise this event the addi-
such as particle size and adsorption onto other tion of the solution to the powder must be slowly and
substances, determine the quality of the mixing. with continuous stirring. Water is a safe solvent for
Differences in properties of colouring agent and active everyone, but evaporates slowly. Ethanol in a concentra-
substance may result in a different distribution for both tion of more than 90 % evaporates quickly, but the use of
substances. A second reason is that colouring agents organic solvents has to be considered carefully because
PRODUCT DESIGN
may cause hypersensitivity. of the possible residues. Water-insoluble colouring
agents, on the other hand, mix well with the diluent in
the dry state.
4.5.1.4 Solvent Method

Mixing of powders with unequal volumes often results in 4.6 Capsules
non-homogeneous mixtures, because it takes more patience
to obtain a homogeneous mixture than when two equal parts Capsules are probably the most versatile dosage form
are mixed. However, small amounts of active substances prepared in the pharmacy. Capsules may contain one active
simply need to be mixed with a large quantity of diluent to substance or a mixture of active substances, usually a diluent
obtain a processable powder mixture. In case of an inconve- and sometimes a glidant or a disintegrating agent or both.
nient mixing ratio, the solvent method might be applicable, Capsules are easy to swallow and can enclose active
if validated carefully. The method has to be investigated for substances with an unpleasant taste. Capsules can be
a specific active substance and standardised formulation. prepared in the range of few units up to hundreds of thousand
Unfortunately the solvent method often appears not to be units. Further advantages, namely by comparison to tablets,
appropriate because there is no suitable solvent, or because are the small number of excipients required to prepare
the active substance is not stable in solution. capsules, and the possibility of having non-compressed
The solvent method basically distributes a small quantity powders, allowing a faster dissolution of the active
of active substance (5 mg or less per dose unit) over a diluent. substance.
The active substance is dissolved in a suitable, volatile sol-
vent, usually in a stainless steel mortar to be able to check if
dissolution is completed. -Subsequently, the solution is mixed 4.6.1 Capsule Shells
with a carrier that does not dissolve in the solvent. The
moistened powder is triturated –until the solvent has Capsules consist of a shell made of a structural polymer
completely evaporated. The powder mixture now consists of (e.g. gelatine, hypromellose, starch) together with other
carrier particles with a coating of the active substance. This excipients that allow the preparation of the shell itself
method is in fact a combination of simultaneous particle size (e.g. plasticizers) or provide some functionality to the shell
reduction and mixing. Another advantage of this method is (e.g. titanium oxide for making capsules opaque). Gelatine is
the reduced loss of the powder mixture during mixing. often extracted from animals (e.g. pig), that is why some
The solvent should comply with a number of requirements: people doesn’t want to ingest them. The pharmacist must
• The active substance has to dissolve well in the solvent, consider possible interactions between the active substance
but not the carrier. or the excipients and gelatine. Alternatively, ‘vegetarian’
• The solvent has to be volatile enough in order that the capsules exist, which consist of gelatine from algae or of a
powder will dry within a limited period of time. cellulose derivative.
• The solvent has to be non-toxic, because a residue of it Empty capsule shells are stored at room temperature in
will always remain in the powder mixture. tight containers that maintain a constant, adequate relative
• The active substance has to be stable in solution. humidity. The Deutsche Arzneimittel Codex (DAC)
For practical examples of this method see Sect. 4.6.2. describes the test for dissolution of capsule shells: empty
capsules should dissolve or at least open in less than 15 min

[30]. Incorrectly stored capsules do not dissolve, they just A way to determine the volume of capsule shells to
swell. Furthermore cycles of high and low humidity and resort to if all other information has been lost, is by
temperature damage the shells irreversibly. filling them with a liquid of known relative density,
In pharmacies hard capsule shells consisting of a body such as ethanol 96 % V/V. Ethanol of high concentra-
and a cap with a locking mechanism are by far the most tion evaporates quickly, so the lower concentrations can
used. These shells come in various sizes: size 5 being the also be used. If pure water is used, a pharmacist must be
smallest and size 00 the largest. Many patients experience fast in a measurement because capsule shell begins to
difficulty in swallowing large capsules. Usually capsule dissolve. From the weight of the capsules and the den-
sizes 1 or 2 for adults and size 3 or 4 for children are used sity of the liquid, the absolute volume can be calculated.
in pharmacy preparation. In some cases the patient is The filling volume determined following this method
instructed to open the capsules to take the contents with does not depend on the filling procedure or the diluent;
food or dissolve it in water, provided that capsules can be it is the volume usually provided by manufacturers.
opened and the drug can be given without the protection of Alternatively, one can use liquid dropping from a
the capsule shell. pipette and the volume of liquid used corresponds to
the volume of the shell’s body.
Four methods will be described for the preparation of

4.6.2 Different Methods for Preparing
powder mixtures for capsules. These methods are about
the Powder Mass
mixing of varying ratios and the preparation of a powder
mixture from capsules and tablets.
As an addition to the general method of preparation of a
powder mixture, for capsules some specific directions apply.
Capsules are filled by volume, therefore, the powder mixture 4.6.2.1 High Dose Method
should be prepared to obtain a specific volume. The correct For capsules with a relatively high dose (>50 mg), first the
volume depends on the capsule size and the number of active substances and, if necessary, the glidant are mixed
capsules to be filled (Table 4.3). following the geometric dilution method (see Sect. 4.5.1.).
The volumes in the table are derived from filling capsules Next, the volume of this mixture is determined using a
with microcrystalline cellulose by tapping lightly or no measuring cylinder, and a diluent is added up to the required
tapping at all. For small batches of small sized capsules no volume without too firmly tapping to prevent too much
numbers are given because preparation cannot be performed compression of the mixture. This mixture is emptied from
reliably. However, even under these circumstances the the cylinder and mixed again. For this method, it is assumed
volume may slightly vary. Moreover, filling capsules with that the losses are relatively small and relatively little
a different diluent or according to a different method, may amount of diluent is needed. The method is based on the
influence the filling volumes. bulk density of the powder mixture, i.e. the density of a bulk
Smaller capsule sizes should not be prepared in small which volume has been measured in a volumetric cylinder,
batches, because a relatively large loss during mixing and for instance.
filling may result in a too low content. Moreover, the mass
deviation and thereby content deviation may become too 4.6.2.2 Low Dose Method
large for such batches, because a small quantity of powder The preparation method for capsules with a relatively low
is hard to divide evenly over the capsules. dose of active substance (50 mg) has been developed to
prevent loss of the active substance. Losses occur mostly
during determination of the volume of the active substance
in a measuring cylinder. Mixing the active substance before-
Table 4.3 Volumes of microcrystalline cellulose filled in hard gela- hand with a known volume of diluent can reduce this loss.
tine capsule shells (in cm3)
So, the volume is determined after mixing of the active
Capsule size substance and diluent. There are two methods of mixing.
Number 00 0 1 2 3 The traditional method of equal parts, geometric dilution,
20 18 13 can be used for capsules with 10–50 mg active substance.
30 28 20 14 11 For less than 10 mg active substance, it is advised to use the
50 46 34 24 19 14
wrapping method. The wrapping method is meant to mini-
60 55 40 29 22 17
mise loss of substances that are static, sticky or coloured. For
90 83 60 43 33 25
this method, at first a layer of diluent is placed in the mortar.
100 92 67 48 37 28
The active substance is added on top, and is covered with
(continued)
4 Oral Solids 63
Table 4.4 Solvent method developed for some low dose capsules
Active substance
and dose: Solvent and amount Deposition and ratio: Diluent Reference
Colchicine Methylene chloride 2 9 mL Diluent 100 times the amount of Microcrystalline cellulose [31]
for 162 mg colchicine colchicine
Diazepam Methylene chloride 2 3 mL Diluent 20 times the amount of diazepam Microcrystalline cellulose [32]
for 120–300 mg diazepam
Ethinylestradiol Acetone 2 3 mL for 100 mg 2 g Colloidal anhydrous silica, Lactose [32]
ethinylestradiol compressed, for 100 mg ethinylestradiol
Hydrochlorthiazide Acetone 2 3–5 mL for 3 g diluent Mannitol with 0.5 % m/V Colloidal [33]
0.5–5 mg 15–150 mg hydrochlorthiazide anhydrous silica, compressed
another layer of diluent. The two layers of diluent that 4.6.2.4 Preparation from Tablets
surround the active substance prevent direct contact with The tablets may be crushed and the resulting powder used as
the pestle and mortar, thereby reducing losses. a source of active ingredient following a low dose method
PRODUCT DESIGN
(see Sects. 4.5.1 and 4.6.1). Addition of a glidant is generally
4.6.2.3 Solvent Method not necessary, because it is already present in the tablet. The
The solvent method is preferably used for mixtures with very final product also contains excipients from the original dos-
unfavourable mixing ratios (<5 mg active substance). This age form, which would have not been necessary if a prepa-
method (see Sect. 4.5.1) needs careful testing and validation. ration from the pure active substance was considered.
For some active substances the solvent method has been When encapsulating tablets for blind studies, the tablet
developed (Table 4.4). If the substance is not listed, the containing the active substance is concealed in a capsule
powder mixture can only be prepared following the low designed for clinical trials. Tablet as a whole may, or may
dose method. not be embedded in powder that has been placed previously
into a capsule shell.
For illustration of the solvent method, the preparation

process of Hydrochlorothiazide capsules NRF [33] is
4.6.2.5 Preparation from Other Capsules
Capsules available as authorised medicines can be the source
quoted:
of the active substance. The capsules have to be opened and
• Hydrochlorothiazide is rapidly dissolved in the first
emptied to obtain the active substance that will be processed
portion of acetone in a metal mortar while mixing
further into the new capsule. Sealed capsules can be difficult
(in process controls: no undissolved crystals; not
to open. If so, use a blade to open the capsule, or smash the
more than 50 % acetone has evaporated).
capsules in a mortar and sieve the contents to remove the
• First portion diluent is mixed with the
smashed shell pieces.
hydrochlorthiazide solution, avoiding excess
force. The mixture has to be loosened from the
side of the mortar and the pestle at least two 4.6.2.6 Supplementing to Volume
times. The mixture has to be removed from the For all methods described above, the final step is to add a
mortar and kept aside (in process controls: powder diluent up to the required volume. Mixing may result in
mixture should be fine again and not smelling of volume contraction, which means that during mixing the
acetone). total volume becomes smaller than the sum of the volumes
• Second portion of acetone is used to rinse mortar of the separate powders. Volume contraction results from
and pestle. small particles creeping in between larger particles. As a
• Second portion of diluent is mixed with the rinsing consequence a relatively large amount of diluent is needed
solution, avoiding excess force. The mixture has to to bring the powder mixture to the volume required, i.e. the
be loosened from the side of the mortar and the total volume of the bodies of the shells to be filled. An uneven
pestle at least two times. The mixture has to be distribution over the capsules may be obtained when the
removed from the mortar and kept aside volume of the powder mixture is too small. Therefore, it is
(in process controls: powder mixture should be important to adjust the volume prior to filling the capsules.
fine again and not smelling of acetone). It must also be pointed out that the measurements in a
• Mixing of both powder mixtures avoiding excess measuring cylinder should be made with care, particularly to
force. avoid tapping the cylinder, otherwise the bulk density may
• Etcetera (adding diluent, mixing, filling capsules). be increased too much and thus ensuring a failure of the
capsule filling process. This may result in a considerable
fraction of the mixture no longer fitting into the available information on the large-scale equipment for coating
volume. capsules can be found in the literature [14].
4.6.3 Filling of Capsule Shells 4.6.5 Release Control and Quality

Requirements
In the pharmacy, capsule filler equipment for 60 or
100 units is used most frequently, but equipment able to This section discusses the non-destructive controls on
fill up to 300 shells are available. For the filling of smaller appearance, average weight and weight distribution. When
numbers of capsules, the holes in the filler can be partly capsules comply with these specifications, and when they are
covered with paper or tape. An even distribution of the filled with a homogeneous powder mixture, they comply
powder mixture over the filler is essential, which can be with the Ph. Eur. monograph ‘Capsules’. When the capsules
obtained by good flowability of the powder mixture and a do not comply, either the batch should be rejected, or a full
correct spreading technique: the placing of a large quantity analysis according to the Ph. Eur. should be performed.
of powder on top of only a section of the capsule bodies in After this analysis, the batch can either be approved or
the equipment should be avoided. The method to fill rejected. More information on the quality requirements for
capsules using capsule filler equipment is described in capsules can be found in Chap. 32 (for instance Table 32.2)
Sect. 28.7.3. and in Sect. 20.4.6 on the distinction between content varia-
tion due to inhomogeneity or to weight variation.
One dose of voluminous powders or high dose active
4.6.5.1 Appearance
substances sometimes will not fit into one capsule.
A simple visual control is sufficient to determine on homo-
Therefore, ‘densified’ or ‘heavy’ qualities of these
geneity of the mass, and whether lumps or agglomerates are
substances may be available, such as for tetracycline
present or not. Filled capsules should be free of dust and well
hydrochloride. For high doses of paracetamol the
closed after preparation. Moreover, they should not be
problem can be solved by using a mixture of large
dented. A dent may lead to a too low dose delivered to
and small particles, designated (in the Netherlands)
patients.
as paracetamol (500–90). This type of paracetamol
has a relatively high bulk density, because the small
4.6.5.2 Average Weight
particles fill up the spaces between the large particles.
The average weight is used to check whether the right
capsule size has been used and to get an impression of the
loss of powder mixture. The average weight is determined
4.6.3.1 In Process Controls on ten capsules (see Sect. 32.7.1). It is advised to sample
The following in-process controls are essential for the prep- selectively by taking the capsules from the centre and the
aration of capsules: corners of the capsule filler. If the amount of powder mixture
• Noting the tare weight prior to adding up with diluent to is insufficient to fill all the capsules, the ones in the corners
weight or volume. usually will not be filled completely.
• The absence of lumps or agglomerates: simple visual The average weight is calculated by subtracting the aver-
control is sufficient to determine whether lumps or age weight of ten empty shells from the average weight of
agglomerates are present or not. ten filled capsules. The theoretical weight is calculated from
• A visual test on homogeneity or evenness of the mass: the weighed quantities of raw materials and the added dilu-
this test is performed after mixing or sieving of powder ent. A difference of more than 3 % between the theoretical
mixtures. weight and the average weight implies in practice that the
• The yield (number of capsules). formulation is not optimal or that the preparation was not
• When the mixture has to be divided over more than one successfully accomplished. For determination of the empty
portion, every portion (including the last one) must be capsule weight, it is important to use capsules of the same
weighed. batch and with the same moisture content as the ones used
for the preparation.
4.6.4 Preparation of Coated Capsules 4.6.5.3 Uniformity of Mass

The uniformity of mass is expressed as the relative standard
In some cases, it may be desirable to coat capsules, for deviation and is determined by dividing the standard devia-
example to make them resistant to gastric juices (enteric tion of the weight of the filled capsules by the average
coating). For this, specialised equipment is required. More weight of the content. The Ph. Eur. (see Sect. 32.7.1) asks
4 Oral Solids 65
to weigh 20 units individually. For capsules with a content swallowing tablets or capsules. Another reason for dispensing
weight less than 300 mg not more than two capsules should single-dose powders is to prevent a high local concentration
deviate more than 10 % of the average and none more than of the active substance in the oesophagus and the stomach, as
20 %. For capsules with a content weight equal to or more might be the case with capsules or tablets. Powders with
than 300 mg these values are 7.5 % and 15 % respectively. active substances with bitter or salty taste can be presented
From experience can be stated that a batch will meet the as effervescent granules [17].
Ph. Eur. requirements when weighing ten capsules and calcu- Powders should be dissolved or suspended in a glass of
lating the average weight and standard deviation: for capsules water or milk or mixed with a small amount of suitable soft
containing less than 300 mg, the relative standard deviation food before ingestion, to prevent aspiration into the lungs, as
should be below 4 %. For capsules containing more than well as to promote direct dissolution of the active substance.
300 mg, the relative standard deviation should be below 3 %. Unlike tablets or capsules, powders provide a rapid onset of
action because they are readily dispersed. They have a large
4.6.5.4 Homogeneity surface area, and they do not disintegrate but rather just
The average weight and the uniformity of mass are indicators dissolve before absorption.
for the weight distribution of the powder over the capsules. A disadvantage of single-dose powders is that preparing
PRODUCT DESIGN
The weight distribution depends on the flowability of the each individual dose is time-consuming. Another disadvan-
powder, the completeness of filling and the operator’s preci- tage is that the patient may have problems opening the
sion. However, it does not give information on the active folded paper without spilling and losing all powder from
substance content per capsule. Due to mixing variation there the folded paper. The total mass of a single-dose powder
will never be a perfect content uniformity. may be too large for neonates, even when mixed with milk,
An assay on separate capsules gives direct information on and undissolved particles may clog small-lumen nasogastric
the mean content of active substance in the capsules and its feeding tubes.
variation between capsules. In pharmacy preparation such
assays are usually performed during the validation of a
Carbasalate calcium is irritating to the gastric mucosa.
formulation and during routine examination of large batches
Therefore, it cannot be administered in capsules. It is
of standardised preparations. But for extemporaneous
administered as single-dose powders in sachets
preparations in-process controls and non-destructive end
instead. The powders should be dissolved in a glass
controls have to be sufficient. The requirements for the
of water before ingestion. When carbasalate calcium
mean content and content uniformity of capsules are
powders are prepared in a pharmacy, the poor flow
described in Sects. 32.4 and 32.7.2.
properties of the active substance may result in a
The combined results of the controls on weight and the
relatively low uniformity of mass. The poor flow of
assay give information on the preparation method. If capsules
the powder is probably due to an irregular shape of the
do not comply with the specifications for uniformity of mass,
carbasalate calcium crystals and perhaps also to a
it can be concluded that the powder was not divided evenly
relatively wide size distribution of the raw material.
over the capsule shells. This may be caused by loss of powder
mixture (the average weight is too low), or by insufficient
flowability of the powder (the average weight may still com-
ply). When both the average weight and the uniformity of 4.7.1.1 Product Formulation and Method
mass comply with the specifications, but the content unifor- of Preparation
mity does not, the cause is a non-homogeneous powder mix- Divided powders usually contain one or more active
ture. In the latter, it can be concluded that the mixing of the substances and excipients. If the quantity of active substance
solids was insufficient. Generally the variation coefficient per powder is low, it is supplemented with diluent up to a
after mixing should be less than 5 % [34]. manageable quantity. A weight range of about 200 mg as a
minimum to 500 mg per powder is widely used and assumed
to bring along minor loss of active substance during the
4.7 Powders process (Fig. 4.2) [28].
The formulation and preparation of the powder mixture
4.7.1 Single-Dose Powders for single-dose powders is to a great extent similar to the one
described previously (see Sects. 4.5 and 4.6.2). Excipients
Single-dose powders are measured quantities of a solid mass that are used for single-dose powders are diluents, and in
packaged in paper or, in the case of industrially manufactured case of poor flow properties, a glidant. A disintegrating agent
products, in sachets. Single-dose powders are traditionally is not needed due to the loose packing of particles in the
prepared for children and elderly because of difficulties in powder.
After all solids are mixed, the powder mixture is divided will be obvious that the dose accuracy is not as good as in
over the dose units. For single-dose powders this is done by single-dose powders, tablets or capsules.
weighing the powders individually on waxed powder papers. The preparation of the powder mixture is analogous to the
Each paper is folded. Powder filling and folding machines preparation of single-dose powders (see Sect. 4.5), but the
are no longer used in most countries. Packets (papers) should flow properties are less critical, because the powder mixture
be checked to see that they are uniform in weight. does not have to be distributed evenly over dose units. A
Effervescent powders contain, besides the active sub- diluent is generally not necessary, but in case it is required,
stance, a combination of an acid and a carbonate or bicar- lactose is often used. Bulk or multidose powders can be
bonate. When the powder is added to a glass of water, packaged in glass, plastic, metal or other containers that
carbonic acid and carbon dioxide are formed and the latter have a wide mouth to allow the handling of the powder-
produces effervescence. During this chemical reaction often measuring device.
a soluble sodium salt of the active substance is formed.
Moreover, the effervescence serves as a natural stirring
Sodium sulfate is an example of multidose powder,
process, which may enhance the dissolution rate.
which is used as laxative in case of intoxication: the
The in-process controls for the preparation of the powder
patient should take several grams. To make this prepa-
mixture are the same for single-dose powders as for
ration more patient-friendly, the required quantity of
capsules.
Sodium sulfate decahydrate can be weighed into a dry
bottle, which basically makes it a divided powder. Prior
4.7.1.2 Release Control and Quality Requirements
to use, the required amount of water is added to dissolve
For single-dose powders, the average weight and the unifor-
the powder. This may be done in the pharmacy or
mity of mass are determined. The specifications for content
elsewhere by the patient or the caregiver. An advantage
uniformity are discussed in Sect. 32.7.2.
of a powder over an oral solution is that the preparation
Often, as is the experience in the Netherlands, the phar-
has a long shelf life without the need for a preservative.
macist can directly, after preparation, have a good perception
of the quality of the batch by assessing the average weight and
weight variation. It appeared that the mean weight of powders
will normally not deviate by more than 5 % from the
theoretical weight, which is different from the deviation met 4.8 Cachets
in practice with processing for capsules (3 %). The unifor-
mity of mass could be expressed, for practical purposes, as the A cachet is a type of shell made from starch. Before admin-
relative standard deviation as determined by dividing the istration, the cachets are immersed in water for a few
standard deviation of the weight of the powder content by seconds, placed on the tongue and swallowed with a draught
the average weight of the content. For powders with a content of water. Cachets were used in pharmacies prior to the
of less than 300 mg, the relative standard deviation usually introduction of gelatine capsules, and in most countries
will be less than 4 % and that of powders with a weight of they are considered obsolete and not in use anymore due to
more than 300 mg, will normally not be higher than 3 %. See stability problems and difficulty in industrial manufacturing.
Sects. 32.6 and 32.7 for the Ph. Eur. test. However, for example in Poland they are very popular, in
contrast to gelatine capsules, which are rarely used. Recently
it has been considered as a reference in the production of
4.7.2 Multidose Powders new hard starch shells resembling hard gelatine capsules, on
providing an alternative polymer to gelatine.
Multidose powders for oral use are mainly used when the The sizes range from no. 1, the smallest, to no. 6, which is
patient has to take large quantities (grams) of an active the largest (Table 4.5). In contrast to hard gelatine capsules,
substance. These powders usually contain non-potent active
substances that should be taken in large quantities, such as
Table 4.5 Sizes and volumes of the cachets
calcium salts (e.g. calcium gluconate and calcium citrate)
and certain nutrients. Multidose powders are dispensed to Size Volume (cm3)
the patient in a bulk container. Multidose powders are usu- 6 1.8–2.0
ally dosed by a measuring spoon or cup. Traditionally 5 1.5–1.6
spoons and cups used as cutlery presented standard 4 1.2–1.3
measures, but nowadays, designers are changing the sizes, 3 1.0–1.1
2 0.7–0.8
thus, the volumes. To prevent variations of volume, patients
1 0.5–0.6
should be given a measuring device with the medicines. It
4 Oral Solids 67
Fig. 4.4 Dimensions of cachets

compared to capsule shells,
# Department of Pharmaceutical
Technology GUMed Gdansk
PRODUCT DESIGN
they are bigger and flatter in shape (Fig. 4.4). Like the microbial growth. When stability is not confirmed experi-
gelatine hard capsules, cachets consist of two shells: a cap mentally, the beyond-use date is, generally, not longer than
and a body. Cachets are manufactured by moulding a mix- 30 days. The preparation is stored at room temperature, in
ture of starch and water, after which the capsules are dried paper or plastic bags or other containers. If the powder is
(“baked”). Separate moulds are used for caps and bodies, hygroscopic, a tight closure is required.
and they are supplied separately as well. The empty cachets
should be stored in dry place.
4.8.1 Filling of Cachets 4.9 Tablets
In pharmacy, cachets are hand-filled with dry powder 4.9.1 Orientation and Definitions
mixtures. Active substances often require adding a diluent
to the active substance to achieve the minimum mass of Tablets are the most popular pharmaceutical dosage form
100–300 mg as in single-dose powders (see Sect. 4.7.1). with many advantages: simple and accurate administration
Lactose is the most common agent used for this purpose. of the correct dose, convenient delivery of active substances,
The powder has to be divided into individual cachets by easy handling and good stability. Degradation of the active
weight, which is time-consuming. Afterwards the caps are substance occurs usually slowly and the microbiological
fitted manually onto the bodies to close the cachets. quality of the dosage form is almost guaranteed. Moreover,
Although special filling apparatus were developed, they are tablets can be prepared at both laboratory and large scale.
not commonly used. However, they present little flexibility on dosage which
makes them inappropriate for patients with special needs,
even if they are manufactured with score lines to divide them
4.8.2 Patient Instruction
into halves or quarters (see Sect. 37.8.3). The majority of
tablets are swallowed whole. Less common are tablets that
In spite of their large size, adult patients can swallow cachets
need to be dissolved or disintegrated before ingestion, or that
upon moistening with water making them soft, elastic and
fizz when in contact with water (effervescent tablets)
slippery. If the size is too big the patient may take the
(Table 4.6).
powder after removing it from the cachet. This is a way to
Other types of tablets may require chewing by the patient
administer them to children.
or dissolution of the active substance in the mouth. The
formulation of tablets is discussed to such an extent as is
4.8.3 Stability necessary to support the adapting of these products into other
oral dosage forms in pharmacies. The preparation of tablets
Cachets are sensitive to moisture that causes softening of the is complex and specialised, hard to perform on a small scale
shell, improve the potential for chemical degradation, and and is therefore beyond the scope of this book. The
Table 4.6 Types of tablets (Based on the definitions of the Ph. Eur.)
Type of tablet Characteristics
Non coated tablet Is designed to be swallowed by the patient
(conventional tablet) Releases the active substance in the stomach, immediately after administration
Coated tablet A coat was applied to a tablet (e.g. protection from the environment)
Enteric coated tablet A gastroresistant coat is applied to the tablet
Effervescent tablet Is prepared by compression
Contains mixtures of weak acids (e.g. citric acid or tartaric acid) and sodium bicarbonate or carbonate, which
release carbon dioxide when dissolved in water
The prepared solution becomes the delivery system of the active substance to the patient
Soluble tablet Tablet to be dissolved in water prior to administration; may or may not be coated
Dispersible tablet Tablet to be dispersed in water prior to administration; may or may not be coated
Orodispersible tablet Tablet designed to disintegrate in the mouth within seconds
Tablet for sublingual Dissolves rapidly in the mouth
application Is designed for sublingual absorption of fast release medicines
Often contains lactose or other excipients easily soluble in water
Tablet for buccal application Is placed in the cheek pouch where the active substance can be absorbed in the mouth
The active substance can be released immediately or, slowly, particularly when adhesive tablets are designed
Chewable tablet Designed to be chewed
Is formulated to have a pleasant taste, without leaving an unpleasant after taste (e.g. by including mannitol,
sorbitol or sucrose)
Is formulated with a high mechanical strength to prevent fast disintegration in the mouth
Modified release tablet Is designed to be swallowed whole
The release of the active substance is not immediate but controlled
preparation method is however discussed briefly, because it Diluents with binding properties are used in tablets that
partly determines the possibilities of adapting. are prepared by direct compression. They are meant for
increasing the mass, but have binding capacities as well.
Since the powder mass is not granulated, they should exhibit
4.9.2 Formulation good flow properties. Furthermore, diluents should not seg-
regate easily. The most often used binding agents are micro-
4.9.2.1 Diluents crystalline cellulose (especially type PH102), various grades
Diluents are added to tablets that are prepared by either wet of lactose, and calcium monohydrogen phosphate dihydrate.
granulation or direct compression to increase the mass. Various qualities of lactose (see also Sect. 23.4.4) are
These agents should comply with the same specifications used as diluents in tablets. For instance alfa-lactose
as diluents in capsules. Generally milled lactose or micro- monohydrate 100 mesh is a sieved product with good flow
crystalline cellulose grade PH101 are used as diluents; properties, although the binding properties are quite poor.
sometimes mannitol or calcium monohydrogen phosphate Consequently it is often combined with another binding
dihydrate act as such. Some of these substances are agent such as microcrystalline cellulose PH102. Granulated
described in the section on capsules (see Sect. 4.6). Good alfa-lactose monohydrate has better binding properties than
flow properties of diluents are less important for tableting by lactose 100 mesh. Anhydrous beta-lactose is an
wet granulation compared to capsule filling. For this reason agglomerated product with good flow and binding
(milled) lactose 100 mesh, with good flow properties, is used properties. Spray-dried lactose also has good flow and bind-
in capsules, whilst the rather poorly flowing (milled) lactose ing properties, but contains about 15 % of amorphous lac-
200 mesh is used in tablets prepared by wet granulation tose, which makes it somewhat hygroscopic. Mannitol is a
(see Sect. 23.4.4). binding agent that can be used in tablets; it is a polyalcohol,
Nowadays some tablet excipients present multi available as binding agent in a granulated grade
functionalities. New excipients are designed to allow a fast (e.g. Pearlitol®). Mannitol is mainly used as substitute for
and effective mixing with the active substance prior to lactose. Co-processed products can also be used for the
compression. Although more expensive, they save produc- production of tablets. These are agglomerates of two differ-
tion time and diminish difficulties on designing a new ent excipients. The best known are Cellactose® (75 % alfa-
formulation. lactose monohydrate and 25 % cellulose) and StarLac®
4 Oral Solids 69
(85 % alfa-lactose monohydrate and 15 % corn starch). 4.9.2.4 Glidants

These products exhibit good binding and flow properties. Glidants promote the flow of granules and tableting powder
More information on binding agents can be found in the mixtures. This causes a more uniform filling of the mould,
literature. and thus a higher uniformity of mass. For tablets prepared by
wet granulation, generally talc is used. Talc also reduces
4.9.2.2 Disintegrants adhesion to the punches and moulds. For direct compression
Disintegrating agents for tablets are either classical a glidant is often not necessary. If it is desirable to use
disintegrating agents or super-disintegrating agents. The glidant, colloidal anhydrous silica is used (Aerosil®
most often used classical disintegrating agent is corn starch 200 V). Magnesium stearate also promotes flow, but is
in fractions between 10 % and 20 %. Starch, which does not mainly used as a lubricant.
compress well, cannot be used for direct compression. In that
case super-disintegrating agents are used, which are already 4.9.2.5 Lubricants
effective in concentrations between 2 % and 6 %. Super- Lubricants are used to minimise friction between particles
disintegrating agents are used in tablets when required inde- and between the particles or the tablet and the mould during
pendently of the preparation by wet or dry granulation or, tableting. The most often used lubricant is magnesium stea-
PRODUCT DESIGN
simply direct compression of excipients and drug. The ones rate in concentrations between 0.5 % and 2.0 %. Magne-
that are used are: sium stearate functions as an anti-adhesive agent: it reduces
• Sodium starch glycolate (type A) (Primojel®). This prod- adherence to the punches and mould. A disadvantage of
uct swells strongly in water and thereby breaks bonds magnesium stearate is its negative effect on the binding
within the tablet. properties of the powder mixture. Moreover, it increases
• Sodium croscarmellose (Ac-Di-Sol®) has about the same the disintegration time of tablets due to its hydrophobic
properties as sodium starch glycolate, but is effective in nature. Alternatives to magnesium stearate, such as stearic
even lower concentrations. acid and hydrogenated fats, are sparingly used because these
• Crospovidone (Polyplasdone® XL) swells sparingly in compounds are less effective.
water. Its mechanism of action is based on capillary
forces, which allow for fast penetration of water into the 4.9.2.6 Mechanical Strength
tablet. In tablets with a high content of highly soluble Tablets should be formulated to have sufficient mechanical
compounds, such as anhydrous beta-lactose, it is more strength to prevent breakage or crumbling during transporta-
effective than both other super-disintegrating agents. tion or further processing, because damaged tablets contain
It is essential to choose the right super-disintegrating less active substance, may be more difficult to deliver to
agent for direct compression. For tablets containing spar- patient and be regarded as a defective product by the patient.
ingly or poorly soluble binding agents, sodium starch
glycolate and croscarmellose are suitable. For tablets 4.9.2.7 Disintegration and Dissolution Rate
containing soluble binding excipients, crospovidone is the Most types of tablets should disintegrate in water within a
better choice. certain time limit (see Sect. 32.9). Disintegration of tablets is
a prerequisite, but not a guarantee for a good bioavailability,
4.9.2.3 Binders for which a good dissolution rate is essential as well.
Binders provide binding in tablets that are prepared by wet
granulation. Binders are polymers that transform into a
sticky mass in presence of water. They can be added to the 4.9.3 Method of Preparation
powder mixture as a solid or in solution. When added as a
solid, the mixture is subsequently wetted with water; when Tablets are prepared by compression of uniform volumes of
dissolved in water, or another convenient non-toxic solvent, particles (powder mixtures) or granules. The choice of
the powder mixture is wetted with the binder solution. The excipients depends on the preparation method: wet granula-
latter approach maximizes the binding property of the tion or direct compression.
binder. In the past, mainly natural polymers were used, The problem that arises with tablets is that it is hard to
such as starch or gelatine. Nowadays, the most commonly produce small batches of tablets of good quality. Mixing,
used binders are: granulation (often required) and tableting equipment are
• Polyvinylpyrrolidone (povidone, PVP) suitable for the manufacturing of tablets on a larger scale
• Cellulose ethers, such as hypromellose (HPMC), methyl- than required in most pharmacies. Only a few pharmacies
cellulose (MC), hydroxypropylcellulose (HPC) and are equipped for the preparation of tablets, which are usually
carmellose sodium (CMC-Na) not commercially available. Alternatively one can use a
• Cold swellable starch mechanical press to prepare individual tablets, although
reproducibility may be a problem. Traditionally small-scale substance content, content uniformity, friability and dissolu-
tableting has not been common practice in pharmacies, but tion rate (see Chap. 32). Most of these requirements are to be
new equipment is allowing the preparation of small batches. found in the Ph. Eur.
In the past, tablets used to be prepared by wet granulation,
but nowadays, more and more tablets are prepared by direct
compression of a powder mixture. Both methods have 4.10 Modified-Release Tablets and Capsules
advantages and disadvantages. Tablets that are prepared by
wet granulation usually contain a diluent, a binder, a Solid oral dosage forms can be modified in various ways to
disintegrating agent, a glidant, and a lubricant. The process alter the release profile of the active substance. Preparations
includes mixing, wet granulation, drying, mixing again and with such an altered release profile are called modified-
tableting and takes quite some time. Tablets that are release preparations. Some of the reasons have been
prepared by direct compression contain one or more binding presented previously (Sect. 4.9.1).
and diluent excipients that have a binding capacity in the dry Modified-release preparations are discussed for several
state. The process runs faster as mixing of powders prior to reasons. At first, a pharmacist should know that such
compression is often sufficient. Direct compressed tablets modifications on active substance release exist, and that he
usually contain additionally a disintegrating agent, a glidant may dispense medicines with a specific release profile. Sec-
and a lubricant. Both types of tablets may also contain other ondly, some active substances are only available as a
excipients, such as colouring agents and wetting agents. modified-release preparation. Thirdly, the administration of
Modified-release tablets contain different excipients and a modified active substance release profile from a tablet
are prepared following a different method. This type of might be due to the properties of the active substance.
tablets is described in Sect. 4.10. These are some aspects that must be considered before
such a tablet is crushed or a capsule is emptied. Enteric-
4.9.3.1 Flow coated tablets and capsules are not described as modified
For even filling of the moulds, it is important that the powder release preparations in the Ph. Eur. [6] but the same care
mass flows well. A classical method to improve the flow must be taken not to damage the coat when using it for the
properties of a powder is granulation. The flow properties of preparation of other dosage forms.
the substances that are present in the granules are irrelevant, Formulation and preparation method of modified-release
only the flow properties of the granules themselves matter. tablets is tuned to the desired release profile, and thus differ
Direct compression, however, requires good flow properties. from conventional tablets. The complex nature of this for-
This can be achieved by use of the right binding agents. mulation and preparation can only occur in large-scale
Tableting of high dose active substances requires good flow industrial production.
properties of these substances as well. The addition of a
glidant may be necessary.
4.10.1 Pharmacokinetics
4.9.3.2 Mixing
It is essential that a powder does not segregate during mixing Not all active substances are suitable for a modified-release
or tableting to achieve a good content uniformity. Granula- tablet. In general, an enteric coating on an ordinary tablet
tion is one technology that can be used to prevent segrega- requires no specific properties of the active substance. How-
tion of powders. For direct compression, choosing the right ever, other types of modified-release may require certain
particle size for the active substances and the excipients can pharmacokinetic properties:
prevent segregation. Micronised active substances are gen- • The pharmacokinetics of the active substance should be
erally distributed over one of the excipients by means of known: an active substance with a long half-life in a slow
ordered mixing (see Sect. 4.5.1) prior to subsequent mixing. release preparation has little added value. An active sub-
Another method to distribute micronised particles over stance with a short half-life may be appropriate for a
excipients is by dissolving them first in a suitable solvent modified-release dosage form, unless a large dose is
(solvent method, see Sect. 4.5.1). required to achieve the therapeutic effect. In that case,
then the size of the dosage form may be too large to be
swallowed by a patient.
4.9.4 Release Control and Quality • The dissolved active substance should be sufficiently
Requirements absorbed in the small and large intestines, depending on
the site of their release, requiring the dosage form to
Once manufactured, tablets will be controlled for weight and remain over time in a specific location
weight variation, appearance, disintegration active (e.g. mucoadhesion).
4 Oral Solids 71
4.10.2 Physico-chemical Mechanisms on Active 4.10.4 Dosage Form

Substance Release
The described physico-chemical mechanisms are applied in
Various physico-chemical mechanisms can be applied to various combinations in licensed medicines. The different
delay the release from a solid oral dosage form. These modified-release dosage forms can be classified in many
mechanisms are usually applied in combination: ways, which can be found in literature.
• Delayed dissolution and diffusion: water (needed for Licensed medicines delivering the same active substance
dissolving the active substance) and, after dissolving, with a modified release profile rarely have the same formu-
the active substance solution have to pass a barrier: lation. What can be distinguished is whether the preparation
through narrow pores or a viscous mass. consists of a matrix, a reservoir system, or a combination of
• Delayed dissolution by applying a layer that dissolves at a both. An example of a combination of a matrix and a mem-
higher pH. brane is a coated hard gelatine capsule filled with small
• Erosion: the mass that contains the active substance matrix pellets (mini matrices). When using these complex
should first erode for the active substance to come into systems for the preparation of other dosage forms, each
contact with water and dissolve. component should be dealt with differently and
PRODUCT DESIGN
• Swelling: excipients swell in contact with water, which independently.
hinders diffusion of the active substance. It can also be distinguished whether the dosage form is
• Complex formation: the active substance cannot be monolithic (one part) or multi-particulate (consisting of
released due to binding to insoluble excipients. multiple small particles). A monolithic dosage form remains
• Osmosis: a semi-permeable membrane containing holes intact or erodes during its residency in the gastro-intestinal
of a certain diameter surrounds the active substance and tract. A multi-particulate system, on the other hand,
an osmotic active agent. In contact with water, the disintegrates and spreads.
osmotic active agent attracts water, which results in Over the last 30 years many studies have addressed the
release of the content through the holes. problem of transit time and active substance site absorption.
• Physical blockade of transportation: the tablet is or Factors such as, dosage form size, density, shape, the fed
becomes so large that pylorus passage is delayed (gastro versus fast status of patient have been studied using different
retention). techniques (e.g. gamma-scintigraphy). Generally low size
and low density dosage forms present a faster transit than
large and dense tablets [35]. Overall the time of a modified
4.10.3 Desired Release Rate release dosage form in the stomach varies with the presence
or absence of food, from minutes to 2–4 h. The stay in the
The desired release profile can be based on various physico- small intestine is quite constant at 3–4 h and in the colon
chemical mechanisms, supplemented with the mechanical from a few hours to days.
effect of the dosage form itself. The mathematical equations
for the release profile in combination with in vitro research
can help on directing the development of new preparations. The advantages of a multi-particulate capsule or tablet
However, the release profile in vivo is hard (often impos- in comparison to a monolithic dosage form are:
sible) to predict. Beneficial is a release profile with little • Transportation is independent of the filling of the
dependence on physiological and anatomical factors, such as stomach (assuming that the particles are < 2 mm).
the degree of filling of the gastro-intestinal tract, the rate of • Spreading of the content over the stomach and
passage, the type of food, the pH, physical activity, age, etc. intestine reduces the chance that the dose is (unin-
These parameters exhibit large inter- and intra-individual tentionally) released at once, which could lead to
variation. Residence times in the different parts of the damage of the gastro-intestinal wall.
gastro-intestinal tract may vary greatly: stomach: The disadvantages are:
0.5 – > 8 h; small intestine: 2–6 h; large intestine: 4–30 h. • The surface area is large, and thus the dissolution
The independence from such factors can be tested to a rate is higher (see Sect. 18.1), which requires a
certain extent in vitro, by determination of the dissolution larger delay.
rate under influence of (a simulation of) the variables. The • In the case where the particles contain hydrophilic
tests described by the Ph. Eur. are limited, namely to the and inert polymers, there is a chance that the cap-
influence of pH [6]. The USP also requires testing for the sule does not disintegrate, and thus acts as a mono-
influence of 15 % ethanol on the dissolution rate (see also lithic dosage form.
Sects. 32.10 and 16.2.3).
4.10.5 Matrix Systems

Examples of plasticisers to improve the workability of
In a matrix, the active substance is dispersed in compressed the polymer, are:
excipients (usually polymers) that retain its shape reasonably • Hydrophilic plasticisers: triethyl citrate (TEC),
long after ingestion. The active substance should be released triacetine (GTA), macrogol, propylene glycol,
through pores in the matrix, or the matrix should erode. The sodium lauryl sulfate, polysorbate 80, water
matrix can be hydrophilic; then swelling is the main • Lipophilic plasticisers: dibutylsebacate (DBS),
delaying mechanism. A matrix consisting of inert plastic tributyl citrate (TBC), acetyl-TBA, acetyl-TEC,
requires the active substance to diffuse through narrow stearic acid, ricin oil, medium chain triglycerides,
pores. Matrices can also consist of fat, for which erosion is acetylated monoglycerides (acetem)
the main principle of delayed release of the active substance. Other compounds that may be present in a reservoir
system are a dispersion medium of solvent, glidants or
anti-adhesive agents (titanium oxide, talc, magnesium
Matrix systems may contain the following
stearate, etc.), and agents that further influence the
excipients [36]:
release (various water soluble, but also fat-soluble
• Polymers for hydrophilic matrices
compounds.
• Semi-synthetic: hypromellose, hydroxypropyl-
cellulose
• Synthetic: polyvinylalcohol, copovidone (poly-
vidone/vinyl acetate)
• Polymers for inert matrices: ethylcellulose, amino- 4.10.7 Adapting Modified-Release Preparations
methacrylate (Eudragit® RS), polyvinyl acetate/
polyvidone (mixture, no co-polymer) When a patient cannot swallow tablets or capsules, has a
• Polymers for a fatty matrix: glycerol behenate, feeding tube, or requires a lower dose of the active sub-
glycerol palmitostearate, waxes, cetyl alcohol stance than present in a commercial product, the pharma-
cist should find a way to administer the active substance.
Sections 37.6.2 and 37.8.3 discuss various strategies to
modify conventional (fast-release) tablets or capsules,
such as the opening and emptying of a capsule, or
4.10.6 Reservoir Systems
pulverisation of a tablet and subsequently mixing it with a
diluent or liquid.
A reservoir system consists of an active substance and a
However, these modification strategies may not be
membrane, and therefore is also known as a membrane con-
possible to apply to modified-release preparations.
trolled system. A membrane or coating can be applied to a
Questions such as the following should be answered: is
whole tablet or capsule, or to a tablet core. Granulates and
it possible to split the dosage form without destroying its
even crystals can be coated as well, which are then processed
function? Is it possible to mix the content of a capsule
into tablets or capsules. Enteric-coated dosage forms have an
without grinding? Can the dosage form be modified into
acid-resistant coating, which dissolves when the pH is
a liquid preparation? And if so, should the dose or dose
increased. An osmotic system may be regarded as a particular
frequency be adjusted?
reservoir system, because it has a semi-permeable membrane
A modified-release preparation should be administered as
that is provided with holes with an exact diameter.
such to have its intended effect. Splitting is not an option,
unless this is provided by the manufacturer and is specified
For reservoir systems and coatings, the following in the product details. Sometimes, asking the manufacturer
polymers can be used for the base of the coating [36]: may give the desired information, but not all manufacturers
• Polymethacrylates (Eudragit® series, Kollicoat® are able or willing to help with the particular situation of an
series) individual patient.
• Cellulose derivates, such as ethylcellulose, cellu-
lose acetate, cellulose acetate butyrate (Ethocel®,
The product details of many licensed products do not
Aquacoat®, Surelease®)
specify what to do when a patient is not capable of
• In acid soluble polymethacrylates and cellulose
taking the capsule of tablet, or requires a different
derivates, Shellac
dose. However, propositions have been made to
• Fats and waxes, such as carnauba wax, glycerol
improve the situation [37]. The EMA has made the
monostearate, hydrogenated ricin oil, for coating
with molten polymers (continued)
(continued)
4 Oral Solids 73
Table 4.7 Cough and Bronchial Tea II [42]

following changes in the guidelines on the content of Aniseed 20 g
the Summary of Product Characteristics (SPCs): Lime flower, cut 50 g
• For scored tablets, the product details should Mallow flower, cut 5g
include whether the tablets may be broken to obtain Primrose flower DAC 5g
half doses, or only to ease the ingestion. Thyme, crushed 20 g
• When the manufacturer has information on alterna- Total 100 g
tive methods for ingestion, this should be stated as
clearly as possible in the product details; for exam-
ple, whether the tablet can be pulverised or broken, dosage forms is a current practice. The main advantage is the
the capsules be opened, or the content be mixed standardisation of the active medicines (often a family of
with food or liquid. The manufacturer should also chemically similar compounds) presented to patients in a
account for patients who receive gavage feeding. stable dosage form as a tablet, which can be coated. Their
• An advice on the handling of a dosage form should production can be difficult due to variations on the herbal
be supplemented with a clarification, such as: ‘do medicine as a raw material (e.g. powdered dried seeds,
leaves or liquid or solid extracts) and their transformation
PRODUCT DESIGN
not chew the tablet, because of the unpleasant
taste’, ‘do not split the tablet, because the coating into a compressible material [38, 39]. Even the dry extracts
protects the stomach’, or ‘do not split the tablet, can exist as a very fine powder, poorly compressible, and
because the coating modifies its release profile’. hygroscopic. Furthermore the disintegration time of high
• For a preparation that can be applied for children in fraction dried extract tablets can be too long [40]. As a
a modified form, the manufacturer should provide consequence it is possible to manufacture solid dosage
detailed instructions on how this should be done, forms in a small scale, it is also possible to design
including the container that should be used and the formulations for herbal medicines, but care and hard work
shelf life. on designing the formulation and defining the processing
A graph of the release profile in the product details conditions are required. Both the USP-National Formulary
would also benefit the application of modified-release and the European Pharmacopoeia present a series of
preparations, as well as information on the dependence preparations from natural products, namely Aloes (extract),
on physiological and anatomical factors. American Ginseng (powder, extract, capsules or tablets),
Belladonna leaf (dried extract, tincture or powder),
Chamomila (flower heads), Garlic (powder) or St John’s
In a specific situation, the pharmacist first studies the Wort (extract, powder).
Summary of Product Characteristics (SPC) to check whether Pharmacy preparations from herbal medicines include
a preparation may be modified and if so, how [37]. Normally, herbal tea mixtures, from which the user to whom it is
this can be found in its Sect. 4.2 Posology and method of dispensed prepares a tea using (boiling) water. According
administration. When the information on modification is to the Ph. Eur., herbal teas consist exclusively of one or more
negative or absent, a pharmacotherapeutic alternative is the herbal medicines intended for oral aqueous preparations by
most obvious choice. Such an alternative may be a different means of decoction, infusion or maceration. The patient
dosage form of the same active substance or a different prepares the herbal tea immediately before use. Instant
active substance with a comparable therapeutic effect. Clin- herbal teas consist of one or more herbal medicine
ical and pharmacokinetic background of the modified- preparations (primarily extracts with or without added essen-
release profile is paramount for making a justified decision. tial oils), and are intended for the preparation of an oral
Clinically superfluous modified release can also be solution immediately before use. Example of formulae for
concluded with such a literature search. oral solid herbal pharmacy preparations can be found in [41]
(Table 4.7).
4.11 Herbal Oral Medicines

4.12 Complementary Information
The use of herbal medicines has attracted attention in recent
years1. Following the millenary use of natural products 4.12.1 Containers and Labelling
worldwide, for instance as teas, their conversion into solid
Many active substances are sensitive to light, and therefore,
oral solid dosage forms have to be packaged in a light-
1
This section was contributed by Herman J. Woerdenbag, Groningen, protecting container. This is especially relevant to capsules
The Netherlands. with a transparent shell. Powders are packaged in a carton
box, plastic jar or plastic sachet. For packaging of licensed

medicines, light-sensitivity of the active substance is gener- Carbasalate calcium is a relatively unstable solid
ally taken into account. When such products are repackaged active substance, as it degrades through hydrolysis in
for automated dispensing systems, the function of the origi- the presence of moisture. Upon degradation, salicylic
nal container should be considered and taken up: for exam- acid and acetic acid are formed. The latter can be smelt
ple protection against light or moisture. in very low quantities. To prevent patients becoming
Single-dose powders are packaged in a suitable powder needlessly worried, carbasalate calcium powders
fold box, a plastic bag with locking clip or, in case of an should be packaged in lightly ventilating material
authorised medicine, in sachets. such as paper.
Containers of solid oral dosage forms should be provided
with a label. When the preparation has a primary and a
secondary container, both containers should be labelled.
The label should meet the requirements described in
Sect 37.3. 4.12.3 Advices on Use
Orally administered medicines require the pharmacist’s

4.12.2 Storage and Stability advice on when (before, with or after the meal) and how
(with a full glass of water, no milk, etc.) to take the medi-
The chemical, physical and microbiological stability of solid cine. When single-dose or multidose powders are dispensed,
oral dosage forms is generally good (see Sect. 22.7.1). patients must be taught on the exact technique for measuring
Chemical reactions and physical degradation processes the dose to be administered and the proper mode of admin-
hardly occur in the absence of water together with the istration. Should the powder be mixed in a liquid? What
potential growth of micro-organisms in the materials. liquid and volume? Can the powder be mixed with food
The amount of water in solid oral dosage forms can vary (hot or cold)? How long it can be kept after mixing?
from less than 1 % up to 10 %. This water exists due to the Medicines can interact in many ways with food or
exposure of materials to the environment. Some active liquids. First, food or drinks may interfere with the perfor-
substances may degrade at high relative air humidities mance of the dosage form, namely on sustaining its migra-
(e.g. carbasalate calcium), or are hygroscopic and attract tion throughout the gastrointestinal tract. They may also
water (e.g. potassium iodide). Degradation reactions such affect the absorption of released active substances due to
as hydrolysis may occur. In these cases an excipient with geometry and structural effects (tablets or capsules versus
water absorption properties (e.g. silica oxide) should be pellets or granules) [43], see also Sect. 16.1.6. Food or
added to the formulations. However, hard gelatin capsule drinks, as such or one of the ingredients can influence the
shells normally contain about 12–16 % water and moisture stability of the active substance e.g. calcium ions present in
can diffuse through the gelatin wall [36]. The preparation the milk may chelate some active substances [44]. The
may be prevented from attracting moisture by keeping it in a absorption of the active substance may be compromised,
dry place or by packaging it in a material that protects for instance when its absorption requires a common cellular
against moisture, such as sealed sachets. Once the problem membrane transporter to some component of food or
of instability in the presence of small amounts of water has beverage.
been solved, the shelf life of solid oral dosage forms is long. Capsules or tablets that get stuck in the oesophagus may
Capsules, powders and tablets should be stored at relative lead to severe oesophageal irritation particularly if the active
air humidity between 35 % and 60 %. Capsules dehydrate substance is released. Furthermore the therapeutic action
and become brittle at lower relative humidity, while at may be compromised. Preparations of active substances
higher values they absorb moisture and become sticky and with a high risk of damaging the oesophagus
flaccid. Consequently, capsules should be stored in dry (e.g. risedronate, alendronate, doxycyline) require the text
places at room temperature rather than stored with a “Take in an upright position with a full glass of water” in
desiccant. the label.
Multidose powders have their containers opened several
times while used, and thus, stability might become a prob-
lem. As a suggestion, when the chemical and physical sta-
bility are unknown, the maximum shelf life of the powders is
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Oral Liquids
5
Antje Lein and Shi Wai Ng
Contents 5.5.7 In-Process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

5.5.8 Release Control and Quality Requirements . . . . . . . . . . . . . . . 96
5.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
5.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.4 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Abstract
5.4.1 Assessment of the Prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Oral liquid medicines may be a good choice of dosage
5.4.2 Choice of the Oral Liquid Dosage Form . . . . . . . . . . . . . . . . . . 79
form for patients who have problems with swallowing
5.4.3 Additional Formulation Demands when the Patient is
on Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 tablets and capsules, or if they have an enteral feeding
5.4.4 Active Substance Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 tube, or for whom the required dose does not fit with the
5.4.5 Vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 available tablet(s) or capsule(s) such as is often the case
5.4.6 Suspending Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
5.4.7 Agents for Emulsifying and Solubilising . . . . . . . . . . . . . . . . . 86
with children and elderly people. A liquid dosage form is
5.4.8 pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 easy to measure and administer.
5.4.9 Preservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Compared to tablets and capsules, oral liquids have
5.4.10 Excipients and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 some disadvantages as well. Their extemporaneous for-
5.4.11 Flavour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
mulation and preparation is not so easy. They may have
5.4.12 Colouring Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
5.4.13 Incompatibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 an unpleasant taste, the use of solvents and preservatives
5.4.14 Chemical Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 is restricted due to their toxicity (especially for children),
5.4.15 Physical Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 and the safe use of suspensions requires proper shaking.
5.4.16 Containers and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
The properties of the active substance dominate and
5.4.17 Dosage Delivery Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
5.4.18 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 often restrict the choice of the type of oral liquid. Oral
liquids are classified according to their physical
5.5 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
5.5.1 Availability and Pre-treatment of the Active Substance . 93 properties as solutions, suspensions, emulsions and
5.5.2 Dissolving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 solubilisates. Solutions and suspensions are treated in
5.5.3 Mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 depth because they are most often dealt with in daily
5.5.4 Dispersing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 practice.
5.5.5 Emulsifying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
5.5.6 Solubilising . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Keywords
Solutions Suspensions Emulsions Solubilisates Oral
Based on the chapter Oraal vloeibaar by Christien Oussoren and
liquids Syrup Flavour Acceptable daily intake
Doerine Postma in the 2009 edition of Recepteerkunde.With advices
from Mark Jackson, Liverpool U.K. Colour Taste Feeding tube Preparation Formulation
A. Lein (*)
Pharmaceutical Laboratory of Deutscher Arzneimittel-Codex/Neues
Rezeptur-Formularium Eschborn, Eschborn, Germany
5.1 Orientation
S.W. Ng
Oral liquids have some advantages compared with tablets
Royal Dutch Pharmacists’ Association KNMP, The Hague,
The Netherlands and capsules. They are more easily ingested by patients
e-mail: [email protected] having problems with swallowing or having an enteral

78 A. Lein and S.W. Ng
feeding tube. An adult dose is easily adapted for children or Powders for the preparation of oral drops generally con-
for elderly patients. form to the definition of Oral powders. They may contain
In nursing homes psychoactive medicines are commonly excipients to facilitate dissolution or suspension in the pre-
administered as drops. If there is no oral liquid form avail- scribed liquid or to prevent caking. After dissolution or
able, the pharmacist may receive a doctor’s prescription for suspension, they comply with the requirements for oral
the adaptation of an oral solid into an oral liquid. Tablets drops.
may be pulverised or capsules can be emptied and Syrups are aqueous preparations characterised by a sweet
administered with semisolid food. However, there may be taste and a viscous consistency. They may contain sucrose at
other solutions such as improving swallowing technique or a a concentration of at least 45 % w/w. The sweet taste can
different administration route. Even for patients with an also be obtained by use of other polyols or sweetening
enteral feeding tube there may be alternatives or at least agents. Syrups usually contain aromatic or other flavouring
points of attention. agents. Each dose from a multidose container is
Oral liquids may have several disadvantages like an administered by means of a device suitable for measuring
unpleasant taste and an insufficient physical, chemical and the prescribed volume. The device is usually a spoon or a
microbiological stability. It may be complicated to formu- cup for volumes of 5 mL or multiples thereof.
late an oral liquid that complies with quality specifications. Powders and granules for syrups generally conform to the
And the relative ease of administration may lead to abuse or definitions in the monograph on Oral powders or Granules.
overdose, especially with children. They may contain excipients to facilitate dissolution. After
After mentioning the relevant definitions this chapter dissolution, they comply with the requirements for syrups.
firstly discusses the assessment of prescriptions for oral Apart from these categories this chapter also covers:
liquids, especially if inadequacy of the corresponding oral Solubilisates for oral use: colloidal solutions of a liquid
solid is the reason for the request. Also the choice between active substance in an immiscible liquid; this term is not on
solutions and suspensions should be made carefully. the list of EDQM standard terms.
Biopharmaceutical aspects are shortly dealt with, A few of the ‘herbal drug preparations’ of the Ph. Eur. are
followed by formulation and preparation method of oral oral liquids: teas and extracts such as tinctures (extracts with
solutions, suspensions, emulsions and solubilisates. ethanol-water mixtures). Teas are dealt with in chapter Oral
solids because they are dispensed as solids, see Sect. 4.11.
Liquid extracts are dealt with in chapter Raw materials, see
5.2 Definitions Sect. 23.12.
An oral dosage form frequently has to be adapted into an
Oral liquids are included in the European Pharmacopoeia as oral liquid to meet the needs of a patient. The action that has
‘Liquids for oral use’, distinguishing the following to be exerted may be called ‘manipulation’. But mentioning
categories of preparations. the actual action (such as crushing) is to be preferred.
Oral solutions, emulsions and suspensions are defined as
being supplied in single-dose or multidose containers. Each
dose from a multidose container is administered by means of 5.3 Biopharmaceutics
a device suitable for measuring the prescribed volume. The
device is usually a spoon or a cup for volumes of 5 mL or Active substances that are dissolved in water are, if they
multiples thereof or an oral syringe for other volumes. remain in solution, immediately available for absorption
Powders and granules for the preparation of oral solutions after taking on an empty stomach. If they precipitate in the
and suspensions generally conform to the definitions in the acidic environment of the empty stomach the precipitation
monographs on Oral powders or Granules as appropriate. will often be so fine that it easily passes the closed pylorus
They may contain excipients, in particular to facilitate dis- and re-dissolves, after which rapid absorption is still possi-
persion or dissolution and to prevent caking. After dissolu- ble. The pharmaceutical availability (actually the dissolution
tion or suspension, they comply with the requirements for rate of the solid substance) of suspensions for oral use
oral solutions or oral suspensions, as appropriate. depends on many factors including solubility in vivo, the
Oral drops are solutions, emulsions or suspensions that crystal modification and the particle size and the viscosity of
are administered in small volumes such as drops by the the suspension. In practice it occurs that an active substance
means of a suitable device. Because dosing in drops is less (such as phenobarbital) may be formulated as a suspension
accurate than dosing with a dosing syringe and because in water or as a solution in a lipophilic solvent such as
using general dropper bottles requires extensive validation, acetem (see Sect. 23.3.6). Beware that changing from a
drops are not dealt with separately. Drops preferably are suspension into a solution may cause a great increase in
replaced by oral liquids, of which a small volume can be absorption rate and thus cause a change in
dosed with a suitable dosing syringe (1 mL). pharmacodynamics.
5 Oral Liquids 79
The absorption of active substances from a lipophilic • Instructing the patient how to process the oral solid for
solvent varies widely and is difficult to predict. The amount ingestion (see Sect. 37.6.2)
and rate of absorption are largely determined by the release
of the active substance from the lipid phase. This depends on
the solubility of the active substance in the lipid phase and 5.4.2 Choice of the Oral Liquid Dosage Form
the composition of the intestinal contents. If the partition
coefficient is large (the medicine resides mainly in the lipid Different oral liquid dosage forms offer the possibility to
phase, see Sect. 16.1.4) the absorption is slower. Bile salts adjust the dosage form optimally to the requirements. The
provide a fine distribution of the lipophilic active substance, options are solutions, suspensions, emulsions or solubilisates.
which promotes the absorption. Some lipophilic solvents The flow scheme in Fig. 5.1 shows a route to the oral liquid
promote the release of bile acids resulting in a quick absorp- form that is to be preferred due to the qualities of the active
tion of the active substance. Other lipophilic solvents slow substance, particularly solubility, stability and taste. The
down the absorption. A deficiency of bile salts can lead to required concentration influences the choice as well.
impaired fat absorption and decreased absorption of The main choice will be between an oral solution and an
lipophilic active substances. In those cases the administra- oral suspension. For some active substances an emulsion or
PRODUCT DESIGN
tion of lipophilic active substances in the form of a solubilisate is the appropriate form. However in some cases
solubilisate is more suitable (see Sect. 5.4.7). (e.g. because of an intermediate solubility of the active
substance) the pharmacist will have no other option than to
dispense an oral solid dosage form and instruct the patient
5.4 Product Formulation how to manipulate it safely (see Sect. 37.6.2). Proper con-
sideration of the options may prevent formulation mistakes
First, the reason why a prescriber may require an oral liquid with probably severe consequences. This especially applies
is discussed. If no standard formula is available, one of the to the unreflected use of ‘suspending bases’ for rendering an
main choices regards whether an oral solution is to be oral solid into an oral liquid.
formulated or an oral suspension. If the patient has an enteral feeding tube, specific
The formulation of a dispersed system is not easily requirements have to be taken into consideration (see
accomplished. With reference to useful physico-chemical Sects. 5.4.3 and 37.6.3).
principles practical guidelines are given. An aqueous solution is the first choice because of high
The general aspects of stability, packaging, labelling and dosage accuracy and homogeneity. If an active substance is
dosage delivery devices conclude this section. not sufficiently water-soluble, a solution may be achieved by
adjusting the pH, by adding co-solvents or the use of a more
soluble salt. A disadvantage of a solution can be the unpleas-
5.4.1 Assessment of the Prescription ant taste or insufficient stability.
A suspension is the first choice if the aqueous solubility is
A prescription for an oral liquid can be assessed as discussed low. Also substances with a very unpleasant taste or substances
in Sect. 2.2. A request for a standard oral liquid formulation that are not stable in an aqueous solution can better be
will appear to be reasonable in many cases. However, if the processed as a suspension. The taste sensation is less promi-
request for an oral liquid comes from swallowing problems nent and they are less susceptible to degradation when dis-
with oral solids, some alternatives should be considered persed and not dissolved. However, as a suspension is a
before the formulation of an oral liquid is started. disperse system, much attention has to be paid to homogeneity
at dosing. This risk has to be considered for potent medicines.
5.4.1.1 Request Because of Swallowing Problems Active substances with intermediate solubility may cause
with Oral Solids the greatest challenge. When the solubility is too low for a
If the request for the preparation, whether standardised or solution but too high for a suspension (because the risk of
not, originates from swallowing problems with oral solids, crystal growth, see Sect. 18.1.6) the best option seems to be
some specific alternatives should be taken into consideration to choose a solid dosage form in combination with
before starting the formulation and preparation. These instructions for the patient how to handle in case of
alternatives are: swallowing problems.
• Improving the swallowing technique (see Sect. 37.6.2) For lipophilic liquid active substances an emulsion or
• Choosing a medicine that uses an alternative administra- solubilisate seems the only option; if a high amount has to
tion route (oromucosal, rectal or transdermal, or parenteral be processed, an emulsion is the best choice; if low amounts
if the administration by doctor or nurse can be organised) are present a solubilisate may be an option.
Tolerable taste and

Aqueous solution
sufficient stability
Sufficient in Taste, Unpleasant taste or

relation to dose stability fast degradation
Oral solid, to be
Intermediate manipulated by the
Active patient
Aqueous Suspension
substance solubility
Lipophilic solution
Practically Solid active or cosolvents
insoluble substance
(< 0,1 mg/mL)
If high: Emulsion
Liquid active
Concentration
substance
If low: Solubilisate
Fig. 5.1 Decision tree relating to the oral liquid form
The choice of a dosage form finally has to be taken into 5.4.3 Additional Formulation Demands when
account that the dose range must be feasible with appropriate the Patient is on Enteral Feeding
volumes and for ease of calculation concentrations such as
1, 2, 5 or 10 mg/mL will be preferred. There are additional requirements for an oral liquid
administered via a nasogastric feeding tube:
• It must not block the feeding tube
A hydrochlorothiazide oral liquid has to be formulated • It must not interact with the enteral feeding
for children, especially for neonates. Because of the • It must not interact with the material of the feeding tube
limited solubility of hydrochlorothiazide in water
(0.6 mg/mL) and to avoid the presence of organic
solvents such medicine may be formulated as a low 5.4.3.1 No Blocking the Tubes
concentrated solution or a higher concentrated suspen- Enteral feeding tubes can be very narrow, especially those
sion. The concentration should be calculated keeping the for children. The minimum external diameter is about
amount of fluid for dosing low. The solution has a 1.3 mm, with the internal diameter depending on the wall
concentration of 0.5 mg/mL below the limit of solubility material: polyvinyl chloride (PVC) being the thinnest,
(Table 5.1). closely followed by polyurethane (PUR), and by silicone
that being relatively thick does not leave much room for
Table 5.1 Hydrochlorothiazide Oral Solution 0.5 mg/mL [1]
the internal diameter.
Hydrochlorothiazide 0.05 g
Citric acid monohydrate 0.87 g
Disodium phosphate dodecahydrate 0.835 g Diameter Feeding Tubes
Orange essence (local standard) 0.052 g The external diameter of feeding tubes is expressed
Methyl parahydroxybenzoate 0.045 g using the Charriere (Ch) or French (Fr) unit (1 Ch
Syrup BP (preserved with methyl 32 g ¼ 333 μm ¼ 1 Fr). The external diameter of the
parahydroxybenzoate 1 mg per g) narrowest tube is Ch 4; the external diameter of the
Water, purified 73.88 g thickest tube is Ch 20, with Ch 8 or 10 being the
Total 107.7 g (¼ 100 mL) most used.
5 Oral Liquids 81
The viscosity of the oral liquid has to be low enough to be 5.4.3.3 Microbiological Quality
administered through an enteral feeding tube. If necessary Enteral feeding does not contain preservatives because of the
they have to be diluted with water. However, some solutions large volume being administered. Although tube feeding is
may precipitate upon dilution, e.g. because they contain used by vulnerable patients, sterility is not necessary. How-
co-solvents. Dilution also causes a decrease of the solubility ever, the food is often sterilised to get a sufficient shelf life.
of the active substance. Therefore solutions with co-solvents If the oral liquid has been prepared from an oral solid using
have to be administered undiluted. potable water, it has to be added immediately after prepara-
The particles of the active substance in oral suspensions tion, thereby causing no larger microbiological load than that
are required not to exceed 180 μm and should therefore not of potable water. Oral liquids made from raw materials are
block the tube. Larger particles may be encountered how- preserved in most cases and thus have a low bioburden.
ever if ground tablets or the contents of capsules are used. In
that case water-soluble fillers (such as lactose) will diminish
the risk of blocking. 5.4.4 Active Substance Solubility
Flushing the feeding tube with 20–30 mL of fresh potable
water before and after each addition of medicines can pre- Aqueous solutions can be formulated if the active substance
PRODUCT DESIGN
vent clogging. But take care: many patients who are being is soluble in the desired concentration. The solubility may be
tube fed require frequent monitoring of the fluid balance. enhanced by adjustment of the pH, addition of organic
The amount of water used to administer medicines (as an solvents (so-called co-solvents) or the use of a better soluble
oral liquid and to flush the tube) may be subject to salt or ester. Some active substances only dissolve in
restrictions and should be recorded in that case. Carbonated lipophilic vehicles, see Sect. 5.4.5.5.
fluids can exacerbate tube clogging by causing feed to coag-
ulate or protein and amino acids to denaturise. Therefore 5.4.4.1 Sufficient Solubility
they should not be used to flush the tube. An active substance such as metoprolol tartrate, which is
very soluble in water, may be processed in a simple aqueous
base (Table 5.2).
5.4.3.2 Incompatibility with Tubes
The relatively short time that the active substance is in
5.4.4.2 pH
contact with the feeding tube may be long enough for
In general salts dissolve well in water but the solubility often
adsorption to the tube. When using lipophilic solvents
depends on the pH (see Sect. 18.1.1). A high pH may not be a
there is also a risk of the leaching of plasticisers from the
good option because an oral solution with a high pH is not
tube. This depends on the material of the feeding tube.
tolerated by the gastrointestinal tract and tastes unpleasant.
The use of PVC feeding tubes is limited. PVC is firm but
A furosemide oral solution may serve as an example
can be uncomfortable for the patient. The plasticisers in
(Table 5.3). The solubility of furosemide in water is less
PVC dissolve when exposed to gastric juices. As a result,
than 0.1 mg/mL but it increases at alkaline conditions. The
the feeding tube becomes hard and fragile and can therefore
solubility at pH 8 is more than 100 mg/mL [5]. An oral
be used for a maximum of 10 days [2]. In practice the use is
solution containing 2 mg/mL can be formulated by setting
limited to 1 week. Lipophilic medicines easily adsorb to
the pH at 6.6–8.0 with trometamol.
PVC. Lipophilic solvents, such as acetem (see Sect. 23.3.6)
when administered through PVC feeding tubes may cause
plasticisers (phthalates) to dissolve and the feeding tube to 5.4.4.3 Co-solvents
crumble. The solubility in mixtures of water with organic solvents
Polyurethane (PUR) feeding tubes can remain in the (co-solvents) can be predicted (see Sect. 18.1.3) but is in
patient up to a maximum of 6–8 weeks. PUR is a rather practice determined by experiment. Information on solubility
flexible and inert material that offers more comfort for the in water or organic solvents may be available [7–10], but
patient than PVC. However, the greater flexibility can make solubility in solvent mixtures is not. It is not correct to make
the insertion more difficult. Adsorption of active substances
rarely occurs. Table 5.2 Metoprolol Tartrate Oral Solution 1 mg/mL [4]
Silicone feeding tubes are even more flexible than PUR Metoprolol tartrate 0.1 g
and thus more difficult to insert. These feeding tubes are Potassium sorbate 0.14 g
used when the tube should remain in the patient longer than Citric acid, anhydrous 0.07 g
4–6 weeks. Silicone is highly resistant to gastric juices. Water, purified 99.69 g
However, silicone feeding tubes are weaker than PVC or
Total 100.0 g (¼ 100 mL)
PUR tubes [3].
Table 5.3 Furosemide Oral Solution 2 mg/mL [6] Table 5.5 Dexamethasone Oral Solution 1 mg/mL (as Sodium Phos-
pate) [12]
Furosemide 0.2 g
Methyl parahydroxybenzoate 0.15 g Dexamethasone sodium phosphate 0.143 g
Saccharin sodium 0.1 g Bananas essence (local standard) 0.1 g
Trometamol 0.1 g Disodium edetate 0.1 g
Water, purified 99.8 g Disodium phosphate docecahydrate 1.9 g
Methyl parahydroxybenzoate 0.15 g
Total 100.4 g (¼ 100 mL)
Sodium dihydrogen phosphate dihydrate 0.21 g
Sorbitol, liquid (crystallising) 25.8 mL
Water, purified 78.4 g
Table 5.4 Phenobarbital Oral Solution 4 mg/mL with Ethanol and
Propylene Glycol [11] Total 106.8 g (¼ 100 mL)
Phenobarbital 0.4 g
Bitter-orange-epicarp and mesocarp tincture 1 mL
Ethanol (96 %) 20 mL
size of the active substance should be paid. Crystal growth
Propylene glycol 10 mL
will more likely occur with very small particles or a high
Saccharin sodium 0.1 g
spread in the particle size. This is called Ostwald ripening
Sorbitol, liquid (crystallising) 60 mL
(see Sect. 18.4.2.3).
Orange essence (local standard) 1 mL
Total 100.4 g (¼ 100 mL) For the indications epilepsy, diuresis, increased intra-
cranial pressure and glaucoma with children an oral
liquid dosage form with acetazolamide 5 mg/mL was
an assumption about solubility based on the solubility in one of required. The aqueous solubility of acetazolamide is
the solvents because all components of the mixture 0.1–1 mg/mL, pKa is 7.2 and the stability is optimal at
influence it. pH 4. To obtain a solution with the concentration
An example of increasing the solubility by using 5 mg/mL the pH has to be fixed at 8 but that caused
co-solvents is a phenobarbital oral solution with ethanol a 20 % degradation of acetazolamide within 2 weeks.
and propylene glycol (Table 5.4). The formula is only suit- For an oral suspension the solubility is relatively high;
able for use of limited duration in adults. Both solvents make for about 2–20 % of the substance would be dissolved,
the solution unsuitable for children. Prolonged use can make giving quite some cause for crystal growth. A solid
the amount of propylene glycol also too high for adults. dosage form would be a better option but the
physicians definitely wanted to be able to adjust the
5.4.4.4 Better Soluble Salt or Ester dose immediately. An oral suspension was designed
Several salts or derivatives (e.g. esters) of active substances are (see Table 5.6). However, a concentration of 10 mg/
more soluble in water than the parent substance (see also Sect. mL was used to decrease the relative percentage of
18.1). Well-known examples are the sodium salts of the phos- dissolved acetazolamide and thus risk for crystal
phate esters of prednisolone and dexamethasone (Table 5.5). growth. During storage the dissolution rate appeared
to decrease which may be a sign of crystal growth.
5.4.4.5 Low Solubility: Suspension Therefore, the shelf life has been limited to 3 months.
As said (Sect. 5.4.2) an active substance that does not dissolve Table 5.6 Acetazolamide Oral Suspension 100 mg/mL [13]
sufficiently to be administered as an aqueous solution can be
Acetazolamide 1g
processed in a suspension. But the solubility of the active
Aluminium magnesium silicate 0.89 g
substance should be sufficiently low, taking into account the
Carmellose sodium M 0.89 g
desired concentration of the active substance in the suspen-
sion. Too high a percentage of dissolved active substance
can lead to crystal growth of the suspended particles. Large Raspberry essence (local standard) 0.3 g
particles settle faster, which can cause insufficient physical Sodium citrate 4.7 g
stability of the suspension and a lower dissolution rate. Syrup BP (preserved with methyl 33.3 g
Ideally, for a stable suspension, the solubility of the parahydroxybenzoate 1 mg per g)
suspended substance should be not higher than 0.1 mg/mL Water, purified 72.5 g
and the proportion of the dissolved substance should be not Total 109 g (¼ 100 mL)
higher than 0.1 % of the total amount of the oral liquid. If
this is not quite to be achieved, extra attention to the particle
5 Oral Liquids 83
This phenomenon of crystal growth is a very realistic risk (e.g. patients with liver diseases, alcoholism etc.) and in
in practice if active substances, whether as raw material or as the handling of machinery are given by the EMA [15].
crushed tablets, are processed in a universal ‘suspension
base’ without noticing that the actual solubility is too high
Children, especially under the age of 6 years, are more
for a suspension. These bases are often not clear and there-
vulnerable to the effects of ethanol.
fore, it cannot be controlled whether the active substance
Adverse effects on the central nervous system are
dissolves or not. If the crushed tablets are processed, the
already evident at blood ethanol concentrations of
control of an eventual dissolution is impossible anyway
10 mg/100 mL in children. Higher peak ethanol
because of the insoluble excipients.
blood concentrations are also observed in children
than in adults for a similar intake [15].
5.4.5 Vehicles
The most commonly used vehicle is water, for solutions as 5.4.5.3 Propylene Glycol
well as suspensions, emulsions and solubilisates. If a solu- Propylene glycol is used as co-solvent in a concentration up
PRODUCT DESIGN
tion is required, co-solvents may be added (see Sect. 5.4.4) to 20 %. It has preservative properties when used in
such as ethanol, glycerol 85 % and propylene glycol. Their concentrations of 15 % or higher. The taste is unpleasant.
toxic and adverse effects should be fully considered. They The acceptable daily intake (ADI) of propylene glycol is
are miscible with water and often have an antimicrobial 25 mg/kg bodyweight per day without mentioning any age
effect as well. Lipophilic active substances may be brought group [16]. Because of the limited hepatic and renal function
into solution by a lipophilic solvent such as acetem. Another in preterm and term neonates the application of medicines
way of processing lipophilic solvents is to convert them into containing propylene glycol may lead to accumulation and
an emulsion. serious adverse effects. Data in chronic use for children are
not available and reports about the tolerance in patients of
5.4.5.1 Water different ages are usually based on IV application. A daily
Usually purified water (Aqua purificata) is used. Because of IV dose of about 34 mg/kg bodyweight is reported to be
the chemical and microbiological quality it is preferred over tolerated in neonates in short time use [17]. As long as there
potable water (see Sect. 20.3.1) although the taste of potable are no data available for oral use the amount tolerated in IV
water may be better due to presence of ions. Water is a good application may be an indication for oral consumption
growth medium for micro-organisms, so aqueous oral as well.
liquids generally have to be preserved, see Sect. 5.4.9.
Water has a low viscosity and high surface tension, which 5.4.5.4 Glycerol 85 %
causes an uneven ‘flow’ when dosing the oral liquid from Glycerol 85 % is used as co-solvent, preservative,
bottles and dosage devices. Thickening agents, especially sweetening agent and viscosity-increasing agent in a con-
cellulose derivatives, may be added to improve this. centration up to 60 %. Its sweetening power is about 0.5
times that of sucrose. It functions as a preservative at a
5.4.5.2 Ethanol concentration higher than 30 %. The osmotic effect of high
Ethanol is used as co-solvent in a concentration up to 20 % concentrated glycerol has to be considered in paediatric use
in oral solutions. If present in a concentration of at least and in patients with enteral feeding tubes because of gastro-
15 %, it also serves as a preservative. intestinal adverse effects (diarrhoea).
In babies ethanol can lead to convulsions. According to
the WHO [14] ethanol has to be avoided in oral preparations 5.4.5.5 Lipophilic Solvents
for children less than 6 years. Chronic exposure to ethanol Lipophilic solvents may be used for dissolution of lipophilic
(>1 week), even in small doses, is in principle active substances. This option is less desirable because most
contraindicated in children aged less than 6 years and should lipophilic solvents do not taste very well and may render the
be limited to 2 weeks in children aged over 6 years, if a preparation (or the labels) a bit messy at use. But for
positive risk-benefit balance is not demonstrated. formulating an oral solution when toxic organic solvents
The influence of ethanol on the responsiveness can espe- such as ethanol or propylene glycol are not suitable, such
cially be a problem for all ages. Pharmacy preparations as in paediatric use, the use of a lipophilic solvent such as
should be labelled with a warning indication as it is directed acetem (see Sect. 23.3.6) may provide a useful preparation.
for licensed products. Guidelines concerning the content of Acetem is allowed in food, also for babies, and there is no
ethanol and how to deal with in high-risk groups restriction on the daily intake. The taste of acetem is
Table 5.7 Phenobarbital Oral Solution 4 mg/mL with Acetem [18] Table 5.8 Phenytoin Oral Suspension 15 mg/mL [20]
Phenobarbital 0.4 g Phenytoin 1.5 g
Peppermint oil 0.04 g Aluminium magnesium silicate 1g
Saccharin 0.05 g Carmellose sodium M 1g
Acetem (Myvacet 9–08)a (local standard) 98.4 g Citric acid monohydrate 0.05 g
Total 98.9 g (¼ 100 mL) Methyl parahydroxybenzoate 0.09 g
Raspberry essence (local standard) 2 dr
a
Distilled acetylated monoglycerides, see Sect. 23.3.6 Silica, colloidal anhydrous, compressed 0.25 g
Sodium citrate 4.7 g
Syrup BP (preserved with methyl 30 g
unpleasant; therefore saccharin and peppermint oil are added parahydroxybenzoate 1 mg per g)
as flavouring agents. A phenobarbital oral solution may Water, purified ad 107.5 g (¼ 100 mL)
serve as an example (Table 5.7).
Lipophilic solutions contain less excipients. By the lack
of water there is no grow of micro-organisms and no decom-
position reactions occur. Preservatives, antioxidants and They may interact and turn a positive effect of the other
buffers are thereby not necessary. substance into a negative effect. As an example cellulose
Lipophilic solvents can be brought into an emulsion, see derivatives may increase viscosity and wettability but
Sect. 5.4.7. decrease resuspendability. The effect of particle size,
settling rate, resuspendability of the sediment and dissolu-
tion rate may be tested by applying the tests of the British
5.4.6 Suspending Agents Pharmacopoeia, as described in the general monograph
Unlicensed Medicines [19].
As is explained in Sect. 18.4.2 the following conditions are
favourable for the formulation of an oral suspension:
5.4.6.1 Wetting Agents (Hydrophilic Excipients)
• Primary particles, no agglomerates or lumps
Substances with high surface energy are sometimes difficult
• Right particle size (not too large but not too small either)
to wet (see Sect. 18.3.2) which makes them difficult to
• Vehicle with increased viscosity and increased density
disperse: they float on the liquid or form lumps. Such a
• Intermediate between a flocculated and deflocculated
substance should be mixed with a hydrophilic substance
sediment (in order to enable safe dosing through easy
before dispersion. Appropriate hydrophilic substances are:
resuspendability and a not too fast settling)
thickening agents, sugar syrup, or silicon dioxide. The addi-
The achievement of the right particle size is discussed in
tion of a surfactant, for example polysorbate or polyvidone,
Sects. 29.2 and 29.3. The primary particle size of substances
to the aqueous phase can improve wetting as well.
processed in suspensions is generally < 180 μm. Wetting
The phenytoin in Table 5.8 is a poorly wettable sub-
agents may be necessary to break up agglomerates, mainly
stance. Therefore it is mixed with colloidal anhydrous silica
through making hydrophilic (hydrophilising).
and subsequently triturated with sugar syrup.
To increase the density of water sugar syrup can be
added. An increase of the viscosity can also be achieved by
the addition of viscosity enhancing substances. The charac- 5.4.6.2 Wetting Agents (Surfactants)
ter of the sediment may be influenced by electrolytes or Wetting of the active substance can be improved by the
surfactants. addition of a small amount of surfactant to the aqueous
Often substances are used that combine different phase. A surfactant reduces the surface tension between the
favourable properties such as increasing viscosity, decreas- water and the solid. A surfactant will also play a role in the
ing surface tension, hydrophilising the particles of the active character of the sediment. An example is polysorbate 80 that
substance etcetera. It depends on the properties of the active is processed in a griseofulvin suspension 25 mg/mL
substance and the other components of the suspension, how (Table 5.9). The disadvantage of surfactants in general (par-
a substance influences the character of the sediment (see ticularly polysorbate) is the unpleasant taste.
Sect. 18.4.2). Polyvidone K30 is used for wetting in a clioquinol
This subsection describes three groups of substances suspension 100 mg/mL (Table 5.10). The addition K30
rated by their main quality: wetting agents (including hydro- refers to the chain length and the extent to which it
philic excipients and surfactants), thickening agents and influences the viscosity in water. This substance has many
flocculating agents. Their effect on the stability of a suspen- uses including thickening agent, wetting agent and improv-
sion has to be determined carefully and in combination. ing dispersion.
5 Oral Liquids 85
Table 5.9 Griseofulvin Oral Suspension 25 mg/mL [21] Table 5.11 Thickening Agents in Oral Liquids
Griseofulvin 2.5 g Concentration
Aluminium magnesium silicate 0.88 g Thickening agent (%) Comment
Carmellose sodium M 0.88 g Carmellose sodium 0.5–1 Incompatible with cations
Citric acid monohydrate 0.066 g (middle viscous)
Methyl parahydroxybenzoate 0.066 g Carrageenan 0.1–0.75 Needs cations (e.g. calcium,
potassium, etc.) for gelling
Polysorbate 80 1g
[23]
Aluminium 0.5–2 Provides electrolytes as well
Syrup BP (preserved with methyl 30.5 g magnesium silicate (for flocculation)
parahydroxybenzoate 1 mg per g)
Hydroxyl 1–1.5
Water, purified 69.9 g ethylcellulose (HEC)
Total 106 g (¼ 100 mL) 300–560 mPa.s
Hypromellose 1–1.5
(HPMC) 4,000 mPa.s
Methylcellulose 2.5
15 mPa.s
PRODUCT DESIGN
Table 5.10 Clioquinol Oral Suspension 100 mg/mL [22] Tragacanth 0.5
Clioquinol 10 g Xanthan gum 1–3 Incompatible with polyvalent
cations
Carmellose sodium M 0.5 g
Citric acid monohydrate (crystalline) 0.1 g
Polyvidone K30 2.5 g Table 5.12 Potassium Hydrogen Tartrate Oral Suspension 188 mg/mL
Saccharin sodium 0.05 g [24]
Potassium hydrogen tartrate 18.8 g
Bitter-orange-epicarp and mesocarp tincture 1g
Ethanol (96 %) 3.3 g
Total 107 g (¼ 100 mL) Methylcellulose 15 mPa.s 2.5 g
Sorbic acid 0.2 g
5.4.6.3 Thickening Agents Total 114.7 g (¼100 mL)
Increasing the viscosity of water by the addition of
thickening agents reduces the settling rate of particles (see
Sect. 18.4.2). For thickening agents reference is made to
pH of this suspension is 3.0–3.5. Cellulose derivatives, such
Sect. 23.7 regarding their chemical composition, general
as methylcellulose, may hydrolyse at low pH. The polymer
use and their way of processing. In Table 5.11 the most
chain is broken down and the viscosity will decrease. The
commonly used thickening agents in oral liquids are listed.
shelf life is therefore limited to 3 months.
Apart from being used for decreasing the settling rate in
A naproxen oral suspension (Table 5.13) is an example
suspensions, they may also be used for shielding the taste
for using tragacanth as a thickening agent. It is combined
buds from an unpleasant taste and for improving the flow of
with sucrose and for taste improvement sodium chloride is
the oral liquid from the bottle or the dosing device.
added.
Using thickening agents of natural origin such as agar,
Ferrous fumarate can be brought into a suspension with
tragacanth or gum Arabic the microbiological quality
colloidal aluminium magnesium silicate (Table 5.14), which
requires constant attention. The sterilisation of the raw
also acts as a flocculating agent.
materials with ethylene oxide is not allowed in pharmaceu-
tical use and autoclaving a thickened base may decrease
viscosity. Therefore an effective preservation is very 5.4.6.4 Flocculating Agents
important. Flocculating agents are added for creating an open and large
Xanthan gum and carrageenan are contained in the volume sediment that can be resuspended easily; they pre-
suspending base Ora-Plus®. vent ‘caking’: the occurrence of a compact sediment on the
Some examples of the use of thickening agents are given. bottom of the bottle (see Sect. 18.4.2). In suspensions with
In a potassium hydrogen tartrate suspension (Table 5.12) negatively charged particles, multivalent cations, such as
methylcellulose 15 mPa.s is applied as thickening agent. The aluminium ions, may cause flocculation. On positively
Table 5.13 Naproxen Oral Suspension 50 mg/mL [25] Table 5.15 Sulfadiazine Oral Suspension 100 mg/mL [27]
Naproxen 5.0 g Sulfadiazine 10 g
Sucrose 22.0 g Aluminium magnesium silicate 0.54 g
Sodium chloride 0.5 g Carmellose sodium M 0.54 g
Potassium sorbate 0.15 g Citric acid monohydrate 0.63 g
Citric acid, anhydrous 0.35 g Methyl parahydroxybenzoate 0.07 g
Tragacanth 0.6 g Raspberry essence (local standard) 0.3 g
Water, purified 81.4 g Sodium citrate 4.7 g
Total 110.0 g (¼100 mL) Syrup BP (preserved with methyl 30 g
Total 114 g (¼ 100 mL)
Table 5.14 Ferrous Fumarate Oral Solution 20 mg/mL [26]
Ferrous fumarate 2.15 g
Aluminium magnesium silicate 2g
Raspberry essence (local standard) 0.05 g Table 5.16 Paraffin Oral Emulsion [28]
Sorbic acid 0.1 g Paraffin, liquid 5.15 g
Sorbitol, liquid (crystallising) 28 g Benzoic acid 0.1 g
Water, purified 76.2 g Citric acid monohydrate 0.1 g
Total 108.5 g (¼ 100 mL) Methylcellulose 15 mPa.s 1g
Peppermint oil 1 dr
charged particles anions such as citrate ions may also have
this effect.
practice with the active substance concerned. This concerns
Aluminium and magnesium ions may be added by means
both the physical and the chemical stability.
of the thickening agent aluminium magnesium silicate. This
substance forms a colloidal solution and gives a low concen-
tration cations that keeps the sediment flocculated (see
example in Table 5.15). 5.4.7 Agents for Emulsifying and Solubilising
Citrate ions are usually added in the form of sodium
citrate or citric acid. Apart from creating a flocculated sedi- Emulsions for oral use are predominantly of the type o/w. In that
ment they create a buffer. An example of a suspension in way the disadvantage of messiness and unpleasant taste of lipids
which citric acid and citrate are applied is given in is partly overcome. Emulsifying occurs by reducing the droplet
Table 5.15. size of the lipid phase and increasing the viscosity of the outer
The choice of the right flocculating substances, the com- phase generally with use of a thickening agent (that lowers the
bination and the concentration depend on the properties and interfacial tension). Thickening agents (see Sect. 5.4.6.3) that are
concentration of the active substance. Adding too many ions used for emulsifying, such as methylcellulose, hypromellose,
can influence the settling behaviour and the resuspendability methylhydroxylethylcellulose and hydroxypropylcellulose,
even negatively. possess interfacial tension-reducing properties.
The combination of carmellose sodium with aluminium An example of an emulsion for oral use is paraffin emul-
magnesium silicate is a common combination in oral sion (Table 5.16).
suspensions. Carmellose enhances the viscosity and is easy Solubilisates are colloidal solutions of a liquid in another
to process. However, it cannot always avoid a compact liquid that is not miscible with it (see Sect. 18.3.3). The
sediment. Aluminium magnesium silicate creates an open fat-soluble vitamins A, D and E are to be administered as
sediment that is easy to disperse. It also has some viscosity solubilisates to patients with impaired fat absorption, such as
enhancing properties. patients with cystic fibrosis, to get the vitamins absorbed.
The base for oral liquid Ora-Plus® contains a combina- Fat-soluble liquid active substances can be solubilised using
tion of xanthan gum and carrageenan as thickening agents, surfactants, whereby colloidal particles, micelles, are
with citric acid as flocculating agent. formed. Relatively high concentrations of surfactants are
The effectiveness of both combinations of thickening necessary because they have to exceed the critical micelle
agents and flocculating agent has to be investigated in concentration. Polysorbate 80 (see also Sect. 23.6.4) is
5 Oral Liquids 87
Solubilisates of vitamin A and E may be prepared in a Vitamin E is available as tocopheryl polyethylene

simpler way if other chemical forms of these vitamins glycol succinate (TPGS). Tocopherol is esterified via
are used. Vitamin A is described as a mixture with a succinate to polyethylene glycol. This substance can
solubilisating substance as raw material in the be dissolved in a high concentration in water under
Ph. Eur.: Synthetic Vitamin A concentrate micelle formation. For the formation of micelles no
(solubilisate/emulsion). This raw material contains excipient (but a preservative) is needed because the
vitamin A, solubilising agent(s) and may contain TPGS has surfactant properties (Fig. 5.2).
preservatives and antioxidants.
Fig. 5.2 Structure of TPGS CH3

CH3
H3C O CH3
O
O CH3 CH3 CH3
O
HO n
O CH3
PRODUCT DESIGN
(continued)
The solubility of active substances often depends on the

Table 5.17 Vitamin A Oral Aqueous Solutiona 50,000 IU/mL [29] pH (see Sect. 5.8.1). By adjusting the pH, a solution or a
Vitamin A concentrate (oily form), synthetic 5g suspension may be prepared (see Sect. 19.1.1). The pH can
1,000,000 IU/g affect the stability of an active substance or excipient. For
Citric acid monohydrate 0.24 g example, the hydrolysis rate of esters depends on the pH (see
Polysorbate 80 12.5 g
Sect. 22.2.1). The pH must be taken into account for the
Potassium sorbate 0.3 g
preservation of an oral solution. The preservative sorbic acid
Star anise oil 0.22 g
is only effective at a pH < 5.5 and the preservative methyl
Syrup BP (preserved with methyl 12.5 g
parahydroxybenzoate 1 mg per g) parahydroxybenzoate undergoes hydrolysis at pH > 8.
Water, purified 73 g The pH can be adjusted with buffering agents. The most
used buffering agents in oral fluids are phosphates or
Total 104 g (¼ 100 mL)
citrates. Citrates may be used for the pH range 3–6,
a
This solution is actually a solubilisate phosphates for the pH range 5–8. To adjust to an even higher
pH, trometamol can be used, which as a solid has the advan-
tage above NaOH solution that it can be weighed.
commonly used as a surfactant for pharmacy prepared
solubilisates.
The proportion between oil and surfactant has to be
5.4.9 Preservation
determined in practice. In a vitamin A oral aqueous solution
containing 50,000 IU/mL the proportion oil:polysorbate
Water supports the growth of micro-organisms, therefore
80 of 1:2.5–3 is used (Table 5.17). This appeared also to
oral aqueous solutions, suspensions, emulsions and
be applicable to the analogous cholecalciferol oral aqueous
solubilisates in multidose containers should be preserved.
solution 50,000 IU/mL.
Preservatives may be used for that purpose as well as
excipients with preservative properties, such as propylene
glycol. See Sect. 23.8 for extensive information on
5.4.8 pH preservatives. Table 5.18 summarises preservatives with
properties especially relevant for oral liquids.
The pH of an oral liquid is important for the flavour, solubil- The choice of the preservative is determined by the pH,
ity and stability of the active substance and for preservation. the presence of antimicrobial co-solvents, the presence of a
The preferred pH for an oral solution is between 5.5 and 7.5. lipid phase and whether, because of the adverse effects, the
A pH < 5.5 often tastes better, but may degrade the tooth liquid is intended for adults or neonates or children. It is
enamel although the total amount of free acid plays a role as shown that oral liquids with a pH > 8 are difficult to pre-
well [30]. A pH above 8 often gives an unpleasant taste. serve, apart from giving taste problems.
Table 5.18 Preservatives for Use in Aqueous Oral Liquids

Concentration in the aqueous
Preservative pH range phase (% g/v) Suitability for neonates and children
Benzoic acid <5 0.1–0.2 Not appropriate: incomplete metabolism in neonates; may cumulate in the
central nervous system
Ethanol Whole 15–20 Not suitable for young children, see Sect. 5.4.5.2: Unpleasant taste should be
range considered
Glycerol 85 % Whole 30 Appropriate, osmotic effect to consider
range
Methyl <8 0.1–0.2 Appropriate in every age group [31]
parahydroxybenzoate
Propyl <8 0.1–0.2 No data in children <2 years, may influence the maturation of the
parahydroxybenzoate reproductive system [31]
Propylene glycol Whole 15 Strict limitation in preterm and term neonates [17]
range Unpleasant taste should be considered
Sorbic acid <5.5 0.1–0.2 Appropriate in every age group
How to Preserve Antacid Suspensions concentration of chloral hydrate. Methylparaben is not

The pH of antacid suspensions is between 7.7 and 8.2. added separately to this solution, it originates from the
This pH range is very unfavourable for the stability and added marshmallow syrup. The concentration
effectiveness of methyl parahydroxybenzoate and no methylparaben in the solution is 0.085 %.
other preservatives are available for that pH range.
Table 5.19 Chloral Hydrate Oral Solution [32]
Propyl parahydroxybenzoate can be added but addi-
tional measures are needed to achieve a reasonable Chloral hydrate 10 g
shelf life: the use of raw materials with a low bioburden, Peppermint oil 0.04 g
preventing contamination during preparation, storage in Water, purified 10 g
the fridge, small bottles, limited usage period. Marshmallow syrup (local standard) 109.9 g
Total 129.9 g (¼ 100 mL)
5.4.9.1 Methyl and Propyl Parahydroxybenzoate Methylparaben must not be combined with polysorbate
Methyl parahydroxybenzoate (MOB or methylparaben) is or used when a lipid phase is present. It forms micelles
most widely used in oral liquids. As an ester it is stable with polysorbate, making it ineffective. If the preparation
between pH 3 and 6. Outside these pH limits methylparaben contains a lipid phase (in the case of an emulsion
will hydrolyse, which amounts for example to 25 % in or solubilisate), methylparaben will dissolve in it rendering
12 months in an oral solution with pH 7.0–7.5 (prednisolone the aqueous phase insufficiently preserved.
oral solution, see Table 23.23) at room temperature. Disadvantages of both methyl and propyl parahydroxy-
At pH 7–8 methylparaben is less stable and also less benzoate are allergic reactions and an unpleasant tingling
effective. Propyl hydroxybenzoate can be added to increase sensation experienced by several patients when the solution
the preservative effect. If the pH > 8, methylparaben is of contacts their tongue.
no use any more.
The solubility of methylparaben in water is about 1 in
5.4.9.2 Benzoic Acid and Sorbic Acid
400 (0.25 %) but will be decreased by the presence of dissolved
Benzoic acid contains a carboxyl group (pKa 4–5) making it
salts, causing methylparaben to precipitate. In oral liquids
only effective at pH < 5. It may cause allergic reactions and
usually 0.15 % of the aqueous phase is used, but 0.1 % in the
is notorious for its toxicity in neonates and babies. Because
presence of a high concentration of salts (see Sect. 23.8.5).
of these disadvantages benzoic acid is rarely used in oral
liquids.
In chloral hydrate oral solution 100 mg/mL Sorbic acid is preferably used at pH 4.5–5.5 and is not
(Table 5.19) methylparaben in a concentration of related to allergic reactions with oral use. For easy
0.15 % would precipitate because of the high processing and obtaining the right pH, sorbic acid is often
applied as combination with potassium sorbate.
(continued)
5 Oral Liquids 89
Sorbic acid has a more suitable fat-water distribution than 5.4.11 Flavour
methylparaben, which makes it better applicable in
emulsions. For solubilisates there is however a problem to Dissolved substances directly touch the taste buds, much
overcome because sorbic acid adsorbs onto polysorbate, heavier than when present in oral solids. An unpleasant
which is often used as a solubilising agent. Therefore the taste can give, especially in children, a tremendous resis-
processed quantity of sorbic acid should be larger than the tance to taking the medicine. This makes taste masking of
solubility of sorbic acid in water. Potassium sorbate is used oral liquids very important. Taste masking in oral liquids is
to achieve this. Potassium sorbate is dissolved in water and often needed to improve palatability of the medicine. Chil-
then converted to sorbic acid using citric acid. Part of the dren have a well-developed sensory system for detecting
sorbic acid dissolves in the lipid phase and adsorbs to the tastes, smells and chemical irritants. They are able to recog-
polysorbate. The free sorbic acid serves to preserve the nise sweetness and saltiness from an early stage and are also
aqueous phase [33]. See further Sect. 23.8.6. able to recognise a sweet taste in oral liquids and the degree
of sweetness. Children seem to prefer sweeter tastes than
5.4.9.3 Other Preservatives adults do. The unpleasant taste of an active substance,
Co-solvents such as ethanol, sugars, polyols, propylene gly- e.g. bitterness or a metallic taste, is, therefore, often masked
PRODUCT DESIGN
col and glycerol, also have preservative properties if they are in an oral liquid by the use of sweetening agents and
present in sufficient concentration (see also Sect. 23.3). flavours. However, a child’s preference for particular
Propylene glycol at 15 % is not quite as effective as sorbic flavours is determined by individual experiences and culture.
acid or methyl parahydroxybenzoate and tastes unpleasant. The target for taste masking needs not necessarily to be
Glycerol 85 % in concentration 30 % preserves less well good-tasting medicines; it should simply be a taste that is
than propylene glycol but tastes slightly sweet. acceptable [35].
Sucrose (present in syrups, see Sect. 23.4.4) preserves in The taste can be improved by the addition of flavouring
concentrations above 63 % m/v. Usually syrups contain agents, by shielding the taste buds and by adjusting the taste
0.1–0.15 % methyl parahydroxybenzoate. of the active substance.
Ethanol preserves in concentrations above 15 % v/v. If
sufficient ethanol is present in oral preparations, no other 5.4.11.1 Flavouring Agents
preservatives are needed. See Table 5.19 however for the A flavouring agent includes the existing taste in a flavour
restrictions for oral liquids for children. that is experienced as less unpleasant. Apart from a suitable
flavour also a smell suiting the basic taste has to be added.
For example, if an unpleasant bitter or sour tasting oral
5.4.10 Excipients and Children liquid has a smell that suggests the bitter, respectively sour
taste, the preparation will be experienced as less unpleasant.
As mentioned in Table 5.18, some of the excipients are not The colour may also play a part by arousing a particular
suitable for children. The information available on the taste.
acceptability of excipients for paediatric age groups is sparse For taste improvement some general principles can be
and distributed over various sources. Hence, European applied:
(Eu) and United States (US) Paediatric Formulation • Sour flavours can be improved with acid flavours proba-
Initiatives (PFIs) are collaboratively creating a database bly in addition with sweet flavourings. Also substances
Safety and Toxicity of Excipients for Paediatrics (STEP). that suggest a sour taste by smell or colour (for example,
This STEP database provides specific safety and toxicity lemon + yellow or raspberry + red) can be used.
data on target age groups, route of administration, treatment • Bitter flavours can be improved with flavourings with a
duration, concentration, maximum daily excipient intake pleasant bitter taste, probably in addition with sweet
and exposure extracted from selected information sources. flavourings, for example chocolate/vanilla.
The data in the STEP database would be derived from • Sweet flavours can be improved with peppermint, proba-
publicly and commercially available information sources bly in combination with sour or bitter flavours. Corrigents
together with any information shared by the industry. It that suggest a sweet taste by smell or colour can be added,
will be accessible freely online thereby facilitating such as vanilla and fruits.
paediatric formulation development. • Salty flavours can be improved with ethanolic anise
Currently, a pilot version of the STEP database compiling extract or liquorice or with tomato juice.
the data for 10 prioritised excipients, for example propylene Non-cariogenic sweeteners and flavours are preferred.
glycol, ethanol and benzyl alcohol, is in process. If the pilot Most essences only influence the odour; they influence
is proved to be successful, the database will be expanded to a the taste if they are combined with a basic taste (usually a
fully released database and will eventually include many sweet substance).
excipients [34]. Table 5.20 summarises taste improving substances.
Table 5.20 Substances that may improve specific tastes

Sweet
Sugars Sucrose, glucose, fructose
Sugar containing products Syrups (10–20 % of the oral liquid), honey, lemonade, fruit juices
Polyols Sorbitol (available as sorbitol solution 70 %), mannitol, xylitol, glycerol
Artificial sweeteners Saccharin sodium (0.01–0.5 %; mostly 0.1 %), aspartame, acesulfame potassium and sodium cyclamate
Sour
Dilute organic acids Tartaric acid, but mainly citric acid and carbonic acid (for example created by effervescent powders)
Products with acids Raspberry syrup, poppy syrup and diluted inorganic acids such as dilute hydrochloric acid, dilute sulfuric acid and
dilute phosphoric acid
Bitter
Orange peel Orange peel syrup, orange peel tincture
Cinnamon Cinnamon syrup or ethanolic extracts
Cacoa Cacoa and cacoa syrup
Other
Essential oils Peppermint oil (1–2 drops per 100 mL), anise oil, lemon oil, cinnamon oil, sweet orange oil
Other volatile, aromatic Vanillin, piperonal
substances
Essences Orange, cherry, raspberry, lemon, banana, vanilla, vanilla-cocos, cognac
Ethanol or alcoholic oral Cognac, brandy
liquids
In literature standard concentrations may be stated but Table 5.21 Midazolam Hydrochloride Oral Solution [37]
they usually refer to foods and beverages, not to bad tasting
Midazolam hydrochloride 0.222 g
active substances. The necessary concentration very much Sucrose 25.0 g
depends on the taste and concentration of the active sub- Potassium sorbate 0.15 g
stance, pH etcetera, and only can be determined experimen- Citric acid, anhydrous 0.2 g
tally. For testing the performance of taste correction specific Raspberry essence 0.11 g
methods have been developed. Water, purified 83.918 g
For children up to about 4 years sweet oral liquids with
Total 109.6 g (¼ 100 mL)
banana or raspberry essence are preferred [36]. A midazolam
hydrochloride oral solution (Table 5.21) usually applied in
the premedication of children before surgery or clinical
allowance for adults must be limited to 20 g. The sorbitol
diagnostics contains sucrose as sweetening agent and rasp-
dose that leads to diarrhoea in children is 0.5 g/kg [38].
berry flavour, which is favoured by younger children.
Some patients consider the energetic value of sugars or
Syrups (see Sect. 23.4.4) are widely used for the improve-
sorbitol as a problem and demand artificial sweeteners in
ment of unpleasant tasting active substances. A disadvantage
their medicines. Their effect depends very much on the
of using sucrose-containing syrups is that these are cario-
active substance in the oral liquid and cannot be derived
genic: bacteria in the mouth convert sucrose into acids,
from usual concentrations in soft drinks.
which cause cavities.
Another disadvantage is supposed to be the caloric value
that diabetics have to take into account. However, with the Investigations of the Laboratory of Dutch Pharmacists
increased use of blood glucose monitors and relatively sim- regarded the replacement of sugar syrup in several oral
ple insulin delivery devices it has become easier to match the solutions as pharmacy preparations. It was shown for
carbohydrate intake to the blood sugar level, especially for instance that in the ‘sweetness area’ of 10–100 %
patients with type I diabetes. Apart from that the contribu- sugar syrup the combination sodium cyclamate with
tion of sugar through medicines is small and it is actually not acesulfame potassium (4:1) tastes good, while the
necessary to develop special sugar-free medicines for corresponding sweetness amount of sodium cyclamate
diabetics. as well as the corresponding sweetness amount of
A 70 % sorbitol solution can be used for its sweetness if saccharoid sodium taste bitter. The latter also applies
no sugar is desired. It has the disadvantage of being an to the combination saccharoid sodium/sodium cycla-
osmotic laxative because it is only absorbed slowly from mate 1:10.
the gastrointestinal tract. To avoid this effect the daily
5 Oral Liquids 91
Table 5.22 ADI-value of some Sweeteners [39] irrelevant degradations. It should of course not be used to
Sweetener ADI mask a relevant decomposition (see Sect. 22.2.2).
Acesulfame potassium 9 mg/kg Only water-soluble colouring agents are processed in oral
Aspartame 40 mg/kg liquids (Table 23.11). They are, whether or not through a
Sodium cyclamate 8 mg/kg dilution, dissolved in the preparation. Colouring agents that
Sodium saccharin 2.5 mg/kg do not dissolve in water (often inorganic substances:
pigments) cannot be processed in liquid forms.
For the application of artificial sweeteners in medicines

that are taken for a long time, the ‘Acceptable Daily Intake’
(ADI) must be taken into account [39]. For some common
5.4.13 Incompatibilities
sweeteners the ADI-values are shown in Table 5.22.
Incompatibilities in oral liquids can take place between
active substances and excipients, among active substances
5.4.11.2 Shielding the Taste Buds
and among excipients. It may regard to formation of insolu-
A simple method for improving unpleasant tastes is local
ble salts or adsorption by thickening agents. Another type of
anaesthesia of the taste buds. This can be achieved by taking
PRODUCT DESIGN
incompatibility is the change of pH brought about by an
the oral liquid immediately from the fridge or by adding
active substance, causing the preservative becoming ineffec-
menthol (peppermint oil, peppermint syrup). Menthol has a
tive. Well-known is the incompatibility of negatively
slight local anaesthetic effect. Taking an oral liquid with
charged thickening agents (carmellose sodium, xanthan
fruit juice, lemonade (syrup), fruit concentrate or food also
gum) with positively charged active substances or
masks the taste buds. Increasing the viscosity by syrups, gels
excipients.
and emulsions is a last option. Enhanced viscosity decreases
Incompatibilities may become relevant from a solution
stimulation of the taste buds and change the ‘taste experi-
that contains more of the dissolved substance than could be
ence’ of an oral liquid.
dissolved by the solvent under normal circumstances (super-
saturated). To avoid these incompatibilities the order of
5.4.11.3 Adjusting the Taste of Active Substances
dissolving and mixing should be so that no high
An alternative approach for the improvement of the taste of
concentrations are created during preparation. For example
an oral liquid is to improve the taste of the active substance.
the relative incompatibility (precipitation) between lido-
This can be achieved by physico-chemical changes:
caine cation and phosphate anion can be circumvented by
• Formulating a suspension from the slightly soluble salt or
dissolving lidocaine hydrochloride after sodium phosphate
less soluble component (see Sect. 18.1). Examples are:
has been dissolved instead of adding both substances to
taking ferrous fumarate instead of ferrous sulfate, taking
purified water at the same time. Substances of vegetable
amitriptyline pamoate [40] instead of its HCl salt, which
origin can cause precipitations and discolouration.
is also applicable to other phenothiazines. Of course
bioavailability has to be assessed anew.
• Decreasing the dissociation. As an example: the bitter
taste of magnesium sulfate is caused by the magnesium 5.4.14 Chemical Stability
ion. The addition of dilute sulfuric acid reduces the dis-
sociation and the number of free magnesium ions, thereby See Chap. 22 for information on Stability. Dissolved
improving the taste. substances are more accessible and thus sensitive to degra-
• Complex formation. An example: complex formation of dation than if present as particles in suspension. Most stabil-
ferrous ion with citric acid, which reduces very much the ity issues arise for that reason in aqueous solutions. The two
concentration of ferrous ions. main degradation reactions are hydrolysis (see Sect. 22.2.1)
and oxidation (see Sect. 22.2.2). The rate and degree of
hydrolysis is pH-dependent.
5.4.12 Colouring Agents
In prednisolone sodium phosphate oral solution (see
Colouring agents, as flavourings, are used to make the medi-
Table 23.23) the main degradation reaction is hydro-
cine more acceptable for the patient. Sometimes colouring
lysis of the corticosteroid-phosphate ester catalysed by
agents are used to prevent mix-ups, which however is con-
hydrogen ions. The phosphate group is split off. At
trary to the principle that the label always should be read
pH 7–8 this hydrolysis is minimal [28], therefore the
well. Colouring agents are also used to protect light-
sensitive medicines or to prevent patients’ concerns about (continued)
crystallising will easily occur. With low-dosed substances

pH of the oral solution in Table 23.23 is 7.1. At this any crystals or precipitate will not always be visible.
pH, however, the preservative methyl parahydroxy- Crystallisation may lead to underdosing and, at a later
benzoate hydrolyses as well. After 12 months, the stage, to an overdose as the settled crystals are taken at the
concentration methylparaben has dropped by 25 %. last dose. This is the reason why some oral liquids need to be
stored at room temperature (15–25 C). Crystallisation and
storage temperature not only concern the active substances
Oxidation, in oral liquids, in practice is inhibited by but also preservatives. The crystallisation of methyl
removal of oxygen from water by boiling, reduction of parahydroxybenzoate is described in Sect. 5.4.9.
headspace by completely filling of bottles, addition of a Suspensions are physically unstable preparations: sedi-
chelating agent (sodium edetate) for the removal of mentation occurs at storage. The monograph Unlicensed
catalysing traces of metals and the addition of antioxidants, medicines in the British Pharmacopeia describes how to
such as ascorbic acid (see Sect. 22.2.2). assess the settling and resuspendability (see Sect. 32.7.2).
Sugars may also protect against oxidation through their
reducing properties. In addition, when using a concentrated
sugar solution less oxygen will be dissolved in it.
Examples of oxidation reactions in oral liquids can be found 5.4.16 Containers and Labelling
at ferrous salts, morphine salts and phenothiazine derivatives.
Ferrous salts are easily oxidised in solution into the inac- Oral liquids are usually delivered in glass or plastic bottles.
tive ferric salts. This can be inhibited by complex formation Generally brown glass is used to protect the content from
with citric acid, addition of reducing sugars, reducing the light. Glass vials may be equipped with a pouring ring.
amount of air oxygen by completely filling of the bottles and General guidelines for the packaging and labelling are men-
by exposing to light. tioned in Chap. 21. Oral suspensions as well as oral
Morphine salts are converted to the inactive emulsions have to be delivered in bottles that leave enough
pseudomorphine at pH > 4.5 in the presence of oxygen. headspace for shaking. A suspension can also be filled into
Therefore in the example formulation of Table 5.23 the single-use (oral) syringes with a closure but only if the
solution is acidified with citric acid to pH 2.5–3.5. Disodium settling behaviour allows easy redispersion.
edetate is added for further protection against oxidation.
Phenothiazine derivatives and related compounds oxidise Packaging in Specific Situations
rapidly if dissolved. This degradation can be inhibited by the Some ferro salts are delivered in bottles of uncoloured
addition of 0.5 % ascorbic acid. glass because oxidation of ferrous to ferric ion is
inhibited by light.
For supplying oral liquids such as methadone oral
5.4.15 Physical Stability solution to drug addicts single-use plastic cups have to
be preferred to prevent abuse. They cannot pretend
Oral solutions can be physically unstable through they have broken a glass bottle or to be tempted to
crystallizing of dissolved solids, which in practice may sell part of the liquid.
occur when solutions are put in the fridge. The solubility An oral gel (for instance a hydrogel with lidocaine
of most active substances is lower at low temperature than at hydrochloride) is best packed in a plastic bottle with
higher temperatures (see also Sect. 18.1). And if they are spout or dosing dispenser because of its rather high
dissolved in a concentration that is just below their solubility consistency.
The label must meet the requirements as mentioned in

Table 5.23 Morphine hydrochloride Oral solution 1 mg/mL [41]
Sect. 37.3.1. The label of suspensions and emulsions should
Morphine hydrochloride 0.1 g
mention “shake well before use”.
Cognac essence (local standard) 0.17 g
Disodium edetate 0.1 g
Ethanol (96 %) 8.1 g 5.4.17 Dosage Delivery Devices
Water, purified 90.6 g Most liquid oral medicines are dosed in millilitres. These are
Total 99.3 g (¼ 100 mL)
measured with a measuring cup (24.4.19.3) or an oral
syringe (see Sect. 24.4.16). The volume of the dosage device
5 Oral Liquids 93
or a multiple thereof should match the dosage or should be processed for oral solutions, or for improving homogeneity
clearly readable in millilitres. See Sect. 37.4.3. and decreasing settling rate when processed in an oral sus-
Some liquid oral medicines are dosed in drops. This may pension. For pulverising see Sect. 29.2.
be practical but the doses that are administered in the form of
drops should meet the requirements for uniformity of weight
and content. For pharmacy preparations the requirements for 5.5.1.2 Use of a Solution Licensed for a Different
oral drops of the Ph. Eur. cannot be achieved with the Route
available dropper devices. See further Sect. 24.4.19.4–6. If there is no raw material available but a liquid preparation
is available with the same active substance as licensed prod-
uct, it may be able to use that preparation. A parenteral
5.4.18 Storage preparation is usually the best option. But especially if the
oral liquid is meant for children, be careful with some
See Sect. 22.7 for the general approach. For standard excipients of which children could be especially sensitive.
preparations the storage temperature and shelf life of an Points to work out when adapting:
unopened container and after opening (in use period) should • Does the demanded concentration require dilution?
• Are the excipients safe?; will particularly complexing
PRODUCT DESIGN
be determined during the design phase. For non-standardised
preparations with a reliable preservation but with an uncer- agents, antioxidants, co-solvents and organic solvents
tain chemical or physical stability it is recommended to limit irritate the gastrointestinal tract or, if administered by an
arbitrarily the shelf life after opening to a maximum of enteral feeding tube, will they be compatible with the
1 month. tube components?
If preservation is not possible due to hypersensitivity or • Will the shelf life be different?; will active substances in
toxicity (for example in premature infants or when a large parenterals that are filled under nitrogen oxidize after
volume is taken at once), or very impractical (if preparing opening?
large amounts of bottles cough syrup from a concentrate), • Will the pH of the parenteral solution cause irritation or
the oral liquid should not be kept longer than 14 days, and decrease absorption?
preferably in the refrigerator. Some oral preparations have to
be stored in the refrigerator (2–8 C) because of the chemical 5.5.1.3 Adapting Oral Solid Dosage Forms
or microbiological stability. Storage in the refrigerator is not If the active substance is not available as raw material it may
always possible if active substances and excipients are about be processed from oral solid dosage forms by adapting those.
to crystallise (see Sect. 5.4.9). In addition, preservatives Not all solid dosage forms however are fit for such an
work less well at low temperatures (see Sect. 23.8). operation. Tablets with a gastro-resistant coating or
modified-release tablets should not be crushed unless the
product information confirms its suitability, see further
5.5 Method of Preparation Sect. 4.10.7.
If there is no problem in adapting the oral solid, several
The preparation of oral liquids generally follows the basic methods of processing present themselves: crushing or
operations such as dissolving, mixing and dispersing pulverising in a mortar, (half-)mechanically pulverising,
described in Chap. 29. The method depends on the dispersing in water.
characteristics of the formulation: solution, suspension,
emulsion. This section discusses as well the increasing
non-availability of the active substance as a raw material. 5.5.1.4 Crushing and Pulverising Oral Dosage
Preparation processes (or steps or unit operations) are Forms
treated as well as in-process controls, release control and Crushing a tablet in a mortar has some disadvantages:
quality requirements. • Loss of active substance because of crushed particles
flying off or because of adherence at the mortar’s wall.
• The operator may get exposed to the active substance;
5.5.1 Availability and Pre-treatment hazardous substances demand specific ventilation or the
of the Active Substance use of personal protecting equipment (see Sect. 26.4.1).
• The need of muscular strength for crushing; RSI (repeti-
5.5.1.1 Pulverising the Raw Material tive strain injury) problems may occur in nursery homes
If the active substance is available as raw material, it some- if caregivers have to crush tablets for many patients.
times has to be pulverised to obtain smaller particles. They These drawbacks are less severe if a mechanical crusher or
may be needed for increasing the dissolution rate when pulveriser is used such as the Pill Drink (see Fig. 37.5).
5.5.1.5 Dispersing in Water

Oral solids can be dispersed in water. Effervescent tablets Rinsing (with propylene glycol; water causes pre-
immediately disperse in water. Granulates and granules, cipitation in the syringe or beaker) is not to be
tablets and orodispersable tablets (melting tablets) are to be recommended because it will increase the amount of
dispersed by shaking with lukewarm water (35 C), for propylene glycol of the liquid.
instance 20–30 mL. If dispersing takes more time, as is the The concentrated methylparaben solution can be
case with coated tablets, it is better to use water with a higher added to a volume of maximal 500 mL at once, after
temperature. Capsules should be opened before dispersing. which the liquid should be shaken vigorously immedi-
The solubility of the active substance determines if the ately. Processing larger volumes manually may lead to
active substance will be dissolved or dispersed, see precipitation due to supersaturation. In that case it is
Sect. 5.4.2. Because most tablet excipients are insoluble, the better to add the methylparaben solution gradually
oral liquid will become a suspension of excipients anyhow. while continuously mixing.
5.5.2 Dissolving If sorbic acid is used as preservative, it is dissolved

in water under boiling. During dissolution, the vessel must
In general, soluble solids, such as buffers and antioxidants,
be covered to avoid evaporation of the sorbic acid with
are dissolved separately in the vehicle. The solution process
steam.
can be speeded up by stirring, by using smaller particles (see
After processing all materials, the liquid should be made
Sect. 23.5), or by heating if the active substance withstands
up with the solvent to 100 % volume. This is because usually
it. Dissolving by heating of substances that are not soluble at
a volume unit is dosed. However, it is highly recommended
room temperature is not reasonable. These substances will
to state the required end weight because this is more accurate
crystallise once the ‘solution’ is cooled down.
and weighings can be recorded unmistakably. If the specific
In many oral liquids the preservative methylparaben is
gravity is not known, the liquid has to be made up to volume,
used. Its dissolution rate can be increased by heating or by
preferably by using a measuring cylinder.
using concentrated solutions in organic solvents such as
propylene glycol (see also Sect. 23.8.5).
Dissolution under boiling improves the microbiological 5.5.3 Mixing
quality of the water. The risk of superheating (followed by
boiling over) however, causing breakage of the glassware, Different liquid excipients are mixed with each other if
may overshadow this advantage especially when large possible. Volume amounts are preferably converted to
vessels are involved. The addition via a concentrated solu- weights (see Sect. 23.1.6). The liquids can be directly
tion is preferred in practice. weighed into the vehicle. If necessary the quantities can be
measured with a measuring cylinder or a pipette and trans-
ferred into the bottle. The measuring cylinder should be
Methylparaben Concentrates in Practice rinsed. The pipette is not rinsed, except for highly viscous
Methylparaben may be used as a concentrate, such as: liquids (Sect. 23.1.6).
methyl parahydroxybenzoate 15 g with propylene gly- For (highly) viscous liquids additional attention has to be
col 91 g (¼ 100 mL). Although weighing a quantity is paid to the mixing process because these liquids are difficult
generally to be preferred over measuring the volume to mix. If ‘strings’ in the solution are visible, it is a sign that
(see Sect. 29.1.2), in case of the addition of a the solution is not sufficiently homogenised.
methylparaben concentrate to oral liquids, volume
measuring has some advantages. These advantages
become clear by the following directions. Insufficient mixing at the preparation of a mixture of
• The liquid has to be shaken immediately after the phytomenadione with arachis oil (for the oral solution
addition to get the methylparaben dissolved; thereof Table 5.24) caused large variations of content
fore the necessary amount of methylparaben needs between the vials of the same batch. Only if
to be weighed or measured beforehand. phytomenadione was mixed with small portions of
• The low necessary amounts would require a bal- arachis oil and the homogeneity was checked (inho-
ance able to weigh milligrams. mogeneity may look like trails or strings) after each
Mind that the concentrate has to be transferred addition, sufficient homogeneity was obtained. By
quantitatively, which is easier with a plastic syringe mixing in a translucent barrel a better visual control
with plunger than from a (glass) weighing beaker. on the homogeneity after mixing is possible.
(continued) (continued)
5 Oral Liquids 95
prepared by processing a suitable thickening agent in the

Table 5.24 Phytomenadione Oral Solution 10 mg/mL [42] aqueous phase. For the dispersion method of the thickening
Phytomenadione 1g agent see Sect. 23.7. The liquid that has to be emulsified is
Arachis oil, refined 90.2 g added drop by drop to the base gel under mixing. With a
rotor-stator mixer a finer divided dispersed phase is
91.2 g (¼ 100 mL)
obtained. Water is added in small portions and mixed care-
fully for the dilution and making up to the right volume.
5.5.6 Solubilising
5.5.4 Dispersing
At small scale solubilisates can be prepared by mixing firstly
Dispersion will take place in a mortar or by means of a rotor- the surfactant and the solubilising liquid in a mortar. Subse-
stator mixer, see further Sect. 29.7.1. An alternative method quently this mixture is mixed with sugar syrup and diluted
may be the use of the precipitation method (see Sect. 29.2.3). gradually with parts of the aqueous phase in which the
In most oral liquids thickening agents are used. They potassium sorbate has been dissolved. Then a solution with
PRODUCT DESIGN
have to be hydrophilised and dispersed in the liquid before citric acid is added and filled up to the right volume. The
they can be dissolved. If not, lumps may be created that mortar should be carefully degreased prior to the preparation
block the dissolution process. The processing of thickening to avoid that the extra fat prevents the formation of a
agents is discussed in Sect. 23.7. solubilisate. But aggregates may be formed instead of
An example of a method for dispersing is given in micelles if the proportion between the amounts of
Table 5.25. The active substance nitrofurantoin is surfactants and fat has been disrupted, for example by incor-
hydrophilised by mixing it with silica. The thickening agents rect calculation, inaccurate weighing or the use of a greasy
are processed into a base solution. Subsequently the mortar. These aggregates are larger than the micelles.
hydrophilised substance is dispersed in that base. The exam-
ple uses a rotor-stator mixer preparation method.
5.5.7 In-Process Controls
5.5.5 Emulsifying For the preparation of oral solutions and suspensions the
following in-process controls may be appropriate:
For the small scale preparation of oral emulsions the liquid • Record the tare or calibrate the utensils if the preparation
active substance is added to base gel. The base gel can be needs to be complemented on weight or volume.
Table 5.25 Nitrofurantoin Oral Suspension 10 mg/mL [43]

Nitrofurantoin macrocrystals (USP) 10 g
Aluminium magnesium silicate 9g
Carmellose sodium M 9g
Silica, colloidal anhydrous, compressed 2.5 g
Syrup BP (preserved with methyl parahydroxybenzoate 1 mg per g) 336 g
Water, purified 703 g
Total 1,071 g (¼ 1,000 mL)
Method of preparation with a rotor-stator mixer:
Dissolve the methyl parahydroxybenzoate in 600 mL purified water while heating to 100 C
Disperse the colloidal aluminium magnesium silicate in the hot solution of methyl parahydroxybenzoate
Disperse the carmellose sodium as well
Dissolve the citric acid monohydrate in about 50 mL purified water
Mix the citric acid solution with the solution: suspension base
Triturate the nitrofurantoin macrocrystals with the colloidal anhydrous silica in a rough mortar
Disperse this mixture of solid substances in the sugar syrup
Mix the solid substances-syrup mixture with the suspension base
Make up with purified water and mix
• Check on replenishment of evaporated water. is for instance made from raw glycyrrhizae extract that
• Measurement of the temperature, for instance, at the contains small amounts of water-insoluble substances. It
dissolution under heating of thermolabile substances also contains ethanolic anise extract that not fully mixes
and when checking for sufficient cooling. with water and turns the liquid lightly opalescent.
• Record the start time and end time of cooling down (in the
refrigerator) of some gels and sometimes at dissolution 5.5.8.2 Suspensions
under heating. The monograph Unlicensed Preparations of the British Phar-
• pH value of aqueous preparations as a check on the macopoeia gives quality requirements for oral suspensions.
correct composition; as such an in-process control the See also chapter Quality requirements, sections on particle
pH measurement may be performed with a pH indicator size (Sect. 32.11), dissolution (Sect. 32.10) and resuspend-
strip. ability (Sect. 32.13). As is said in Sect. 32.1 these qualities
• Clarity after each dissolution process. are mainly design qualities and should be defined specifi-
• Homogeneity (absence of mixing strings) after mixing cally per product.
liquids. Suspensions should be homogeneous and well
• Total weight or yield, the total weight after supplementing resuspendable and not settle (too) fast. Absence of lumps
with water or other solvent. can visually be checked after shaking. To determine the
• Control of cleaning the utensils after use. homogeneity of oral suspensions a method is described in
In addition, for suspensions, the following in-process the British Pharmacopoeia (see Sect. 32.7.2).
controls may be useful:
• Checks for the absence of lumps or agglomerates; a
simple visual inspection may be sufficient; if using a
5.5.8.3 Emulsions
Emulsions are visually checked for homogeneity and even-
rotor-stator mixer, there should not remain any lumps
ness. They should not contain large droplets and no phase
on the shaft.
separation should occur. The drop size of emulsions can
• A visual test on homogeneity after mixing.
eventually be measured with particle counters, see Sect.
In addition, for emulsions, the following in-process
35.9.3.
controls may be useful for testing the dispersion
homogeneity:
• The absence of large oil drops on the surface: a simple 5.5.8.4 Solubilisates
visual inspection is sufficient to determine this. A solubilisate is clear to weak opalescent and contains no
• A visual test on homogeneity or evenness of the mass. particles. If aggregates are formed instead of micelles the
In addition for solubilisates: solubilisate will not be clear but has the appearance of
• A solubilisate should be clear or slightly opalescent (not (diluted) milk.
resembling diluted milk).
References
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Pulmonary
6
Anne de Boer and Ernst Eber
Contents 6.6 Medicine Formulations for Nebulisation . . . . . . . . . . . . . . . 125

6.6.1 Medicine Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 6.6.2 Medicine Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.2 Definitions and Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 6.6.3 Stability of Formulations for Nebulisation . . . . . . . . . . . . . . . . 126
6.2.1 Definitions in the European Pharmacopoeia: Preparations 6.6.4 Mixing of Formulations for Nebulisation . . . . . . . . . . . . . . . . . 127
for Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
6.2.2 The Other Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.3.1 The Human Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
6.3.2 Spirogram and Lung Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Abstract
6.3.3 Target Areas for Inhaled Medicines . . . . . . . . . . . . . . . . . . . . . . . 106 The two main determinants for medicine deposition in the
6.3.4 Side Effects and Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
respiratory tract are the aerodynamic size distribution of
6.4 Mechanisms of Aerosol Deposition and Aerosol the aerosol and the manoeuvre with which the aerosol is
Characterisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 inhaled. They govern the mechanisms that are responsible
6.4.1 Forces Acting on Inhaled Aerosol Particles . . . . . . . . . . . . . . 107
6.4.2 Deposition Mechanisms in the Respiratory Tract . . . . . . . . 108 for particle deposition in the lungs. By varying the inhala-
6.4.3 Sedimentation Takes Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 tion manoeuvre, not only the distribution in the airways for
6.4.4 The Influence of Particle Shape and Density . . . . . . . . . . . . . 109 the same aerosol is changed; in many cases also the amount
6.4.5 Polydisperse Aerosols and the MMAD . . . . . . . . . . . . . . . . . . . 109 and properties of the delivered fine particle dose are
6.4.6 Deposition Efficiencies and the Most Preferable Size
Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 affected. The complex interplay between inhalation
6.4.7 Medicine Distribution over the Entire Respiratory Tract 110 manoeuvre, aerosol properties and site of deposition has
6.4.8 Practical Implications for the Inhalation Manoeuvre . . . . . 111 led to many misconceptions regarding the best inhaler
6.5 Aerosol Generation Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 choice for individual patients and the way these inhalers
6.5.1 Dry Powder Inhalers (DPIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 need to be operated to achieve optimal therapy for the
6.5.2 Metered Dose Inhalers (MDIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 patient. In this chapter the medicine deposition
6.5.3 Nebulisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6.5.4 Novel Liquid Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
mechanisms for inhaled aerosols are explained as functions
of the variables involved. In addition, the working
principles of different inhaler types are described and it is
discussed how their performance depends on many inhala-
tion variables. Finally, some persistent misconceptions in
the literature about the most preferable dry powder inhaler
Based upon the Chap. 28 Luchtwegen by Anne de Boer and Liesbeth
Ruijgrok in the 2009 edition of Recepteerkunde.
properties and performance are unravelled.
A.H. de Boer (*)
Department of Pharmaceutical Technology and Biopharmacy,
Keywords
University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, Deposition mechanisms Inhalation manoeuvre Pulmo-
The Netherlands nary administration Pulmonary drug delivery Thera-
e-mail: [email protected] peutic aerosol Biopharmaceutics Particle size Dry
E. Eber powder inhaler Metered-dose inhaler Nebuliser Novel
Respiratory and Allergic Disease Division, Department of Paediatrics liquid inhaler
and Adolescence Medicine, Medical University of Graz,
Auenbruggerplatz 34/2, 8036 Graz, Austria

100 A.H. de Boer and E. Eber
6.1 Orientation
Aerosol generation
(device) Aerosol properties
Pulmonary administration of medicines currently has the pri-
mary objective to achieve local effects in the respiratory tract
of patients with chronic diseases like asthma, chronic obstruc-
tive pulmonary disease (COPD) and cystic fibrosis (CF). For
half a century, inhalation therapy has been the cornerstone in
the management of these diseases and the often life-time
Inhalation manoeuvre Lung deposition
therapies aim to suppress inflammatory processes and bacte-
rial infection in order to reduce hospitalisations and to
improve the patient’s quality of life. They also give relief to
the patient in moments of bronchoconstriction. The Fig. 6.1 Principle variables and interactions in pulmonary administra-
advantages of pulmonary administration of medicines for tion of medicines
local treatment are well known. The active substances are
delivered directly to the site of action which leads to a faster in the human respiratory tract and the underlying mechanisms
response than via the systemic route. It may also result in for that will be discussed as well.
higher local active substance concentrations and this could In contrast with oral administration of tablets or capsules,
reduce the total dose by as much as a factor 10 compared to pulmonary administration is a complex process with many
oral or intravenous administration. This has the advantage that variables involved as well as several interactions between
systemic side effects are reduced and in combination with these variables depending upon the type of aerosol genera-
being a non-invasive method of administration, inhalation tion device used. The most basic scheme of variables and
therapy may lead to better patient compliance. interactions is presented in Fig. 6.1.
More recently, it has been recognised that pulmonary For many inhalation devices, the inhalation manoeuvre
administration of medicines may be a good alternative for has an influence on the aerosol generation process. Either the
other therapies too. The respiratory tract is the port of entry air stream through the aerosolisation device delivers the
for many bacteria and viruses and infectious diseases like energy for the aerosolisation process (e.g. for passive dry
influenza, tuberculosis and measles which can be prevented powder inhalers), or it alters the aerosol properties from the
or treated effectively with inhaled vaccines, antibiotics and device (e.g. by coalescence or evaporation of droplets from
anti-viral medicines respectively. Lastly, the respiratory tract nebulisers and metered-dose inhalers). The aerosol genera-
can be used for delivering systemically acting medicines tion device may also influence the inspiratory flow manoeu-
which are not effectively absorbed by the gastro-intestinal vre by its resistance to airflow. A high resistance limits the
tract or are rapidly metabolised by the first-pass-effect in the flow rate to be achieved and this influences the deposition
liver. Inhalation can potentially replace the more invasive pattern in the respiratory tract in a positive way. Generally, a
parenteral routes of administration used for these active poor understanding exists regarding the precise role of air-
substances to increase their bioavailability and the adherence flow resistance, flow rate and aerosol properties in pulmo-
to therapy. An example is loxapine for acute treatment of nary therapies particularly with dry powder inhalers.
agitation in patients with bipolar disorder or schizophrenia Therefore, it is the aim of this chapter not only to explain
which has only 30 % bioavailability after oral administration, the influence of the inhalation manoeuvre on the working
versus 90 % after intramuscular injection. Very recently principles of various aerosol generation devices and the
(2012), approval for an inhaled loxapine formulation has mechanisms that govern aerosol deposition in the respiratory
been received which has a very high absorption of > 90 % tract, but also to unravel some persistent misconceptions.
within seconds (Adasuve®, Alexza Pharmaceuticals). Cur- Administration devices for medicines used to treat
rently many more devices and formulations for such new asthma and COPD are prescription products, with an excep-
applications are in development or being tested and it may tion for some nebulised (medicine) formulations. Medicines
be expected that in the very near future several of them will be such as amphotericin B or antibiotics (colistimethate
introduced to the market. Because most inhaled products are sodium, tobramycin sulphate or gentamicin) for nebulisation
registered combinations of an active substance or a combina- in CF therapy are sometimes still partly prepared by hospital
tion of substances and a suitable administration device, their pharmacists, and so are nebulised solutions for bronchial
manufacturing is not described in this chapter. Instead, their challenge testing. Although product formulation and the
principles of operation are explained in relation to the method of preparation of formulations for inhalation are
variables that influence their performance. Basically these not the main subjects of this chapter, recommendations are
variables are the same as those controlling particle deposition given in the subparagraphs about nebulisation.
6 Pulmonary 101
specifications in the Ph. Eur. to meet this most important

6.2 Definitions and Terms parameter. Some specific terms and definitions related to
pulmonary administration of medicines are given and
6.2.1 Definitions in the European explained in this paragraph. For various terms different
Pharmacopoeia: Preparations definitions or explanations are given in the literature and
for Inhalation specific product information leaflets and it is important to
recognise the implications of that.
The European Pharmacopoeia (Ph. Eur.) describes
preparations for inhalation as liquid or solid preparations
intended for administration as vapours or aerosols to the
6.2.2 The Other Definitions
lung to obtain a local or systemic effect. These preparations
may contain one or more active substances and, depending
6.2.2.1 Adhesive Mixture
on the type, also propellants, co-solvents, diluents, antimi-
An adhesive mixture is a type of formulation for micronised
crobial preservatives, and solubilising and stabilising agents
active substances for inhalation in which the small active
that do not adversely affect the functions of the mucosa of
substance particles adhere by natural forces (mainly Van der
the respiratory tract or its cilia. The Ph. Eur. refers to three
PRODUCT DESIGN
Waals forces) to the surface of much larger carrier (or host)
types of administration devices for inhalation preparations:
particles.
nebulisers, pressured Metered-Dose Inhalers (MDI) and Dry
Powder Inhalers (DPI). An appropriate size distribution has
to be delivered to the patient so that a significant fraction is 6.2.2.2 Aerodynamic Diameter (DA)
deposited in the lung and fine particle characteristics are The aerodynamic behaviour of aerosol particles depends on
determined by one of the methods for “Aerodynamic assess- their diameter, density and shape. To compare the behaviour
ment of fine particles” in the Ph. Eur. The Ph. Eur. of particles that have different properties with each other, the
distinguishes between “Liquid preparations for inhalation” aerodynamic diameter (DA) has been introduced, which
and “Powders for inhalation”. standardises for particle shape and density. By definition
The liquid preparations for inhalation are divided into the aerodynamic diameter of a particle is the diameter of a
(A) preparations intended to be converted into vapour, sphere with unit density having the same terminal settling
(B) liquid preparations for nebulisation and (C) pressurised velocity as the particle in consideration. Only for aqueous
metered-dose preparations for inhalation. They are added to droplets with a spherical shape and unit density the aerody-
hot water to obtain inhalable vapours or converted into namic diameter equals the geometric diameter. For
aerosols by continuously operating nebulisers or metered- non-spherical particles, the aerodynamic diameter can be
dose nebulisers, and they can be solutions, suspensions or expressed in terms of equivalent volume diameter (DE),
emulsions. They may be prepared by dilution of particle shape factor (χ) and particle density (ρ) (see
concentrated preparations or by dissolution of powders. definitions): DA ¼ DE.(ρ/χ)0.5
The pH of liquid preparations for use in continuously
operating nebulisers has to be within the range between 6.2.2.3 Aerosol
3 and 8.5. Suspensions or emulsions have to be readily An aerosol is a (colloidal) dispersion of particles in a gas,
dispersible on shaking and remain sufficiently stable to which for therapeutic aerosols is air. There is no definition
enable the correct dose to be delivered. for the particle size distribution of an aerosol, but most
Powders for inhalation are not defined other than that they airborne particles are within the size range between 0.2 and
are presented as single-dose or multidose powders and that 20 μm.
the active substances may be combined with a suitable
carrier to facilitate their use. If the powder is for a single- 6.2.2.4 Breathhold Pause
dose (pre-metered) inhaler, the device is loaded with This is the period during which breathing is interrupted after
powders pre-dispensed in capsules or other suitable pharma- inhalation of an aerosol. By not immediately exhaling after
ceutical forms. For inhalers using a powder reservoir, indi- inhalation, particles in the central and peripheral airways are
vidual doses are isolated from the bulk with a metering given time to deposit by sedimentation and make contact
mechanism within the inhaler. with the epithelial lining fluid of the airways.
Important for all different preparations and delivery
devices is that they meet the requirements for uniformity 6.2.2.5 Carrier Particle
of the delivered dose and the number of deliveries per See adhesive mixture. Carrier particles in marketed
inhaler for multidose inhalers. Also the fine particle dose formulations are exclusively alpha lactose monohydrate
has to be tested and calculated, but there are no crystals, mainly in size distributions between 20 and
150 μm, but they may contain substantial amounts of fine 6.2.2.10 Drag Force (FD)
lactose < 10 μm. Particles moving relative to the surrounding air are subjected
to a resisting force by collision with air molecules. This force
6.2.2.6 Deposition is the same whether the particle moves through the air or the
This is the act of bringing an aerosol particle in contact with airflows past the particle. For small airborne aerosol particles
the airway wall. Different deposition mechanisms exist and the resisting force, or drag force (FD), is described by Stokes’
it depends primarily on the particle’s aerodynamic diameter law: FD ¼ 3.π.η.U.D, to which several correction factors may
(see definition) and velocity in which part of the airways an be applied (as for the shape factor: see definition). In this
aerosol particle is most likely to be deposited. equation η is the dynamic viscosity of the air, U is the particle
velocity (relative to the air) and D is the particle diameter.
6.2.2.7 Deposition Mechanism
Deposition mechanisms are principles by which particles 6.2.2.11 Equivalent Volume Diameter (DE)
can be deposited onto airway walls. For inhaled aerosol The equivalent volume diameter (DE) of an irregularly
particles only two major mechanisms are important: inertial shaped particle is the diameter of a sphere having the same
deposition and sedimentation (see definitions). In the litera- volume as the particle in consideration. The equivalent vol-
ture also diffusion, interception and electrostatic precipita- ume diameter is used to describe the dynamic particle
tion are sometimes mentioned as deposition mechanisms, behaviour of non-spherical particles in combination with
but these mechanisms, if occurring at all, are of lower the shape factor (see definition).
relevance.
6.2.2.8 Deposition Modelling 6.2.2.12 Fine Particle Dose (FPD) and Fine Particle
Deposition modelling consists of simulation of the deposi- Fraction (FPF)
tion in the lungs on the basis of deposition probability Fine particle dose (FPD) and fine particle fraction (FPF)
equations for inertial impaction, sedimentation, and have to be defined by particle size (distribution). Based on
diffusion. their ability to target the site of action in the lungs, FPDs in
the literature are frequently defined as the mass fractions of
6.2.2.9 Dose particles < 5 μm in the delivered aerosol. However,
The dose is the amount of active substance (to be) delivered particles < 1 μm are not desired as they are exhaled to
from the inhalation device. Different definitions for the dose large extent, whereas for total and deep lung deposition
can be given for MDIs and DPIs. Basically, there is a particles in the narrow size range from 1 to 3 μm may be
difference between the label claim (also: nominal dose) more appropriate. FPD is given in microgram or milligram
and the delivered dose (also: emitted dose). The label active substance. FPF is a relative measure of FPD,
claim is the dose as measured into the dose compartment expressed as percent of the dose for which both the label
of the device (for single-dose or multiple unit dose dry claim and the delivered dose can be used (see label claim).
powder inhalers) or as measured by the device (for MDIs
and multidose DPIs which both have a metering chamber). 6.2.2.13 Geometric Standard Deviation (GSD)
The delivered dose is the amount of active substance leaving Geometric standard deviation (GSD) is a measure of the
the mouthpiece of the inhaler, which is lower than the label distribution of particle sizes which can be used for
claim due to inhaler (mainly in the mouthpiece) retentions log-normal volume (or mass) distributions as function of
(for MDIs and DPIs) and incomplete emptying of the dose the diameter:
compartment (for DPIs only). Some manufacturers of DPIs
weigh between 10 % and 20 % more than the label claim GSD ¼ ðD84:13 =D15:87 Þ0:5
into the dose compartments to compensate for the inhaler
retention, whereas others use an average delivered dose as D15.87 is the diameter corresponding with 15.87 % cumula-
label claim. This shades the difference between label claim tive volume (or mass) and D84.13 is the diameter
and delivered dose. Delivered doses vary not only between corresponding with 84.13 % cumulative volume (or mass).
devices; for DPIs they mostly also depend on the flow rate
for the same type of device. A special situation concerns 6.2.2.14 Impaction Parameter (IP)
nebulisers where the delivered lung dose may not only The impaction parameter (IP) of an aerosol particle is
depend on the retention in the nebulisation cup, but also on the product of the particle density (ρ), the square of the
aerosol losses during periods of exhalation. Next to (nominal particle’s (aerodynamic) diameter (D) and its velocity (U):
or delivered) dose, the fine particle dose (or fraction) is
important (see FPD and FPF). IP ¼ ρ:D2 :U:
6 Pulmonary 103
The parameter predicts the chance of impaction against an which is an estimated value for the amount of active sub-
obstruction in the flow direction of the particle and can for stance leaving the mouthpiece. For fine particle fractions
instance be used to predict oropharyngeal deposition. Prac- (FPFs) it is important to know which type of label claim
tically, instead of particle velocity sometimes the flow rate has been used as reference, or a comparative evaluation
(Φ) through an inhaler is used, but this does not enable between different devices will be impossible.
comparative evaluations between different inhalers when
the cross sections for airflow in the mouthpieces are differ- 6.2.2.19 Median Diameter
ent between the inhalers as this will result in different The median diameter corresponds with the 50 % value of a
velocities. cumulative number, volume or mass percent distribution as
function of the diameter. Fifty percent of the volume (num-
6.2.2.15 Impactor ber or mass) of the aerosol is in larger, and 50 % is in smaller
Multistage impactors or cascade impactors are used for particles than the median diameter. For a volume distribu-
aerosol particle size analysis. By drawing a constant flow tion it is the volume median diameter, for a mass distribution
rate through an impactor nozzle, airborne particles may or the mass median diameter. When the mass percent is expressed
may not be collected on an impaction plate underneath the as a function of the aerodynamic diameter, reference can be
PRODUCT DESIGN
nozzle depending on their aerodynamic diameter and veloc- made to the mass median aerodynamic diameter (MMAD).
ity. The cut-off diameter of an impactor varies with the flow
rate through the nozzle, and by placing impactors with 6.2.2.20 Mass Median Aerodynamic Diameter
decreasing nozzle diameters in serial arrangement a mass (MMAD)
distribution as function of the aerodynamic diameter can be The MMAD is a parameter frequently used to characterise
obtained. The United States and European Pharmacopoeias therapeutic aerosols. MMAD alone is not very useful how-
show different types of impactors to be used for aerosols of ever, as it provides no information about the size distribution
which the nine-stage Andersen impactor is most popular in in the aerosol and the mass fraction of the dose (label claim)
the USA and the seven-stage Next Generation Impactor processed into a suitable aerosol. Fine particle dose and
(NGI) is most frequently used in Europe. fraction are more meaningful parameters, particularly for
DPIs (see definitions).
6.2.2.16 Inertial Impaction
One of the two dominant deposition mechanisms for aerosol 6.2.2.21 Monodisperse Aerosol
particles in the respiratory tract (see definitions) is inertial In a monodisperse aerosol all particles have the same diam-
deposition or impaction. Inertial deposition is based on the eter. In practice, monodisperse aerosols are very difficult to
particle’s inertia or momentum, which is the product of obtain and therefore, aerosols are considered monodisperse
particle mass (m) and velocity (U). Inertial deposition occurs when their geometric standard deviation (GSD) is smaller
particularly in the upper respiratory tract where air velocity than 1.2 (see definition).
is high and the largest aerosol particles are still airborne.
6.2.2.22 Plume Velocity
6.2.2.17 Inspiratory Flow Rate The plume velocity is the velocity with which an aerosol is
The volume of air per unit time through an inhaler during released from an MDI. Generally, the plume velocity from
inspiration is the inspiratory flow rate, which is expressed in hydrofluoroalkane (HFA) holding MDIs is much lower than
L/min. Generally, the flow rate through an inhaler quite that from chlorofluorocarbon (CFC) holding MDIs, but this
rapidly reaches a maximum value (peak inspiratory flow, may depend on the presence of a co-solvent.
PIF) followed by a slower decrease to zero flow. As a
general rule, the average flow rate equals approximately 6.2.2.23 Polydisperse Aerosol
70 % of PIF. From the average flow rate and the total In a polydisperse aerosol the particles have different
inhalation time the inhaled volume (V) can be computed. diameters and the size distribution is such that the geometric
The flow rate influences the particle size distribution in the standard deviation (GSD) has a value larger than 1.2 (see
aerosol and the deposition pattern in the respiratory tract. definitions).
6.2.2.18 Label Claim 6.2.2.24 Resistance (Against Airflow)

The label claim of DPIs and MDIs is the amount of active Inhalers are flow constrictors which reduce the flow rate (Φ)
substance corresponding with a unit dose. Different label to be achieved during inhalation. Their behaviour in this
claims are used and there is a tendency in Europe to change respect complies with the general equation for orifice types
from metered dose to delivered dose for the label claim, of airflow resistances (Φ ¼ Fu(A).√dP), where Fu(A) is a
function of the cross section (A) for airflow and dP is the

pressure drop across the inhaler (in kPa). Fu(A) may be 6.3 Biopharmaceutics
complex but fairly constant over a wide range of flow rates
and contains flow coefficients depending on the precise Aerosol particles carrying the active substance have to make
inhaler design. The reciprocal value of Fu(A) is the inhaler’s contact with the walls of the respiratory tract in the target
resistance to airflow (R). area and the medicine has to be dissolved before it can
become active. In this paragraph, the anatomy of the
human respiratory tract is described in view of its function
6.2.2.25 Sedimentation as transport route and target area for inhaled medicines.
One of the two dominant deposition mechanisms for aerosol
particles in the respiratory tract (see definitions) is sedimen-
tation or stationary settling. Sedimentation occurs under
6.3.1 The Human Respiratory Tract
influence of the force of gravity and settling (falling)
particles reach a terminal (stationary) settling velocity once
For pulmonary administration of medicines the mouth is the
the force of gravity is in equilibrium with the drag force (see
port of entry (see Fig. 6.2). Inhaled air carries the aerosol
definitions). The terminal settling velocity (UTS) is propor-
from the inhalation devices past the oral cavity, pharynx and
tional to the square of the particle diameter (D) and also
larynx before it enters the tracheobronchial tree. Starting
depends on particle density (ρ) and shape factor (χ: see
with the trachea (generation 0) most airways branch into
definitions):
two (some in more) smaller airways, which comprise the
UTS ¼ (ρ.D2.g.Cc)/(18η.χ) in which g is the acceleration
following generation. The trachea branches (bifurcates) into
of gravity, Cc is the Cunningham correction factor for slip
two main bronchi (generation 1) which bifurcate further into
flow and η is the dynamic viscosity of the air.
five lobar bronchi (generation 2) and so on, until eventually
the alveolar sacs (alveoli) are formed. Estimates for the
6.2.2.26 Shape and Shape Factor (x) number of branchings (airway generations) from the trachea
Only aqueous aerosol droplets and some particles obtained to the alveoli in the literature vary between 20 and 28 and the
from (spray) drying of droplets are perfectly round. Most number of airway ducts in each generation is roughly 2 to the
solid aerosol particles have other shapes, and also when power of the generation number; for example, in generation
spherical particles cluster together their shape changes 8 there exist 28 (256) airway ducts. The number of alveoli
from round into irregular. The shape of a particle affects its does not comply with this geometric sequence however, and
drag force (see definition) and in particle dynamics shape is is much higher up to an estimated 300–800 million [1]. The
characterised by a (dynamic) shape factor. This factor for a airway system can be subdivided in many different ways.
non-spherical particle is defined as the ratio of the actual Clinically, large airways (with diameters > 2 mm) are fre-
resistance force to the resistance force of a sphere having the quently distinguished from small airways (with diameters
same volume and velocity relative to the air. The factor is < 2 mm). In addition, the terms upper and lower airways are
applied to make corrections for Stokes’ law for the drag frequently used, but with different definitions. From the
force (see drag force) which influences both inertial impac- viewpoint of fluid and particle dynamics dividing the
tion and sedimentation. airways into conducting, transitional and peripheral airways
seems more practical. Clear definitions for these regions
have never been given but on the basis of airflow velocity
6.2.2.27 Stopping Distance
and functional and anatomical differences the conducting
The stopping distance or inertial range is the distance a
airways are referred to as the generations 0–11, the transi-
particle will travel in still air with all external forces
tional airways as the generations 12–16 and the peripheral
eliminated, except for the drag (resistance) force of the air
airways as the generations 17–23 in this chapter. In aerosol
which decelerates the particle to zero velocity. The stopping
deposition studies with radiolabeled substances partitioning
distance depends on the particle’s momentum, which is the
is often into central, intermediate and regional airways on
product of particle mass and velocity (m.U).
the basis of two-dimensional γ-camera images. The average
angle of bifurcation is 37 which from the fluid dynamics
6.2.2.28 Target Area point of view is the angle with the least disturbance of the
The target area is the area in the respiratory tract where the flow pattern. Lung models used for deposition simulation in
action of the inhaled medicine is most needed. The target the literature mostly give only 23 generations (e.g. the
area may either be part of the respiratory tract or the whole Weibel model) and only few are extended to 26 generations
lung, depending on the medicine. (e.g. the Hansen and Ampaya model) [2].
6 Pulmonary 105
Fig. 6.2 The airways as

transport route for aerosols. The
anatomical dead volume of 0.15 L
is for adults; the total number of the nose as normal pharynx
airway generations (23), based on entry for inhalation
the Weibel model, is by larynx
approximation. Source:
Recepteerkunde 2009, #KNMP
the mouth as entry for
inhaled aerosols
ADV: anatomical ‘conducting airways’

dead volume generations 0-11
(approx. 0.15 L) with cartilage
PRODUCT DESIGN
‘transitional airways’
generations 12-16
‘respiratory airways’
generations 17-23
From the trachea to the small bronchi cartilage is present

in the walls of the airways. In the trachea cartilages are Different lung models are used to describe the human
C-shaped, in the bronchi they appear as interspersed small airways as transport route for inhaled aerosol particles
plates of elastic tissue. The cartilages in the trachea are [2]. All these models have in common that they are
joined by smooth muscle which continues into the bronchi simplifications of reality presenting the airways as
and bronchioles where the muscles encircle the airways round pipes with defined lengths and diameters.
completely. Further down the respiratory tract, smooth mus- From the trachea with an estimated diameter of
cle becomes less until it is absent in the alveoli. The airways 15–18 mm (in adults) the airway diameter decreases
are covered with epithelium of which the type varies within towards the alveolar ducts, whereas the number of
the tract. There are glands (upper respiratory tract) and airways increases. The increase in number (from 1 to
mucus producing goblet cells, and most of the epithelial approximately 8 106, assuming 23 generations) is
cells (into the bronchi) are ciliated cells. The cilia beat much higher than the decrease in diameter (from 18 to
upwards, moving mucus (including all, in the mucus, approximately 0.4 mm). As a consequence, the cross
entrapped foreign inhaled particles) towards the throat section for airflow, after an initial decrease in the first
where it is swallowed. In the alveoli neither mucus nor four generations, increases exponentially towards the
ciliated cells are present and mainly alveolar macrophages alveoli, which corresponds to an exponential decrease
are responsible for destroying foreign material. The walls of of the air velocity. In the terminal bronchioles the air
the alveoli contain surfactant secreting cells. Surfactant stands practically still and its velocity reaches the
decreases the surface tension of the alveolar lining fluid same value as the terminal settling velocity of particles
preventing collapse and assisting re-inflation of the lung in the size range between 5 and 6 μm.
after exhalation.
6.3.2 Spirogram and Lung Volumes those mediating bronchoconstriction belong to the
M3-receptor subtype on endothelial cells which release nitric
The total lung capacity (TLC) of healthy adult subjects oxide (NO). Muscarinic receptors of the M3 subtype also
varies between approximately 4 L (female) and 6 L (male), mediate mucus secretion and so do receptors of the M1
but during tidal breathing at rest only a fraction of this subtype, whereas autoreceptors in the human airways belong
volume is refreshed: approximately 0.5 L. During severe to the M2 subtype. Medicines like ipratropium bromide
exercise, this tidal volume (TV) increases to about block prejunctional M2-receptors and postjunctional
1.5–2.5 L, which means that a considerable part of the M3-receptors in airway smooth muscle with equal efficacy.
TLC is not used. In fact, a residual volume (RV ¼ approxi- The presence of M2-receptors has also been demonstrated in
mately 25 % of TLC) cannot be exhaled at all to prevent airway smooth muscle and M1- and M3-receptors are both
collapse of the lungs. Tidal breathing is not on top of the present in submucosal glands, whereas M1-receptors can
residual volume, but on top of the functional residual capac- also be found in the lung parenchyma. Recently, it has
ity (FRC), which after exhalation leaves a volume of about been suggested that muscarinic receptors may have a much
2.3 L of air in the lungs for an adult male. The alveolar greater role in the pathophysiology of obstructive airway
volume is about 2.1 L and this implies that during tidal diseases than previously thought [4]. Active substances
breathing air refreshment by convective transport takes like tiotropium may potentially inhibit airway inflammation
place mainly above the alveolar volume. Hence, to reach and remodelling, and it has recently been shown that
the alveoli effectively with an inhaled aerosol, a preceding aclidinium may play an important role in inhibiting
exhalation to residual volume is necessary. fibroblast-myofibroblast transition, which is a key step in
peribronchiolar fibrosis formation [5]. Deposition in the
whole lung is therefore desirable for anticholinergics in
6.3.3 Target Areas for Inhaled Medicines spite of the fact that cholinergic activity in the lung is most
pronounced in the large airways [6].
The precise area to target in the lungs depends on the type of Inhaled corticosteroids (ICSs) are the mainstay of asthma
medicine given and the mechanism of action for this medi- management. Their effects are mediated by glucocorticoid
cine. Most of the active substances used for inhalation inter- receptors in target cells of the lung. Almost every cell has
act with cell receptors in the respiratory tract [3]. For asthma glucocorticoid receptors, but the number per cell varies with
and COPD these include mainly β2-adrenoceptor agonists the type of tissue and in the airways the highest density is
and muscarinic receptor antagonists (anticholinergics). The found in endothelial and epithelial cells [3]. Airway epithe-
distribution of receptors over the lung is an important deter- lial cells, which express multiple inflammatory proteins
minant of both the clinical effect of the medicine and the dominating the inflammation in asthma, may be the major
desired site of deposition for the active substance. The pri- target for ICSs. Because epithelial cells are present through-
mary action of β2-agonists is to relax airway smooth muscle. out the entire lung, all airways have to be targeted with ICSs.
β2-agonists target β2-receptors that are present in high con- Many specific mediator receptors are involved in asthma
centration in lung tissue and localised to several cell types but they are so abundant that specific antagonists for these
which, next to smooth muscle, are epithelium, vascular receptors have little effect, with an exception for cysteinyl
smooth muscle and submucosal glands [3]. They also target leukotriene-1 (cys-LT1) receptors which are distributed pre-
β1-receptors localised to submucosal glands. There is a dominantly on airway smooth muscle and (to a lesser extent)
uniform distribution of β-receptors also on the alveolar on macrophages. Their numbers are small, however, and this
wall with a ratio of β1 to β2 receptors of 2:1. The density of may explain why antileukotrienes like montelukast and
β2-receptors in airway smooth muscle does not change down zafirlukast, which prevent predominantly leukotriene-induced
the respiratory tract and is the same in small and large bronchoconstriction, are less effective than β2-agonists.
airways. Therefore β2-agonists may dilate all airways and
this is relevant to asthma and COPD where small airways are
involved. To achieve acute relief of bronchoconstriction, 6.3.4 Side Effects and Toxicity
reaching the larger airways, which have the highest resis-
tance to airflow, is mostly sufficient. Side effects can be the result of unwanted systemic action,
Inhaled anticholinergics are the most effective class of toxicity, irritation and hypersensitivity following
bronchodilators in COPD patients. Muscarinic receptors are sensitisation. Both the active substances and excipients can
localised to smooth muscle of all airways, but the density cause side effects and in addition to the chemical nature of
decreases down the respiratory tract. They are also localised the inhaled compounds, also physical properties can be
to airway epithelium and submucosal glands [3]. Four relevant. An example can be given for salbutamol, for
subtypes of muscarinic receptors exist in the lungs and which it has been shown that increasing the dose may result
6 Pulmonary 107
in increased side effects without improving the therapeutic instance occur in curved airways, at bifurcations or around
effect [7]. Also specific salts of an active substance may be local obstructions. In such areas or in turbulent air streams
less favourable, as they can increase the degree of irritation particle trajectories and velocities may differ from the
from particle deposition on the mucosa [8]. Irritation may stream lines of the air and under these conditions, a drag or
result in severe cough and chest tightness; both may further resistance force of the air is added to the force of gravity
depend on the precise site of deposition which depends on acting on the particle. Whereas the particle’s inertia tends to
particle size and/or flow rate. Dry powder formulations for maintain particle motion in the original direction, the drag
low dose substances in asthma and COPD therapy previ- force tends to change this direction into that of the air
ously contained only alpha lactose monohydrate as carrier stream. The tendency of a particle to maintain its state of
(or diluent) excipient. In some countries, there has been motion in still air is expressed by its stopping distance
concern about the use of lactose in inhaled medication (S) which is related to the particle momentum. For the sake
because of some rare cases of bovine spongiform encepha- of simplicity and an easier understanding, it can be imagined
lopathy (BSE), but it is highly unlikely that the prions that a particle following a curvilinear trajectory is subjected
causing BSE can be found in this excipient. Currently, to a centrifugal force. This adds a third force acting on
many formulations are introduced to the market which con- particles in a bent airway as depicted in Fig. 6.3.
PRODUCT DESIGN
tain magnesium stearate as force control agent to improve
powder dispersion (e.g. Chiesi Foster NEXThaler®, FC ¼ m:UT2 :R‐1 ð6:1Þ
Novartis Seebri Breezhaler® and GSK Breo Ellipta®).
Although the use of this practically insoluble excipient has FD ¼ 3:π:η:UPA :D ð for spherical particles
ð6:2Þ
been approved, its long term safety may be questioned. Still >1 μm with unit densityÞ
uncertain are also the long term effects of various excipients
in high dose medicines, such as lung surfactant (dipalmitoyl- FG ¼ m:g ð6:3Þ
phosphatidylcholine, DPPC) in various particle engineered
powders, hydrogenated soya phosphatidylcholine (HSPC) Where:
and cholesterol in liposomal formulations, and poly lactic m is the particle mass
acid (PLA) and poly lactic-co-glycolic acid (PLGA) in UT is the tangential velocity
insoluble microspheres. The arguments for safety are that R is the radius of the bent
the compounds are not foreign to the lungs or that they do η is the dynamic viscosity of the air
not interfere with physiological processes. However, inter- UPA is the particle velocity relative to the air velocity
ference for substances like DPPC are likely to depend also D is the particle diameter
on their concentration, and for instance metabolic lactic acid g is the acceleration of gravity
is an important mediator of myofibroblast differentiation via Of these forces, the centrifugal force and force of gravity
a pH-dependent activation of transforming growth factor-β are a function of the particle mass, which is proportional to
[9]. MDI formulations contain various excipients too, of the third power of the particle diameter, whereas the drag
which some have been less abundantly used since the force is proportional to the first power of the diameter. The
replacement of CFC by HFA propellants. Furthermore,
most HFA-MDIs have a lower plume velocity and a higher
plume temperature than CFC devices which reduces the
cold-freon effect and local side effects from substantial
throat deposition.
6.4 Mechanisms of Aerosol Deposition

and Aerosol Characterisation
6.4.1 Forces Acting on Inhaled Aerosol

Particles
Aerosol particles transported in a steady laminar air stream

have basically the same velocity and flow direction as the
air, but in contrast with the air molecules particles have a
much higher inertia. Therefore, they cannot follow rapid Fig. 6.3 Forces acting on airborne particles in a bent airway. Source:
changes in velocity or direction of the airflow, which for Recepteerkunde 2009, #KNMP
drag force and the centrifugal force depend on the particle 6.4.3 Sedimentation Takes Time
velocity, whereas the force of gravity does not. This has the
important implication that the balance between these forces Particle settling in the respiratory tract occurs under the
can be influenced by changing the particle diameter, particle influence of the force of gravity and the drag force. In the
velocity, or (as a determinant for particle mass) particle stationary situation these forces counterbalance each other
density. Because the particle shape influences the drag and this enables to calculate the stationary or terminal
force, the shape factor is a fourth determinant for a particle’s settling velocity (see terms and definitions) which is propor-
aerodynamic behaviour. tional to the square of the particle diameter. For spherical
particles with unit density in the range of diameters between
0.5 and 5 μm, which covers the range of interest for inhala-
6.4.2 Deposition Mechanisms tion, the terminal settling velocities are given in Table 6.1.
in the Respiratory Tract Table 6.1 shows that particles of 1 μm, or smaller, are less
favourable for inhalation because their settling time is too
The balance between the three forces acting on airborne low. Even for a total residence time of 7.5 s in the smallest
particles results in dominance of either inertial impaction airways, the falling distance of a 1 μm particle is no more
or sedimentation, which are the two main deposition than 50 % of the diameter of that airway, if the air stands
mechanisms in the respiratory tract. Inertial impaction completely still. In practice, the air velocity remains much
occurs when particles have a high momentum and the air higher than the particle’s settling velocity, even in these
suddenly changes its direction. This situation is met in the most distal airways (e.g. 2.5 mm/s in generation 22 at an
human throat and the upper airways where the air velocity is inspiratory flow rate of 60 L/min), and this can influence
high and the largest particles in the aerosol are still present in sedimentation in a negative or positive way. Moreover, most
the inhaled air stream. For such particles the ratio of centrif- distal airways are not horizontal ducts and a falling distance
ugal force to drag force is relatively high, meaning that they of 50 % of the airway diameter does not provide an average
have a great chance of colliding with the airway wall based 50 % chance for deposition of particles entering the airway
on their high inertia, which event is referred to as inertial randomly distributed over its cross section. As a conse-
impaction. As the largest particles are removed in the upper quence of all this, the deposition efficiency of very fine
airways and the air (and thus particle) velocity decreases particles is low and exponentially decreases with decreasing
down the respiratory tract, particle inertia and the drag force diameter. This is reflected in the fraction of small particles
decrease and the force of gravity becomes more dominant. exhaled again, which is known for particles in the size range
This leads to settling (falling) of particles in the central and between 1.5 and 6 μm [11]. Figure 6.4 shows the relationship
peripheral airways and when the settling time is long enough between particle diameter and measured exhaled fraction for
it could result in deposition by sedimentation. For a small monodisperse aerosols, and the extrapolation of this rela-
fraction of the finest particles (D
1 μm) Brownian tionship towards particles of 1 μm. The trend computed
motion may become noticeable. This mechanism of dis- matches very well the relationship which presents the time
placement, resulting from particle collision with surrounding needed to fall a distance equal to the diameter of a peripheral
air molecules, causes particle movement with a randomly airway (0.43 mm).
changing direction which could lead to contact with the wall
of an airway. However, because the displacement velocity
by Brownian motion (or diffusion) is very low, and so is the
mass fraction of the dose represented by particles smaller
than 1 μm, this mechanism of deposition does not contribute
substantially to total deposition. Also electrostatic capturing Table 6.1 Terminal settling velocities in still air of spherical particles
with unit density
of particles is mentioned in the literature as a possibility to
bring aerosol particles in contact with airway walls but for Particle diameter Terminal settling velocity Average settling
(μm) (μm/s) timea (s)
the relevance of this mechanism there is no experimental
0.5 7.5 30
evidence. One aspect that is still relatively unexplored and
1 30 7.5
needs further investigation is the possibility that particles
2 120 1.9
change their mass during passage through the respiratory 3 271 0.8
tract, e.g. by moisture sorption [10]. Such particles may be 4 482 0.5
inhaled as small (submicrometer) to avoid high deposition 5 753 0.3
fractions in the oropharynx and larger airways and increase a
The average settling time is the time needed to fall a distance (H) that
in weight in the high humidity within the airway system to equals 50 % of the diameter of a respiratory bronchiole
enhance sedimentation deposition in the deep lung. (H ¼ 0.225 mm)
6 Pulmonary 109
100 different directions and therefore, a unique diameter to char-

acterise such particles cannot simply be given. For this
percent exhaled (%) and s
80 flow rate: 31 L/min reason, the equivalent volume diameter (DE) was
flow rate: 67 L/min
introduced, which is the diameter of a spherical particle
60 settling time for 0.45 mm (s)
with the same volume as the non-spherical particle. Finally,
the drag or resistance force strongly depends on the particle
40
shape. This does not show in the equation given in Fig. 6.3,
20 which is therefore only valid for spherical particles. To
standardise for both shape and density, the aerodynamic
0 diameter is used, which by definition is the diameter of a
0 2 4 6 8 sphere with unit density having the same terminal settling
particle diameter (μm) velocity as the irregular particle in consideration.
Fig. 6.4 Trends for the percentage particles exhaled and the time
needed to fall a distance that equals the diameter of a peripheral airway
(0.43 mm), both as function of the aerodynamic particle diameter. The
percentage exhaled for 1 μm particles is obtained from extrapolation 6.4.5 Polydisperse Aerosols and the MMAD
PRODUCT DESIGN
(using a second order polynomial equation); exhalation data for 1.5;
3 and 6 μm particles derived from Usmani et al. [11] and extrapolation
of the correlationships towards particles of 1 μm All currently marketed inhaler devices produce polydisperse
aerosols of which the individual particles have different
sizes. Therefore, they cannot be characterised by a single
6.4.4 The Influence of Particle Shape diameter. In fact, for most solid aerosols from dry powder
and Density inhalers the particles may have different shapes too, which is
the reason to characterise them with aerodynamic diameters.
The terminal settling velocities and average settling times To be able to express polydisperse aerosols with a single
given in Table 6.1 are for spherical particles with unit den- parameter, the median aerodynamic diameter (MAD) was
sity which is the density of water (1 g/cm3). This may well introduced. When the aerodynamic size range which covers
apply for wet aerosol droplets from aqueous solutions of the population of particles in the aerosol is divided into
active substances which take a spherical shape as soon as different classes and the volume or mass fraction within
they have been formed under the influence of the surface each size class is expressed as function of the class mean
tension. Solid aerosol particles from dry powder inhalers diameter, a volume or mass distribution as function of the
have different properties. Such particles may exhibit a vari- aerodynamic diameter is obtained. This volume or mass
ety of different shapes and also have different densities, frequency distribution can be transferred into a cumulative
depending on how they were prepared. Particles obtained percent distribution of which the 50 % value corresponds
from micronisation are mostly crystalline and have density with the volume or mass median aerodynamic diameter
values typically in the range between approximately (VMAD or MMAD). This is the diameter indicating that
1.25–1.55 g/cm3. Due to the size reduction process (breaking 50 % of the total aerosol volume or mass is in larger, and
of larger particles) micronised particles have irregular 50 % is in smaller particles. When particles of all sizes in the
shapes which, however, never deviate extremely from the aerosol have the same density, which is mostly the case, then
spherical shape. This is in contrast to particles obtained with VMAD equals MMAD.
anti-solvent precipitation or super critical drying which can MMAD is frequently presented as the parameter
have shapes varying from cubic to plate or needle like. An characterising aerosols from inhalation devices best. This
increasing number of high dose medicines for inhalation are is not true however. To judge the quality of a therapeutic
currently produced with spray drying techniques, yielding aerosol from a particular type of inhaler, more information
particles with high internal porosity or corrugated surfaces to is needed. The MMAD does not give any information about
enhance dispersion during inhalation. Such particles may the size distribution of the aerosol particles. Substantial mass
largely be spherical, but they have low densities, frequently fractions may be outside the desired size range for adequate
much smaller than 1 g/cm3. Both the particle density and deposition of active substance in the target area, even when
shape influence the aerodynamic behaviour of aerosol MMAD looks very favourable. Moreover, MMAD does not
particles and this affects deposition in the human airways. give information about the mass fraction of the dose (label
Figure 6.3 shows that the force of gravity and the centrifugal claim) that has been delivered within the desired size range.
force both depend on the particle density (ρ). All three forces For all types of inhalers, the delivered fine particle dose
furthermore depend on the particle diameter, but (FPD) is much lower than the label claim and this may
non-spherical particles have different dimensions in vary from 10 % to 60 % for DPIs and up to 90 % for
MDIs. For these reasons it is best to define first the FPD in

terms of desired size range and mass percent (of the label unless they are inhaled very slowly which from dry
claim, yielding the fine particle fraction, FPF) and next powder inhalers is often not possible. Large particles
compute the MMAD for this size range. In the literature, also deposit effectively in the larger airways where
mostly FPF < 5 μm is mentioned as the relevant fine parti- initially the velocity increases (until generation 4)
cle fraction, but practically FPF 1–5 μm is more meaningful before it slows down. This has the consequence that
because of the low deposition efficiency of submicron particles larger than 3 μm from DPIs do not effectively
particles (Fig. 6.4). enter the peripheral lung.
The residence time is more relevant to small particles

6.4.6 Deposition Efficiencies and the Most which have to deposit mainly by sedimentation in the central
Preferable Size Distribution and peripheral airways. In these regions, the flow rate is
strongly reduced and large particles are not present in large
The deposition mechanisms mentioned previously have dif- numbers due to which inertial impaction is less prominent.
ferent efficiencies which, in addition to the particle Sedimentation takes time however, as explained above, and
properties, depend on the velocity with which the particles particularly for particles in the size range below 1.0–1.5 μm
enter the respiratory tract and their residence time in the a residence time of several seconds may be needed to obtain
tract. The velocity is most important for inertial impaction a noteworthy deposition by sedimentation. This practically
in the oropharynx and larger (mainly conducting and transi- confines the diameter for most effective total lung deposition
tional) airways. The likelihood of particles to be deposited in to the very narrow aerodynamic size range between 1 and
the mouth and throat or larger airways is a function of their 1.5 and 3 μm. Only for bronchodilators which need to target
momentum, which is the product of particle mass and veloc- predominantly the larger airways, particles in the size range
ity and can be predicted with the impaction parameter. between 3 and 6 μm may be more effective [11].
An experimental relationship between impaction

parameter (based on inhaled flow rate) and oropharyn- 6.4.7 Medicine Distribution over the Entire
geal deposition from a study with monodisperse Respiratory Tract
particles is shown in Fig. 6.5. The highest value in
this relationship is for 6 μm particles inhaled at a flow One of the aspects that is often neglected, but may be of
rate of 67 L/min; the lowest for 1.5 μm particles utmost importance for effective therapy, is the active sub-
inhaled at 31 L/min [6]. stance concentration achieved in different lung regions.
Most in vivo deposition studies with radiolabeled substances
100
from dry powder inhalers teach that the deposition fractions
% oropharyngeal deposition
trend line
80 Flow rate: 31 L/min in the central, intermediate and peripheral lung are very
Flow rate: 67 L/min roughly one third of the total lung dose each [12–14]. This
60 is more or less confirmed by deposition modelling studies
with monodisperse particles of 3 μm inhaled at a moderate
40 flow rate of 30 L/min [15], although a good comparison in
this respect is not possible as different lung regions are
20
defined differently in these studies. Considering the expo-
0 nentially increasing internal surface area of the airways from
0 500 1000 1500 2000 2500 3000 the trachea to the alveoli, which differs roughly by a factor
impaction parameter (IP)
130 between the generations 0–11 (conducting airways) and
Fig. 6.5 Experimental relationship between percent oro- 17–23 (peripheral airways) based on the Weibel model, it
pharyngeal deposition and impaction parameter computed as may be concluded that there must be a dramatic difference in
IP ¼ D2.Φ, where D is the aerodynamic particle diameter active substance concentration (in μg/cm2) between these
(micrometre) and Φ is the flow rate with which the particle is regions. A difference in definition for the different lung
inhaled (L/min). Data derived from Usmani et al. [11]
regions, or a considerable deviation from the deposition
distribution (approximately one third of the total lung dose
The figure makes clear that substantial lung doses in each region) does not really change this conclusion. This
cannot be obtained with particles larger than 6 μm, may have the consequence that the peripheral lung is
underdosed with for instance antibiotics, which need to
(continued)
6 Pulmonary 111
reach their minimum inhibitory concentration (MIC) value and they may also have significantly different performances.
to become effective. In fact, not reaching the MIC value In the following paragraphs, firstly the conceptual design of
could result in bacterial resistance development and this is the different types will be described and then their working
an aspect that will need serious consideration when changing principle will be explained. This has to be known to make
from systemic to pulmonary administration for therapies the best possible choice for individual patients and to give an
against pulmonary infections. In this respect, also changing appropriate instruction for use. Only examples of specific
from approved formulation-device combinations to off-label devices will be discussed in more detail, because the still
combinations (e.g. in nebulisation) is potentially a risk when growing number of devices in each category is too extensive
the delivered fine particle dose and the inhalation manoeuvre to make a complete survey.
are not exactly the same.
6.4.8 Practical Implications for the Inhalation 6.5.1 Dry Powder Inhalers (DPIs)
Manoeuvre
DPIs are relatively new and their designs and working
PRODUCT DESIGN
The optimal inspiratory manoeuvre for inhalation of a thera- principles may not only be quite complex but also rather
peutic aerosol depends on how it influences the aerosol diverse between the different types, which easily leads to
generation process and the deposition pattern in the respira- incorrect or suboptimal use. DPIs contain the active sub-
tory tract (Fig. 6.1). Its effect on the aerosol properties will stance in the dry state which is beneficial from the viewpoint
be discussed in the next paragraphs in which the working of stability. They can deliver much higher doses than MDIs
principles of different aerosol generation devices are and be disposable which is particularly desired for hygro-
explained. From the deposition point of view particularly scopic formulations of active substances, antibiotics against
the (peak) flow rate, the inhaled volume and a certain which bacterial resistance development has been reported
breathhold pause are relevant, but good inhalation starts and single-dose administrations such as vaccinations. Aero-
with exhalation to residual volume. As explained above, sol generation in DPIs is mostly breath activated, which
only with an inhalation from residual volume the alveoli eliminates the need for a good hand-lung coordination but
can be reached effectively. Considering the dependence of requires the generation of sufficient flow rates and inhaled
inertial impaction in the oropharynx and first airway volumes to release a sufficiently high fine particle dose. DPIs
generations on the particle velocity, it may also be clear have much higher airflow resistances than MDIs, which
that a high flow rate during inhalation should be avoided, limits the attainable flow rate and by that, oropharyngeal
but the optimum in this respect depends on the performance deposition. Furthermore, DPIs can deliver higher fine parti-
of the aerosol generation device too. For good (dry powder) cle fractions and finer aerosols at higher flow rates, which
inhaler performance, even the acceleration to peak flow compensates to a certain extent for the increasing losses in
(flow increase rate) may be important. Inhalation should be the mouth, throat and upper airways when the patient inhales
continued until total lung capacity is reached. Premature more forcefully, which results in an increased dominance of
stopping of the inhalation manoeuvre again has the conse- inertial particle impaction. DPIs exist not only in a large
quence that the most distal airways are not reached with the variety of different designs, they also have different perfor-
aerosol, but it can also mean the total dose is not delivered. mance properties and resistances to airflow. These
Once the smallest aerosol particles have reached the periph- differences in design and performance may be functional
eral lung, they must stay there for a certain period of time to and have been chosen carefully to obtain the most optimal
give sedimentation a chance and a breathhold pause of deposition of the active substance at the site of action.
several seconds (preferably 5–10) is desired before starting However, in many cases they may also be different for the
exhalation. same type (or class) of active substance(s), all having the
same target area. These differences may lead to considerable
variation in the delivered fine particle dose at this site of
6.5 Aerosol Generation Devices action. Differences in ease of handling, the flow manoeuvre
needed and airflow resistance may be aspects to consider
Basically four different types of commercially available particularly for special patient groups, such as children and
aerosol generation devices exist: dry powder inhalers severe COPD patients. In the next paragraphs, the general
(DPIs), metered-dose inhalers (MDIs), classic jet and ultra- design with some specific examples of DPIs will be
sonic nebulisers and a new class of high-performance liquid presented and discussed in relation to their performances
inhalers. Each of these categories has many different and the required operational procedures to obtain the best
variations of the same basic design and working principle delivery of active substance.
6.5.1.1 Basic Design of DPIs improving their flow properties and increasing their volume.
The primary functional parts of a dry powder inhaler are They are formulated into free-flowing powders either by
schematically shown in Fig. 6.6 and include a powder for- blending with coarse lactose carrier particles into so-called
mulation, a dose (measuring) system, a dispersion principle adhesive mixtures or by preparing highly porous soft spheri-
for the powder formulation, a mouthpiece and a housing for cal agglomerates with or without micronised lactose excipi-
all parts. Additionally, the inhaler may have various second- ent. For high dose medicines in the range from a few to a few
ary features, including a dose counter, giving the number of 100 mg, frequently special particle engineering techniques
doses left in the device, a compartment with desiccant to are used which produce low density particles or particles
keep the powder formulation dry and a signalling to the with a corrugated surface. Both types of powders, which
patient that the inhalation manoeuvre is correct or has been require the use of special volatile agents or surfactants and
completed. Different choices can be made for each of the often multi-step processes, have improved flowability and
functional parts and a good and compatible combination has can be delivered without further dilution or formulation.
to be chosen and developed to obtain the maximal result.
6.5.1.3 Dose (Measuring) Systems
6.5.1.2 The Powder Formulation for the Powders
The powder formulation contains the active substance in the Basically two different types of dose principles exist for the
correct aerodynamic size distribution, which for most cur- inhalation of powders in currently marketed inhalers;
rently marketed formulations is either obtained by preloaded single-dose compartments or multidose reservoirs
micronisation or by spray drying. Both techniques produce with a measuring mechanism that has to be operated by the
polydisperse particles and their mass median aerodynamic patient. Both principles have pros and cons and which type is
diameter is preferably in the range between 1 and 5 μm, most appropriate also depends on the properties of the powder
depending on the precise target area. Particles within this formulation. Preloaded single-dose compartments include
size range are extremely cohesive, whereas the powder mainly capsules and blisters. Capsules are stored separately
masses to be measured are miniscule and mostly less than and inserted individually into the inhaler when needed. They
5–500 micrograms for the active substances used in asthma have to be pierced to discharge the powder which in currently
and COPD treatment. Such small quantities of micronised used inhalers occurs during high speed spinning (e.g.
powders cannot be delivered in a reproducible way without Breezhaler®) or vibration (e.g. Boehringer HandiHaler®) in
Fig. 6.6 The primary functional

parts of a dry powder inhaler
including a powder formulation, a
dose (measuring) system, a
powder dispersion principle and a
mouthpiece (with flow control
and aerosol directing functions)
6 Pulmonary 113
swirl chambers or narrow channels during inhalation. Hard is less critical. On the other hand, the mechanical stability of
gelatine capsules have been the standard for more than such pellets is less than that of adhesive mixtures and this
30 years in dry powder inhalation, but many newly developed makes the inhaler more sensitive to falling or violent
medicines are now delivered with hydroxypropylmethyl- motions. All multi-reservoir inhalers are protected against
cellulose (HPMC) capsules. Particularly for moisture sensitive double dosing. When the dose measuring mechanism is
formulations HPMC capsules are more appropriate as they operated repeatedly without inhalation in between, the dos-
contain less water. HPMC capsules are also less prone to ing disk or cylinder is rotated with filled cavities into which
tribocharge during spinning and vibration and their tendency no additional powder can be measured. The only risk of not
to fragment or indent at extremely low and high relative inhaling after dose activation is powder waste from the dose
humidities of the air is considerably less when being pierced. cavity which is in line with the discharge channel. This leads
This reduces the risk of inhalation of capsule fragments and to inhaler pollution. The (Meda) Novolizer® and Genuair®
poor capsule emptying. Gelatine capsules on the other hand have a different protection principle. Their measuring slide
have a much lower oxygen permeability. Capsules size 3 for is put into position for inhalation with a knob and drawn
inhalation typically contain powder masses between 5 and back to the filling position automatically by an air valve only
45 mg depending on the type of active substance and formula- when sufficient flow rate is generated by the patient to
PRODUCT DESIGN
tion. Aluminium blisters used for inhalation are mostly smaller guarantee good emptying and dispersion. Patients that are
and contain less than 10 mg of powder. Blisters can be provided unable to generate this flow rate cannot use these dry powder
individually (e.g. Elpen, Elpenhaler®), be part of a disk inhalers and need to be treated with an MDI. The
(e.g. GSK Diskhaler®, with four to eight cavities), or be on a NEXThaler® has a similar dose measuring slide which is
long strip for 60 doses which is coiled into a spiral in the inhaler transported (to and fro) by the protective hood of the inhaler
(e.g. GSK Diskus®). Access to the powder is obtained either by whereas an air triggered valve removes a plate which covers
piercing the blister foil and cover lid (Diskhaler®) or by the powder cup until sufficient airflow has been generated.
separating both parts from each other (Diskus® and For extreme moisture sensitive powders, multidose reservoir
Elpenhaler®). For blisters on a disk or a strip, a transport inhalers may be less appropriate.
mechanism is needed as part of the inhaler design. When the
blister foil and cover lid are pierced, parts of the lidding strip 6.5.1.4 Powder Dispersion Mechanisms
projecting into the powder cup may prevent complete emptying As explained above, micronised particles of active
of the dose. Although this is not likely to result in serious substances are formulated (by agglomeration) into freely
underdosing, it causes inhaler pollution which may be a burden flowing powders to facilitate reproducible dose measuring.
to the patient. The agglomerates prepared are too large to reach the target
In contrast to single-dose compartments, multidose area in the lungs and they must be dispersed
reservoirs require good flow properties for the powder for- (de-agglomerated). Particles of active substances blended
mulation. To isolate single doses from the powder bulk, a with coarse carrier particles into so-called adhesive mixtures
slide (e.g. AstraZeneca Genuair®), disk (e.g. AstraZeneca have to be detached from the lactose carrier particle surface
Turbuhaler®) or cylinder (e.g. Orion Easyhaler®) with onto which they adhere mainly by Van der Waals forces. In
small cavities is used as measuring principle making contact soft spherical agglomerates, cohesion (or adhesion) forces of
with the powder container. A transport mechanism displaces the same nature between the small active substance (and
the measuring principle and the filling of the cavities is excipient) particles have to be overcome during inhalation.
basically by action of the force of gravity. This requires Different types of de-agglomeration forces can be used and
that the inhaler is kept in the prescribed position during frequently emptying of the capsules and blisters and disper-
dose measuring to assure good powder flow into the measur- sion of the powder formulation occurs (at least partly) simul-
ing cavity. Disks and cylinders have several dose cavities taneously. Most effective are inertial forces which are the
along their circumference and transporting them means that result of particle collision against inhaler walls or that of
a filled cavity is positioned in line with the powder channel high speed particle spinning and circulation. Particles may
towards the dispersion principle, whereas simultaneously an also impact with each other. Inertial forces as generated in
empty cavity is positioned underneath the powder container the Novolizer®, Genuair®, (Teva) Spiromax®, (MSD)
which is then filled. Slides have a single cavity which is Twisthaler® and (Chiesi) NEXThaler® are proportional
pushed forward for the inhalation and drawn back for filling. with the third power of the particle diameter. Drag and lift
The Turbuhaler® has a more complex dose measuring forces occur during emptying of the dose compartment or in
mechanism as this inhaler makes use of spherical turbulent air streams in or around special flow bodies. They
agglomerates which are scraped into tiny dose measuring are the result of considerable differences between the air and
holes in a series of successive scraper chambers between the particle velocities and are largely proportional to the first
bulk container and the discharge channel. Therefore, the power of the particle diameter. Therefore, they are much
position in which the inhaler is held during dose measuring lower than inertial forces. They are also less effective when
the carrier particles have a high surface rugosity. The resistance of the inhaler. This principle has been used in the
Turbuhaler® makes use of friction forces in addition to Novolizer®, Genuair® and Diskus®. The Diskus® has two air
inertial forces. The soft agglomerates in this device pass a holes on either side of the exit channel for the aerosol whereas
spiral-shaped channel in which centrifugal forces are respon- the Novolizer® and Genuair® have a bypass that creates a
sible for considerable friction with the outer wall of this clean air sheet around the aerosol to reduce deposition in the
channel. The interaction between the drag force of the air oral cavity. Compared to other DPIs, the Novolizer® and
stream pushing the particles forward and the friction forces Genuair® have a different discharge pattern for the carrier
with the inhaler wall causes internal shear which leads to particles as a consequence of which these particles are not
disruption into smaller particles. deposited in the throat, but in the mouth from which they can
All dispersion forces in so-called passive (breath operated) easily be rinsed to prevent local side effects.
inhalers are derived from the kinetic energy of the inhaled air
stream. For well-designed inhalers with effective
de-agglomeration principles this leads to a better dispersion The Inhaler Resistance
at a higher flow rate. In addition to that, the particles in the Resistance to airflow is an inhaler property that is a
aerosol may become finer. In contrast with what is frequently direct consequence of its basic design, but can be fine-
claimed in the literature [16], this is an advantage as it tuned with the mouthpiece. Persistent misconceptions
contributes to a more constant (patient independent) therapy. exist about the inhaler resistance and hamper an optimal
The finer particles reduce the increased deposition propensity inhaler choice for individual patients and the correct use
in the oropharynx and upper airways, whereas the higher fine of DPIs. It is often postulated that operating a high
particle dose compensates for higher losses in the same resistance inhaler requires a greater effort and a higher
regions. This results in a more constant central and peripheral amount of work than using a low resistance device
lung deposition as has been shown for the Novolizer® in a [18]. It has also been described that patients have to
study with radiolabeled budesonide [12]. Dispersion of the inhale deeply and forcefully when using a DPI in order
formulations is also improved by utilising the available energy to receive the correct dose and that failure in this way is a
within the inhaled air stream more efficiently. In most multi- common error when patients use their DPI [19]. This has
dose reservoir inhalers, the powder is released from the inhaler resulted in the belief that patients with reduced vital
mouthpiece within split seconds. Hence, a major part of the capacity may have difficulties in operating high resis-
kinetic energy remains unused for dispersion. By keeping the tance inhalers effectively [16, 20]. As a response to this,
particles in circulation for a certain period, a better the ERS/ISAM task force group has classified DPIs
de-agglomeration can be obtained, providing that the bulk of according to their flow rate (Φ) corresponding with a
the aerosol is delivered within the first litre of air inhaled. The 4 kPa pressure drop across the inhaler into low resistance
classifier types of dispersion principles in the Novolizer® and (Φ > 90 L/min), medium resistance (60 L/min < Φ
Genuair® have the longest circulation times followed by the < 90 L/min), medium/high resistance (50 L/min < Φ
Spiromax® and NEXThaler®, which have different circula- < 60 L/min) and high resistance (Φ < 50 L/min)
tion chambers. However for all these devices, the dose emis- [19]. They also explained that ‘because the internal
sion times remain shorter than those for most capsule inhalers. energy in a DPI will be the same whether a patient
All these differences in design lead to considerable differences inhales slowly through a DPI with a high resistance, or
in dispersion efficiency and thus result in a large variation of inhales quickly through a DPI with low resistance, the
fine particle doses at the same pressure drop across the inhaler. de-agglomeration of the powder will be the same’.
They also result in considerable differences in how the fine Reality is rather different, however. The amount of
particle dose changes with the flow rate and thus, the degree of work for inhaling a certain volume of air through
compensation for the effective flow rate on lung deposition. inhalers is independent of the inhaler resistance, as can
be computed by expressing the energy in terms of flow
6.5.1.5 The Mouthpiece rate, pressure drop and inhalation time. A lower flow
The inhaler mouthpiece can have different functions. It has rate at the same pressure drop through a high resistance
been shown that minor variations of the mouthpiece geometry inhaler is completely compensated by the longer time
of an inhaler like the (Novartis) Aerolizer® may have a great needed to inhale the same volume. Patients do not nec-
effect on the throat deposition [17]. Active substance deposi- essarily have to inhale deeply and forcefully to receive
tion in the throat is not only relevant because it reduces the the correct (lung) dose. On the contrary, some inhalers
lung dose but also because of possible local side effects, are more effective when the flow rate is limited and a
particularly from inhaled corticosteroids. Throat deposition maximal value is not exceeded, as will be explained
is for a large part caused by carrier particles onto which a below. Therefore, whether patients with reduced vital
significant part of the dose remains attached during dispersion.
The mouthpiece may also be used to fine-tune the total airflow (continued)
6 Pulmonary 115
capacity, e.g. severe COPD patients, have difficulties single dose. Furthermore it has to be acknowledged
with operating a DPI correctly does not depend on the that the total inhalation time including preceding exha-
inhaler resistance, but on the severity of their disease. In lation and a breathhold pause is much longer than the
fact all subjects, healthy or not, are able to generate a time needed to inhale a certain volume of air and the
higher pressure drop across a higher resistance [21], but DPI resistance has only a minor effect on that.
the value achieved at any resistance decreases with the
degree of vital capacity reduction. Whether the pressure
drop value achieved is sufficient for good DPI perfor-
mance or not depends on the fine particle dose delivered
at that pressure drop. There is no such thing as an 6.5.1.6 DPI Performance and Its Relevance
internal energy in a DPI. What does exist is the kinetic to the Therapy
energy of the inhaled air stream which is utilised to The airflow resistances of some currently marketed devices
generate the de-agglomeration forces. Because different are presented in Table 6.2.
de-agglomeration forces are applied in different DPI The difference between the highest and lowest flow rates
PRODUCT DESIGN
designs, which may have different dispersion corresponding with 4 kPa is by the factor 2.7. Although a
efficiencies, de-agglomeration cannot be expected to good comparison between different inhalers cannot be made
be the same on the basis of equal kinetic energy. In in this respect because different mouthpieces may result in
fact, fine particle doses vary considerably between different exit velocities at the same flow rate, the effect of
inhalers at the same pressure drop and inhaled volume flow rate on oropharyngeal losses for the same DPI may well
as will be shown and discussed in the next paragraph. be estimated from Fig. 6.5. Such a great difference in flow
Patients with severely reduced vital capacity are rates as between the extremes in Table 6.2 is likely to
often short-winded and have high breathing influence oropharyngeal losses considerably and the losses
frequencies. Despite the fact that they may be capable become more pronounced when the particle diameter
of achieving sufficient pressure drop across the DPI, increases. In addition to that, the lung deposition in the entire
they may be unable to inhale sufficiently long to lung is shifted to larger diameters when the flow rate is
release the total dose from the inhaler or to transport increased. Whether this is disadvantageous for lung deposi-
sufficient aerosol to the central and deep lung. And tion or not depends on many factors, including the precise
inhaling against a high resistance may feel less com- target area for the active substance, the size distribution of
fortable than inhaling against a low resistance because the aerosol and the range over which the flow rate can be
it takes much longer before the same volume of air is varied. Lung deposition also depends on how the delivered
inhaled, even if the amount of work is the same. fine particle dose changes with the flow rate. If the target
Therefore, the choice of DPI resistance for a particular area is in the larger airways the effect of the flow rate on the
patient has to be balanced between patient acceptance deposition pattern is less important than when the central or
and the benefits of a high resistance regarding lung peripheral lung has to be targeted. The relatively high con-
deposition. In this respect, it should also be taken into centration of active substance in the larger airways com-
consideration that many DPIs allow for a number of pared to the peripheral lung is partly responsible for that;
short inhalations to complete the administration of a for most inhaled medicines the upper airways are relatively
overdosed.
(continued)
Table 6.2 Airflow resistances and flow rates corresponding with 4 kPa pressure drop for a number of currently marketed dry powder inhalers with
asthma and COPD medication
Inhaler Resistance (kPa0.5.min.L1) Flow rate at 4 kPa (L/min)
Budesonide Cyclohaler 0.019 105
Flixotide Diskus 0.026 78
Seretide Diskus 0.027 75
Budesonide Novolizer 0.028 71
Rolenium Elpenhaler 0.029 68
Budesonide Easyhaler 0.033 61
Symbicort Turbuhaler 0.034 59
Foster NEXThaler 0.034 59
Pulmicort Turbuhaler 0.037 54
Spiriva HandiHaler 0.051 39
Some fine particle doses as percent of the label claim be clear that inhalation through the Elpenhaler®,
are presented in Fig. 6.7 as function of the pressure Diskus® and Cyclohaler® should not be forcefully,
drop for ICS from ICS-DPIs or inhalers with a combi- as recommended in the ERS/ISAM task force report
nation of ICS and a β2-agonist. The differences are [19], because this will not result in a higher delivered
rather extreme and roughly two different categories fine particle dose. On the contrary, a lower peripheral
can be distinguished: inhalers with a constant fine and central lung dose will be obtained due to higher
particle output (e.g. Elpenhaler® and Diskus®) and oropharyngeal losses and the changes in lung distribu-
inhalers of which the delivered FPF becomes higher tion. For the Turbuhalers, Novolizer® and Easyhaler®
when the flow rate is increased. Obviously, a high FPF the effect of inhalation effort is less critical because
is desired and most preferable is a high FPF delivered the losses and shift in deposition are more or less
at a low flow rate. From the combination of the data in compensated by the increasing FPF, and the compen-
Table 6.2 and Fig. 6.7, it can be concluded that the sation is highest between 2 and 4 kPa. But even for the
Symbicort Turbuhaler® (29.5 %), Flixotide Diskus® Turbuhalers and Novolizer®, an inhalation effort that
(28.1 %) and budesonide Novolizer® (22.9 %) deliver will result in pressure drops higher than 4 kPa is not
the highest FPFs (<5 μm) at 2 kPa, corresponding with needed. Much more important it is to exhale deeply
flow rates of 41.5, 54.5 and 50.5 L/min, respectively. first before inhaling to total lung capacity, to assure
The budesonide Cyclohaler® delivers the same FPF aerosol penetration into the most distal airways, and
at 2 kPa as the Novolizer®, but this is at a much higher finally to keep the breath for approximately 5–10 s to
flow rate of 74.5 L/min. From Fig. 6.7 it may also give sedimentation a chance.
Fig. 6.7 Fine particle

fractions < 5 μm (expressed as
percent of the label claim) as
function of the pressure drop
across the inhaler
(continued)
6 Pulmonary 117
Aspects needing careful consideration when choosing a 6.5.2.1 Basic Design of MDIs
DPI for the individual patient are the ease of handling and The general design of an MDI is shown in Fig. 6.8. The main
risk of inhalation errors. Both are relevant to good adherence body of an MDI is a small canister for the medicine formu-
to the therapy and the efficacy of the treatment. In spite of lation which is sized to contain sufficient volume for the
numerous publications on these aspects good labelled number of doses. The formulation contains a pro-
recommendations cannot be given because of the pellant (a gas with a high vapour pressure) which is one of
contradicting outcomes of the studies, of which several the key components of an MDI. On top of the medicine
were reviewed by Lavorini et al. [22]. What does assist in formulation canister a metering valve or chamber is
the correct use of a DPI is signalling to the patient, as for crimped. This has to separate a defined volume of the solu-
instance given by the Novolizer® and Genuair®. Both tion or suspension from the canister containing the amount
devices give acoustic and visual signalling when the flow of medicine for a single dose. The metering chamber is
rate for good performance is achieved, after which the connected to a hollow stem that ends against the actuator
patient has to continue inhalation with the same effort for orifice. On actuation of the MDI, the stem penetrates the
another 1–1.5 s. metering chamber which becomes closed to the formulation
reservoir and opens to the nozzle block in the actuator. This
PRODUCT DESIGN
results in discharge of the formulation from the metering
6.5.2 Metered Dose Inhalers (MDIs) chamber through the stem and atomisation through the actu-
ator orifice by propellant evaporation and gas expansion.
In contrast to DPIs the basic design of MDI hardware is well
described in the literature [23, 24]. Most MDIs apparently 6.5.2.2 The Medicine Formulation
have a simpler design than DPIs and a key advantage of MDI In contrast to DPIs, most MDIs contain a wide variety of
systems is their low cost per dose. They are portable, conve- different excipients. In the original design of the first MDIs
nient and have widespread acceptance by patients and on the market in 1957 (Medihaler-EpiTM and -IsoTM,
clinicians. Basically they all have the same operational 3M-Riker), the propellant was a relatively low-pressure
principle and furthermore all MDIs deliver a constant fine chlorofluorocarbon (CFC11, 12 and 114, or a mixture of
particle dose (independent of the flow rate). Whereas they these compounds). Initially, the choice of the type of propel-
have a relatively low resistance to airflow and this all makes lant was rather driven by manufacturing convenience and
the inhalation instruction less dependent on the individual formulation stability than by performance, and delivery to
type of MDI. The most relevant differences between types the lung was frequently as low as 5–10 % of the label claim.
are in the actuator design and medicine formulation (solution The Montreal protocol signed in 1987 and ratified in 1989
or suspension), in which the type of propellant and the put an end to the use of CFCs because of their contribution to
presence of co-solvents play an important role because of the depletion of the ozone-layer, and the CFCs needed to be
their influence on the (plume) velocity with which the aero- replaced by hydrofluoroalkanes (HFAs) of which HFA
sol is released from the actuator and rate of droplet 127 and 134a evolved as most suitable. Both HFAs used
evaporation. have broadly similar thermodynamic properties as CFC
Fig. 6.8 Basic design of an MDI canister for the

before (left) and during activation drug formulation
(right). Source: Recepteerkunde
2009, #KNMP
metering chamber
with valves
stem
nozzle block
with sump
spray nozzle
12, but they are chemically different and this raised

problems with certain active substances regarding solubility based MDI was explained by the much finer aerosol
[25]. The active substance solubility problem is further (with an average particle size of 1.1 μm) compared to
complicated by the fact that previously used surfactants or CFC-BDP metered-dose inhalers, which deliver
other excipients for CFC-MDIs are insoluble in the HFAs aerosols with average particle diameters of 3.5–4 μm
too. For that reason co-solvents are currently often added to [26]. This led to the conclusion that from a HFA-MDI
the formulations. Solution MDIs may have several only half the BDP dose is needed for the same efficacy
advantages over suspension aerosols, including a higher as from a CFC-MDI [27]. More important for delivery
physical stability, a more homogeneous formulation and of active substance to the lung may be the difference in
potentially a larger fine particle dose. On the other hand, plume velocity between CFC and HFA containing
the primary co-solvent ethanol may change the size distribu- MDIs, however. In different studies the spray patterns
tion of the aerosol and the evaporation rate of these droplets, [28], velocities [29] and impact forces [30] of different
whereas the excipients used in solution aerosols may also MDI types have been measured and the results show
influence the pharmacological effect [25]. that CFC products have forceful plumes whereas most
Suspension aerosols require that the active substance is HFA systems produce much softer plumes. The use of
added in a suitable size distribution to the formulation. The HFA does not guarantee a lower plume velocity, how-
size distribution is obtained with the same techniques as ever. The difference in velocities between CFC and
used for dry powder inhalers, including micronisation in a HFA is for a large part due to the difference in nozzle
fluid energy mill, spray drying and super-critical fluid dry- diameters between both systems and some MDIs
ing. Whether this size distribution is the same as needed for which use HFA propellants have a high aerosol veloc-
adequate deposition in the target area depends on the con- ity too (e.g. GSK Flixotide®).
centration of active substance in the suspension. If the con-
centration is low, individual droplets from the actuator
contain single particles of active substance and the size
distribution of the suspended particles equals that required 6.5.2.3 The Metering Chamber (Valve)
for lung deposition. If the concentration is high, droplets The metering chamber is the MDI part with greatest com-
may contain multiple particles of active substance which plexity. To deliver a consistent amount of medicine, the
cluster into small agglomerates upon evaporation of the valve must release a consistent mass of the bulk formulation
volatile excipients. Such MDIs need finer particles in sus- with each actuation and the concentration of active sub-
pension. A primary concern for suspension MDIs is their stance in the measured mass must each time be the same.
physical instability due to phase separation, flocculation, In fact the metering chamber has two valves. At rest, one
agglomeration and sedimentation. Some of these processes (inner) valve is open to the canister to fill the chamber and
may be irreversible and moisture ingress may negatively this valve closes upon actuation after which a second (outer)
influence them. The active substance must also practically valve is opened to release the contents of the chamber
be insoluble in the formulation to prevent Ostwald ripening through the stem (Fig. 6.9).
or the suspension must be thermodynamically stable if a The metering chamber, sealed with a ferrule onto the
certain level of solubility exists. Stability may further canister, must meet many other criteria amongst which low
depend on the anomeric form or salt used for the active leakage during storage, low moisture transmission, low
substance. In addition to co-solvents, a wide variety of actuation forces and low extractables and leachables are
other excipients may be present in the formulation, including the most important. Different designs exist for the metering
surfactants (e.g. soya lecithin, sorbitan trioleate or oleic chamber and many MDIs have a concept with a so-called
acid), suspending aids (e.g. PEG, PVP), bulking agents for retaining cup around the actual metering chamber. Without
low-concentration suspension MDIs (e.g. lactose, maltose, the retaining cup the metering chamber may drain out during
glycine and leucine) and traces of lubricant (silicone oil) for storage of the MDI between inhalations or due to ‘shake out’
the metering valve. by the patient through the open valve between the metering
chamber and the canister. The retaining cup is filled from the
top of the canister when the MDI is in the inverted position
The change from CFC to HFA propellants had (as during inhalation of a dose) and remains thus filled when
consequences for delivery of the active substance to the MDI is placed with the metering chamber in upright
the respiratory tract. Improved delivery of position. Retaining cups prevent not only loss of prime but
beclomethasone dipropionate (BDP) from a HFA also increase consistency of delivered dose when the canister
approaches the end of labelled contents. Many other special
(continued)
6 Pulmonary 119
Fig. 6.9 Design of a outlet valve inlet valve

jet nebuliser.
Source: Recepteerkunde
2009, #KNMP
baffle
reservoir cup for

the drug solution
PRODUCT DESIGN
nozzle
pressurised air
metering chambers, e.g. with narrow and tortuous inlet chambers). Also the mouthpiece shape and diameter affect
channels, or ‘fast-fill, fast empty’ (FFFE) principles are in aerosol delivery. Although several improvements have been
use or in development. They have been described or referred implemented through the years, in many respects the actua-
to elsewhere and will not be discussed here [31]. tor is still quite similar to its original design [31].
6.5.2.4 The Actuator 6.5.2.5 MDI Design and its Relevance

The actuator is the patient interface of the MDI in which the to the Therapy
aerosol is formed. It is the mouthpiece of the MDI where the As a consequence of its push-and-breath design, MDIs
tip of the hollow stem from the metering chamber is posi- require a good hand-lung coordination. Depending on the
tioned against a ledge in a nozzle block (Fig. 6.8). The actuator design, the discharge time of a dose is typically
nozzle block has a small expansion chamber (sump) which between 0.1 and 0.5 s [24] and poor coordination may result
ends in a spray nozzle (also: atomisation or actuator orifice). in high losses in the mouth and throat region (in combination
The atomisation process is complex and starts already in the with the high exit velocity of the aerosol) and insufficient
hollow stem when vapour cavities are formed in the liquid penetration of the active substance into the peripheral lung.
medicine formulation due to rapid expansion after the pres- Due to the extraction of heat from the mouth and throat
sure is reduced compared to that in the confinement of the cavity for evaporation of the propellant, patients may expe-
metering chamber. This process of expansion is continued in rience a ‘cold-freon’ effect which could negatively influence
the sump, followed by rapid flashing of the propellant after the inhalation manoeuvre. This cold freon-effect is particu-
exiting the spray nozzle [24]. Nozzle diameters are typically larly noticeable for CFC-MDIs having generally much lower
in the range between 0.3 and 0.6 mm and the precise geom- plume temperatures (20 C to 30 C) than HFA systems,
etry of the various parts of the actuator control the although some HFA-MDIs also produce very cold plumes
atomisation time as well as the size distribution of the (e.g. Flixotide). To overcome these problems, particularly
aerosol and by that, the delivered fine particle dose. Also for small children and elder patients, various add-on devices
relevant is the geometry of the mouthpiece of which the can be used which either elongate the distance between the
length was originally 3–4 times longer than that for currently nozzle and the throat, or keep the aerosol in storage until
marketed MDIs. A long mouthpiece collects droplets that it is inhaled. Aerosol storage in so-called valved holding
would otherwise be deposited mainly in the oropharynx. chambers (VHCs) not only reduces the high throat deposi-
Shortening has improved portability, but it introduces the tion and the cold-freon effect, it also eliminates the hand-
need for add-on devices (spacers or valved holding lung coordination problem. However VHCs may cause
considerable reduction of the delivered lung dose depending asthma and recurrent cough, species of Bacillus and Staphy-
on how they are used, as discussed in the next paragraph. lococcus could be detected. In a total of 64 VHCs only one
Healthcare workers giving instructions for use, should be was infected with Pseudomonas aeruginosa and no other
informed about the design and properties of the MDIs they pathogenic organisms could be found. The presence of
prescribe, as well as about the way these MDIs are used by Bacillus and Staphylococcus appeared to be independent of
their patients in order to estimate the risk of incorrect medi- the type of VHC used and the cleaning procedure [33].
cine delivery. For correct use of a suspension MDI, good
shaking of the canister prior to dose activation is necessary
in order to homogenise the suspension. Some patients tend to 6.5.3 Nebulisers
use their MDI upside down which could lead to incorrect
refilling of the metering chamber, depending on its design. Nebulisers are less frequently used than DPIs and MDIs and
their application is mainly confined to active substances that
6.5.2.6 Valved Holding Chambers (VHCs) are not available in registered inhalation devices (which can
VHCs are storage chambers for the aerosols from MDIs with for instance be high dose medicines) or to the administration
a valve in the mouthpiece. The one-way valve, which is of medication to ventilated patients.
meant to prevent exhalation through the VHC, should also Basically three different types of nebulisers exist:
remain closed during firing of an aerosol into the chamber 1. Jet nebulisers, which consist of a two-fluid nozzle
and open when the patient inhales through the mouthpiece. connected to a reservoir cup for the medicine solution
Different types of VHCs exist with different volumes, made and a compressor or a compressed air system
of different construction materials. VHCs reduce the oro- 2. Ultrasonic nebulisers
pharyngeal deposition from MDIs with a high plume veloc- 3. (Vibrating) membrane inhalers with a high output rate
ity, but they also reduce the inhaled dose as the result of based on different aerosol generation principles, designs
losses into the chamber which may be the result of inertial and performances
impaction against the end with the valve, electrostatic Jet nebulisers in the home situation are increasingly replaced
interactions with the chamber walls and sedimentation. To by (vibrating) membrane inhalers which give better control
reduce the losses by electrostatic interactions, it is over the medicine delivery to the respiratory tract than the
recommended to wash the spacer before use with a highly classic jet and ultrasonic nebulisers, and may increase the
diluted solution of household detergent and dry it to the air adherence to the therapy.
(dip and dry method). This method is equally effective as In contrast to DPIs and MDIs, nebulisers do not contain a
priming with doses, which is a loss of medication. Also after medicine formulation. Nebulisers receive market clearance
coating with detergent or priming, losses in a VHC can be in the USA via a 510(k) premarket notification (CDRH
substantial, however, and they increase with decreasing rel- Guideline 784) and by CE marking in Europe. They can
ative air humidity (RH). For corticosteroids the dose from a either be developed for the administration of a particular
well prepared VHC at low RH (30 %) may be reduced to type of a solution or suspension of an active substance, or
20–40 % of the dose directly from the MDI. At higher RH a medicine may be licensed for the administration with a
(75 %) the reduction may still be 40–70 % of the MDI dose, particular type of nebuliser. An example is tobramycin solu-
depending on the type of VHC and medicine formulation tion (TOBI®, Novartis) which is licensed in the USA for use
used. Metal VHCs or antistatic VHCs do not need priming or with the Pari LC Plus® nebuliser in combination with the
washing, but losses in antistatic plastic VHCs are influenced DeVilbiss Pulmo-Aide® compressor. In Europe, a ‘suitable’
by the RH too. Losses due to sedimentation are less extreme compressor is allowed, which for TOBI® for the LC Plus®
and limited to approximately 30 % after 20 s (compared to nebuliser is specified as a compressor with a jet pressure
the delivered dose immediately after firing into the VHC). between 110 and 217 kPa or a jet flow between 4 and
Special attention should be given to VHCs used in combina- 6 L/min. In practice, suitable compressors are not always
tion with a face mask for very young children. When the used and the LC Plus® is also frequently exchanged with
mask does not fit closely to the child’s face, unmedicated air vibrating mesh devices, like the Pari eFlow rapid®. This is a
is inhaled. A small leakage of approximately 0.5 cm2 may consequence of the fact that in most countries the purchase
result in near-complete bypassing of the VHC which has the of nebulisers is not regulated as tightly as the purchase of
consequence that only a fraction of the dose is delivered to medication and patients can get hold of nebuliser equipment
the respiratory tract [32]. without medical advice. This situation has not really
Because patients may accidentally exhale through their changed since the European Respiratory Society (ERS)
VHCs depending on the design or performance of the valve issued their guidelines on the use of nebulisers in 2001
system, contamination with micro-organisms is possible. In [34]. In fact, many nebuliser systems are still sold without
VHCs used over a period of 4 months by children with or with no printed information regarding their use and the
6 Pulmonary 121
hope of the ERS task force that their guidelines would which open and close in an alternating way during the
improve clinical practice in the use of nebulised therapy inhalation cycle. Upon inhalation, the inlet valve opens to
throughout Europe has not come true. enable the inhaled air to entrain the aerosol from the aerosol
chamber. Meanwhile the outlet valve, which is in an elon-
6.5.3.1 Basic Design of Jet Nebulisers gated mouthpiece, is closed. During exhalation, the inlet
The basic design of a jet nebuliser is shown in Fig. 6.9. A jet valve closes to prevent aerosol escaping from the nebuliser
nebuliser has a reservoir cup for the solution (suspension) of whereas the outlet valve opens to bypass the exhaled air. In
the active substance and a nozzle. The nozzle starts at the the meanwhile, the aerosol produced accumulates in the
bottom of the medicine reservoir and consists of two aerosol chamber and elongated mouthpiece. The outlet
co-axial tubes ending on the same level above the medicine valve may be connected with a filter to collect exhaled
solution. One of the co-axial tubes is connected to a supply aerosol particles. With such a double valve (with filter)
system for compressed air, the other tube is open on its lower system, the aerosol losses to the environment can be
side to allow medicine solution to enter this tube. For minimised. Inlet valves may be complex to reduce the
reasons of design, mostly the inner tube is for compressed range of attainable flow rates in favour of central and deep
air, whereas the outer tube is for the medicine solution. The lung deposition (e.g. Pari LC Sprint® with PIF control).
PRODUCT DESIGN
air jet leaving the nozzle exit entrains liquid from the outer Such valves have an increased resistance when the flow
tube by momentum transfer. The liquid jet disrupts by shear rate becomes too high and limit the flow rate to approxi-
forces into droplets with a size distribution that is too wide mately 25 L/min. Mechanical breath actuated nebulisers
for inhalation. For that reason, a baffle is placed at a short (e.g. Trudell AeroEclipse®) interrupt aerosol production
distance above the nozzle. Droplets that are too large to during periods of exhalation. They have a diaphragm
reach the site of action in the lungs impact against this baffle which moves down an actuator piston to start the
according to the same principle as described for medicine nebulisation process when the flow rate has reached a thresh-
particle deposition in the oropharynx and return to the liquid old value of approximately 8–15 L/min [35]. During exhala-
reservoir. Only the smallest droplets can pass the baffle and tion, the actuator piston moves up again to stop the aerosol
mix with the inhaled air stream. production and to eliminate waste to the environment. Some
Many different types of jet nebulisers exist and they differ modern liquid inhalers have an electronic instead of a
not only in the properties of the delivered aerosol regarding mechanical breath actuation system, but they will be
the size distribution and output rate, but also in the efficiency discussed separately.
with which the aerosol is delivered to the patient. They can
be distinguished in: 6.5.3.2 Jet Nebuliser Use, Performance
• Nebulisers without valves and Maintenance
• Nebulisers with open valves The performance of a jet nebuliser depends on many differ-
• Nebulisers with breath assisted valves ent parameters. The jet pressure, or jet flow rate, is one of the
• Breath actuated nebulisers (BAN) primary determinants for the droplet size distribution of the
Most basic nebulisers (e.g. Hudson T Updraft®) have no delivered aerosol [36]. A higher jet flow rate results in
valves. They continuously produce the aerosol which is smaller particles and because the size distribution of an
released into a chamber connected with a T-shaped mouth- aerosol affects the site of deposition in the respiratory tract,
piece. One of the branches of this mouthpiece delivers the replacing the compressor by another type may change the
aerosol to the patient’s respiratory tract during inhalation. efficacy of the therapy if the jet pressures of both
Aerosol losses to the environment are relatively high compressors are not the same. The jet flow rate furthermore
because the patient also exhales through the same determines the nebulisation time. Additionally, the physical
T-shaped mouthpiece and the approximate ratio for exhala- properties of the solution of the active substance may influ-
tion to inhalation time during normal breathing is 2:1. ence the size distribution of the aerosol and the output rate of
Exhaled air may entrain aerosol from the nebulisation cup a nebuliser [37]. These properties, of which the surface
too and release it to the environment. For that reason, differ- tension, viscosity and density are the most relevant, depend
ent valve systems have been developed to increase the aero- not only on the type of active substance in solution, but also
sol mass delivered to the patient. The most simple example on the concentration of the active substance [36–39]. Fur-
is an open valve (e.g. Respironics Sidestream®) which thermore, the flow rate may influence the size distribution of
directs (part of the) inhaled air through the aerosol chamber the aerosol from a jet nebuliser and the influence increases
to flush this chamber, thereby increasing the aerosol output. with decreasing jet flow rate [36]. Finally, good maintenance
Open valve systems have further evolved into breath assisted of a nebuliser is important. Nebuliser cups are used over
open valve nebulisers (e.g. Repironics Sidestream Plus® and longer periods, varying from several months to years, and
Pari LC Plus®). Such nebulisers have inlet and outlet valves particularly when antibiotics are nebulised, good cleaning
and disinfection on a regular basis are of utmost importance. medicine solution [43]. Basically two different classes of
Disinfection may prevent bacterial resistance development ultrasonic nebulisers exist: those in which the ultrasonic
in the medicine administration device and re-infection of the vibration is directly transmitted to the medicine solution
patient by medicine-resistant strains. During cleaning and and those in which the oscillation is transmitted indirectly
disinfection, nebulisers are frequently disassembled and via an outer bath. A third type of ultrasonic nebulisers
patients should take care that re-assembling occurs precisely making use of perforated membranes (vibrating membrane
as prescribed. Small variations in the distance between the technology) will be discussed in Sect. 6.5.4.
nozzle exit and the baffle considerably influence the size
distribution of the aerosol and so does a minor change in
6.5.3.4 Ultrasonic Nebuliser Use
the diameter of the nozzle exit. Clogged nozzle exits should
and Performance
therefore never be opened with a sharp pin, but by submer-
As for jet nebulisers, a great variety of different designs
sion in warm water with some household detergent and using
exists for ultrasonic nebulisers. Which type to select primar-
the compressed air from the compressor to remove the plug
ily depends on the desired droplet size distribution. The
if it does not completely dissolve.
design, in particular the operating frequency, is a major
Major disadvantages of jet nebulisers are their long prep-
determinant for the aerosol characteristics but also incorrect
aration, cleaning and nebulisation times and their low lung
use may influence the aerosol properties. Particularly the
deposition efficiency. Total administration times can cumu-
filling degree of the outer bath of jacketed nebulisers proves
late to more than 30 min, whereas estimated mean lung
to be very critical for performance. Ultrasonic devices may
doses in well controlled clinical studies vary between only
also have a baffle to return large droplets to the medicine
9–20 % for breath enhanced and breath-actuated nebulisers
reservoir and a fan to assist the fine particle output. The size
[40]. The lung deposition in real life may even be consider-
of the droplets is often larger and the aerosol output rate
ably lower as patients are tempted to combine nebulisation
higher compared to jet nebulisers. Evaporation is less
with other activities. This may for instance result in keeping
extreme in ultrasonic nebulisers however, and therefore the
the nebulisation cup not in the prescribed position. It has
increase in concentration of the active substance with
been shown that controlling the inspiratory flow manoeuvre
aerosolisation time is lower. Residual volumes in ultrasonic
significantly increases the lung dose and reduces the
nebulisers are higher. Solutions of high viscosity and
variability in lung deposition from jet nebulisers. Flow and
suspensions of active substance (e.g. budesonide) cannot
volume regulated inhalation technology with the Akita Jet®
efficiently be atomised by ultrasonic nebulisers. In contrast
(Activaero) has shown that 60 mg nebulised tobramycin
to jet nebulisers, where a drop in temperature can be
with this system and the LC Star® nebuliser can result in
observed due to evaporation, the temperature of solutions
the same serum level after 1 h as 240 mg nebulised
in the reservoir of ultrasonic nebulisers increases during the
tobramycin with an LC Plus®/PariBoy® N combination in
atomisation process. This may result in partial degradation
less than half the administration time [41]. The Akita system
of heat sensitive substances, such as proteins. Liposomal
is voluminous however and reduces the mobility of the
formulations have successfully been delivered with ultra-
patient. Finally, and in contrast, the delivered lung dose
sonic nebulisers, although some disruption of vesicles has
may considerably deteriorate from using long, tortuous
been observed and increasing the vesicle stability by use of
and/or corrugated tubings as in the treatment of mechani-
substances such as cholesterol is recommended [44]. Ultra-
cally ventilated patients. Total lung deposition in such
sonic nebulisers do not require compressors and are gener-
patients from jet nebulisers may be as low as 2.3 % [42].
ally much smaller and less heavy than jet nebulisers. In
Successful administration of inhaled medication to mechan-
addition, they are almost silent, but these advantages have
ically ventilated patients requires special equipment and
not made them very popular in most European countries
arrangements which is not further discussed in this chapter.
[34]. Therefore, they are not discussed further (see also
novel liquid inhalers).
6.5.3.3 Basic Design of Ultrasonic Nebulisers
Ultrasonic nebulisers make use of piezo technology to create
an aerosol from a solution of active substance. In such 6.5.3.5 The Choice of Device and Instructions
nebulisers the high frequency mechanical vibration of a for Use
piezoelectric element is transmitted to a solution of the A great variety of jet and ultrasonic nebulisers is available
medicine which creates standing capillary waves on the for a wide range of size distributions and different output
surface of that solution. Small droplets break free from the rates [45]. If an inhaler is approved for the administration of
crests of these waves and constitute the aerosol. The mean a particular type of medicine formulation, it should be the
droplet diameter is a function of the frequency of the acous- first choice for that application. If the nebuliser or compres-
tic signal, the surface tension, density and viscosity of the sor (for jet nebulisers) is not available, as for instance
6 Pulmonary 123
(in Europe) the DeVilbiss Pulmo-Aide® compressor for • (Optional) Breath controlled or adaptive medicine
TOBI®with the LC Plus®, an alternative with the same delivery
specifications should be selected. For a compressor, this is • (Optional) Patient monitoring and feedback
the jet flow through the nebuliser cup. Also when a jet Reduction of the nebulisation time and a greater conve-
nebuliser is connected to a compressed air system (as is nience in handling may increase the patient’s acceptance
mostly the case in hospitals and nursing institutes) it should and this can reflect positively on the adherence to the ther-
be controlled such that the pressure regulator is set to the apy. Many novel liquid inhalers are electronic devices. This
correct value for the type of nebuliser cup used. This must be offers possibilities for patient monitoring and feedback, but
checked when the nebuliser is operated. Only when patient also for so-called adaptive aerosol delivery (AAD), a princi-
adherence to the therapy is very low, for instance due to very ple of medicine delivery which has been described else-
long nebulisation times, a change of device may be consid- where [46]. In brief, a flow sensor in the inhaler measures
ered, as a (slightly) different lung deposition pattern could be the patient’s breathing pattern and the system’s software
less bad for the patient than omitting the medication on a computes the mean of a few breathing cycles. The average
regular basis. breathing cycle is the basis for pulsed aerosol delivery only
during periods of inhalation, thereby avoiding waste during
PRODUCT DESIGN
exhalation. It is believed that the narrow size distributions of
the aerosols from membrane nebulisers contribute to better
6.5.4 Novel Liquid Inhalers
targeting, but there is no evidence yet for that from deposi-
tion studies.
In addition to classic jet and ultrasonic nebulisers a new class
Different novel liquid inhalers are on the market for
of high-performance novel liquid aerosol delivery devices
different applications and only some representative
has become available. They have a high aerosol output rate
examples are described in more detail in this section.
in common (yielding a dense mist) and most of them have a
perforated vibrating membrane (mesh) as aerosol generator.
The oscillations are obtained with piezo technology which in 6.5.4.1 Respimat®, Boehringer Ingelheim
combination with the membrane is referred to as vibrating The working principle of the Respimat® has been described
membrane technology (VMT). Basically two slightly differ- before by Zierenberg [47]. In the Respimat®, a medicine
ent principles can be distinguished: those in which the mem- reservoir is connected to a capillary tube with a one-way
brane is oscillated (e.g. Pari eFlow rapid®) and those in valve. During preparation of the device, a spring is loaded
which a horn transducer adjacent to the membrane is and medicine solution is drawn through the capillary into a
vibrated (e.g. Philips Respironics I-neb®). The perforated metering chamber. When the patient presses the dose release
membrane makes contact with the medicine solution and the button, the metered volume of medicine solution is pressed
pressure pulses of the liquid against the membrane force the through a so-called uniblock with a nozzle by mechanical
medicine solution (or suspension) through the tiny holes power of the preloaded spring. The nozzle releases two
which determine the size of the droplets. Principles based converging jets at precisely controlled angles which collide
on Rayleigh break-up of liquid jets forced through the with each other at a short distance from the nozzle exits. This
perforated membrane under a constant pressure are still in creates a slow-moving fine mist. The inhaler is re-usable but
development (e.g. Aradigm AERx Essence®). Only one the medicine reservoir is replaceable. When a new cartridge
alternative principle is currently available on the market: is inserted, the inhaler has to be primed to expel air from its
the Respimat® soft mist inhaler (Boehringer Ingelheim). inner parts. The Respimat® is available with tiotropium
Although the Respimat® has a different design, it will also bromide (Spiriva®) and ipratropium bromide with
briefly be explained in this paragraph. A good review of salbutamol (Combivent®). The inhalation technique is sim-
novel liquid nebulisers based on different aerosolisation ilar to that for an MDI and requires a good hand-lung
principles has been given by Knoch and Keller (2005) [46]. coordination. The emission time is longer (approximately
Compared to classic jet and ultrasonic nebulisers, most 1.5 s) and the exit velocity is lower (approximately 0.8 m/s)
novel liquid inhalers have the advantages of: compared to MDIs, however. The fine particle dose from the
• Much shorter nebulisation times Respimat® strongly depends on the inspiratory flow rate,
• Delivering narrower size distributions which due to the low resistance can be very high (2 kPa
• Being small and portable corresponds with 125 L/min). Measured with a cooled
• Being battery operated, which eliminates the need for Next Generation Impactor to minimise droplet evaporation,
mains FPF 1–5 μm from the Spiriva Respimat® decreases from
• Being less noisy over 40 down to 28 % when the flow rate is increased from
• Having lower fill and residual volumes 30 to 90 L/min. The reason is a strong reduction of
particularly the larger particle fractions (from 35 % at developed a function test for the membrane and a cleaning
30 L/min to 20 % at 90 L/min for the fraction 3–6 μm). As device (easycare), but after a number of cleanings the mem-
a consequence, the fraction < 3 μm remains more or less brane should be replaced.
constant (18 % at 30 L/min versus 22 % at 90 L/min), but
this is partly the result of a much higher fraction < 1 μm at
6.5.4.3 I-neb®, Philips Respironics
the higher flow rate (8.0 % versus 1.8 %). Therefore, it
The I-neb® is a membrane (mesh) nebuliser with an AAD
should be recommended not to inhale with much greater
system which is approved for the delivery of iloprost in the
effort as during tidal breathing through the Respimat®.
USA and in Europe as a multipurpose nebuliser for special
applications included in the medicine license [51]. The
6.5.4.2 eFlow (Rapid)®, Pari
I-neb® consists of a mouthpiece, a medication chamber
The Pari eFlow rapid® is an example of a vibrating mesh
and a handpiece. The medication chamber comprises a
nebuliser [48]. The eFlow® platform makes use of the
horn with the mesh plate which has 5,000–6,000 holes of
TouchSprayTM (piezoelectric) technology [49] and the
3 μm in diameter. The piezo crystal imposes a high fre-
rapid®, as one of the members of the eFlow® family, is
quency upward and downward movement upon the horn
designed to deliver nebulised medicines used in CF therapy.
and this pushes the liquid through the holes in the plate.
It reached the European market in 2005 and according to the
The I-neb® is operated with discs that are programmed for
manufacturer, this device has already reached approximately
delivery of specific medicine formulations. These discs have
75 % market share amongst European CF patients. The
microchips that correspond with the I-neb® handpiece about
eFlow rapid® consists of a controller and a handset. The
the dose, the dosing frequency, the number of doses and
handset comprises the medication reservoir with an aerosol
other variables related to the medicine administered. The
chamber, the vibrating membrane in contact with the medi-
I-neb® AAD system has two different modes of operation:
cine solution and the mouthpiece. The membrane has a large
the tidal breathing mode (TBM) and the target inhalation
number of tapered holes that narrow towards the aerosol
mode (TIM) which is for slow and deep inhalation. The
release side. During vibration, sound pressure is build up in
TBM mode is suitable for most adults and children of
the vicinity of the membrane thus ejecting the fluid through
2 years and older; for optimal use of the TIM mode, patients
the holes. Because all holes have the same size, the droplet
need to have a forced vital capacity > 1.75 L. Breathing
size distribution in the aerosol is rather narrow. According to
with TIM increases lung deposition and reduces total treat-
Pari, the hole diameters can be adjusted from 2 μm upwards
ment time. It is claimed that the majority of medicine in the
to meet the requirements for different therapeutic
aerosol from the I-neb® (60–80 %) is within the size frac-
applications. Also according to the manufacturer, the mass
tion < 5 μm. Due to its higher efficiency compared to clas-
median aerodynamic diameter of TOBI® (tobramycin),
sic jet nebulisers, a threefold reduction in medicine volume
measured at 28.3 L/min, is 3.95 μm from the eFlow rapid®
and up to a fivefold reduction in nominal dose may be
versus 3.5 μm for the Pari LC Plus® jet nebuliser with
possible with the I-neb® with the AAD system [51].
PariBoy N® compressor. The difference has to be confirmed
in several independent studies and it can increase when a
more powerful compressor (with higher jet pressure) is used Similar portable mesh nebulisers are available from
for the LC Plus®. On the basis of the differences in MMAD Omron (MicroAir NE-U22®) and Aerogen (Aeroneb
and the span of the size distribution, it must be expected that Go®). The Aeroneb Go® is based on the OnQTM
both nebulisation devices result in different distributions of vibrating mesh technology which comprises a dome-
active substance over the lung and therefore, they cannot be shaped aperture plate containing over 1,000 precision-
considered completely equivalent in this respect. The aver- formed tapered holes, surrounded by a vibrational
age nebulisation time with the eFlow rapid® is considerably element. The aperture plate is caused to vibrate at
shorter than with classic jet nebulisers and the reduction can over 128,000 times per second. Aerogen also have a
be more than 50 %. CF patients do use their eFlow rapid® multidose vibrating mesh nebuliser (Aerodose®) [52]
also for the administration of other medication, like and two VMT devices for hospital use (Aeroneb Pro®
salbutamol, ipratropium bromide, terbutaline, colistimethate and Aeroneb Solo®). The Aeroneb Pro® is a reusable,
sodium, rhDNase and acetylcysteine. This has the risk of multi-patient use nebuliser which is suitable for hospi-
membrane pollution, as patients do not always clean their tal environments where the appropriate sanitisation
nebuliser equipment properly after use. It can result in clog- facilities are available. This autoclavable nebuliser
ging of holes in the perforated membrane, which does not provides effective dose delivery of physician-
result in a change in particle size, but in a reduced output rate prescribed inhalation solutions for infants through
[50]. This leads to longer nebulisation times and may be at
the cost of the patient’s adherence to the therapy. Pari has (continued)
6 Pulmonary 125
and immediately after use according to the instructions in

adults in both on and off ventilator applications. The order to prevent clogging of the apertures in the membrane.
Aeroneb Solo® is a single-patient use nebuliser for In practice, patients are not always compliant with the
continuous and/or intermittent nebulisation, ensuring instructions, however, and it has been shown that off-clinic
targeted delivery of active substance to the smallest use may result in a significant change in performance within
airways in the lungs. The silent operation of the a period of 6 months [50]. Finally, also the most recently
Aeroneb Solo® allows it to be used in paediatric developed systems require at least 2–4 min for the adminis-
ICUs where noise levels are critical. The Solo® has a tration of a dose and this excludes the time needed for
low residual volume (<0.1 mL for 3 mL dose). The preparation and cleaning of the equipment. For patients
Omron MicroAir NE-U22® has a vibrating horn with multiple medicine therapies, this is still burdensome.
within the liquid reservoir that pushes the liquid For a number of applications, dry powder inhalation may be
through the membrane. The frequency of oscillation a better alternative, also because dry powders are more
of this horn is 180 kHz and the particle diameter stable than medicine solutions. Therefore, they need no
claimed for the MicroAir is 5 μm. For the MicroAir cold chain storage.
it is recommended that the vibrating mesh cap is
PRODUCT DESIGN
replaced every 6 months to maintain its peak
performance. 6.6 Medicine Formulations for Nebulisation
Many marketed medicine formulations for nebulisation are

The novel liquid inhalers have several specific pros and available, but in contrast to preparations for dry powder
cons. An attractive feature is the potential for a single plat- inhalers and metered-dose inhalers, solutions and
form to deliver multiple inhaled medicines in complex treat- suspensions for nebulisation are also prepared in
ment regimens, like in CF [51]. However, it has to be pharmacies. Marketed formulations may furthermore have
recommended that patients and physicians do not decide to to be diluted, depending on the type of inhaler used. Many
change from an approved (medicine-nebuliser) combination nebulisers have a residual volume between 1 and 2 ml and
to a novel liquid inhaler when the medicine formulation has the fill volume has to compensate for these losses. Compen-
not yet been tested first in the VMT device. Neither should sation is also needed for the amount of medicine in the
patients decide to use their inhaler for other medication than residual volume. Diluted formulations must be used within
the medicine for which their mesh nebuliser was prescribed. 24 h after preparation because of poor stability. Most
Different solutions of active substance may result in aerosols nebulised medicines fall into two physico-chemical
with different size distributions due to differences in categories: solutions and suspensions [34]. For solutions it
physico-chemical properties and this can lead to poor is assumed that the medicine is homogeneously distributed
targeting of the site of action (poor efficacy of the therapy) throughout all droplets. Suspensions are inherently more
compared to delivery with the approved nebuliser. Another complicated as their density may be less homogeneous and
advantage of the new class of nebulisers is the wide range of individual droplets may contain different amounts of the
doses that can be delivered with these devices. Pari claim a active substance. This could lead to a droplet size dependent
range from a few micrograms up to several grams. Also the concentration of the active substance or a considerable
possibility to store data about the use of the inhaler and to change in concentration with nebulisation time. Below
give immediate feedback to the patient about the inhalation some of the most relevant aspects regarding the preparation
performance may be an advantage. Synchronising aerosol of medicine solutions and suspensions for nebulisation are
delivery with the breathing manoeuvre (as with AAD) may summarised; additional general recommendations for prepa-
furthermore considerably improve the efficacy of the deliv- ration, labelling, testing and packaging can be found else-
ery of active substance to the lungs. Reduced nebulisation where in this book.
time, smaller and mostly battery operated devices and a
more silent operation are likely to increase patients’ adher-
ence to the therapy compared to classic jet and ultrasonic 6.6.1 Medicine Solutions
devices, but whether a better adherence is really achieved
has still to be proven. The high price of most novel liquid Medicine solutions for nebulisation may contain several
inhalers is a serious drawback and could become a reason for additives such as co-solvents, solubilising and stabilising
healh funders to deny reimbursement when improved adher- agents, antimicrobial preservatives, salts and pH-regulators
ence is not shown. Vibrating meshes are also vulnerable to to adjust the acidity and tonicity of the solution. Additives
pollution and the need for good cleaning must be may contribute to the osmotic value. Both high and low
emphasised. Patients should clean their inhaler thoroughly osmotic values can produce cough and bronchoconstriction
(or both). If the patient shows signs and symptoms of bron-

chospasm, baseline spirometry before dose administration is [56], but liposomal amphotericin B for injection or
recommended, followed by spirometry at 15 and 30 min infusion is frequently used for nebulisation against
post-dose. Active substances such as salbutamol, terbutaline invasive fungal pulmonary infections. Compared to
and ipratropium are mostly dissolved in isotonic saline amphotericin B, which is relatively instable and there-
(0.9 % sodium chloride). Sodium chloride strengths between fore commercially available as a complex with sodium
3 % and 7 % are also used for nebulisation, but they may not desoxycholate, the liposomal formulation has a higher
be mixed with other medicines. To enhance the solubility of tolerability profile. Most liposomal formulations are
active substance in water or saline, the addition of a currently developed for sustained release however,
co-solvent may be needed and surfactants can be added. and two liposomal antibiotics for nebulisation
Also controlling the acidity may lead to a better solubility (Arikace®, Insmed, for amikacin and Lipoquin® and
and the European Pharmacopoeia allows to vary the pH Pulmaquin®, Aradigm, for ciprofloxacin) have
within the range between 3 and 8. However, it is known received orphan drug designation to treat lung
that aerosols with a pH below 4.5 can cause cough and infections caused by nontuberculosis mycobacterial
bronchoconstriction, particularly in asthmatic patients, and (by the European Medicines Agency) and for inhala-
some caution is therefore required. The medicine in solution tion in bronchiectasis (by the US Food and Drug
may also change the pH of the solvent and pH-regulators Administration (FDA)) respectively. Which type of
such as sulphuric acid and sodium hydroxide are frequently nebuliser to use best for liposomal formulations may
added to keep the acidity within the desired range. If the not only depend on the desired particle size distribu-
solubility of active substance and stability allow for it, it is tion of the aerosol and aerosol output rate, but also on
best to keep the acidity close to neutral as the pH in healthy relevant physico-chemical properties of the formula-
lungs ranges between 7 and 8. tion. Both jet and ultrasonic nebulisers damage the
liposome structures and the smaller the droplet size,
the greater the damage may be. The degree of disrup-
tion also depends on the excipients used, and the
6.6.2 Medicine Suspensions
inclusion of cholesterol or DPPC increases the resis-
tance to disruptive forces [44]. The liposomal cipro-
Currently, suspensions prepared from micronised active
floxacin Pulmaquin® is developed for Aradigm’s
substances are the only marketed delivery system for
AERx® pulmonary medicine delivery platform (with
nebulisation of poorly water soluble substances such as
perforated mesh).
steroids and cyclosporine [53]. Several problems are inher-
ent in nebulising micro-suspensions and they vary from
non-optimised lung deposition for the active substance to
heterodispersity of the active substance concentration in the
aerosol droplets and poor compatibility with different types
6.6.3 Stability of Formulations
of nebulisers, particularly ultrasonic devices. Suspensions
for Nebulisation
may also have poor stability and the two components (solid
and liquid) tend to separate with time within the formulation
Most ready-to-use liquid preparations for nebulisation are
by sedimentation or flocculation, depending on the particle
supplied in single-dose vials and according to the European
density relative to that of the liquid. Several jet nebulisers can
Pharmacopoeia, they have to be sterile and preservative-
deliver suspensions quite effectively, even independently of
free. When they are supplied in multidose containers, they
the primary particle size [54], but ultrasonic devices may
have to be sterile if they do not contain an antimicrobial
convert primarily the continuous phase into aerosol whereas
preservative or when the preparation does not have adequate
vibrating mesh inhalers can be blocked by particles being
antimicrobial properties itself. The multidose containers
larger than the pore diameter of the membrane.
have to be designed to prevent microbial contamination of
their contents during storage and use. A wide variety of
In addition to solutions and suspensions, liposomal preservatives is available but some of them, like phenol,
formulations of active substances are used and various bisulfites, edetate and benzalkonium chloride can cause air-
nanoemulsion-based formulations and micellar way irritation and result in bronchoconstriction or reduce the
solutions are explored for nebulisation [55]. Currently, efficacy of the medicine [57]. Other compounds such as
no marketed inhaled liposomal products are available chlorobutanol, methyl- and propyl-parahydroxybenzoate
and also benzalkonium chloride are ciliotoxic at
(continued)
6 Pulmonary 127
concentrations equal to or lower than those in use for pre- or precipitation. For instance, benzalkonium chloride may
serving aqueous formulations [58, 59]. Ciliotoxicity, form an oily, non-crystalline complex with cromolyn,
reduced medicine efficacy and airway irritation resulting in depending upon its concentration [64]. Benzalkonium chlo-
cough and chest tightness are the reasons why many bacteri- ride is also incompatible with colistin, whereas edetate is
cidal agents have been removed now from marketed medi- known to increase the activity of azithromycin [65] and
cine formulations. Some alternatives have been presented as colistimethate sodium [66] by chelating divalent cations
less harmful, like chlorocresol and chlorbutanol [60] but such as calcium. The effect of mixing medicine solutions
generally it may be safer to supply sterile preservative-free or suspensions on nebulisation performance is studied even
liquid formulations for nebulisation in unit dose vials. less although for a few combinations data can be found in the
In formulations for nebulisation also the stability of the literature. For instance, it has been shown that inhalation
active substance itself in solution must be taken into consid- solutions of Pulmozyme® can be mixed with tobramycin
eration. For instance, colistimethate sodium (CMS), increas- (Bramitob® or TOBI®) as one of the few examples of
ingly used to treat multi-resistant gram negative infections compatibility for dornase alpha without changing the stabil-
by nebulisation, spontaneously hydrolyses in aqueous solu- ity of these products and their aerosolisation performance
tion to form colistin A (polymyxin E1) and colistin B (poly- [67]. In contrast, mixing salbutamol with other medicine
PRODUCT DESIGN
myxin E2/B). High levels of these decomposition products solutions may change the mass median aerodynamic diame-
have been associated with nephrotoxicity and even death and ter in either direction, depending on the combination and the
in 2007 the FDA issued an alert after a patient died following type of nebuliser used [68]. The changes in median diameter
the inhalation of a solution of CMS. CMS is supplied as a can be as high as 50 % and also the span of the size distribu-
lyophilised powder and current recommendations state that tion and the delivered respirable mass are influenced. This
CMS should be reconstituted no more than 24 h prior to the may have a considerable effect on the dose delivered to the
administration by nebulisation [61]. It is important to note site of action and thus the efficacy of the therapy. For these
that sterile water is the diluent recommended by the major reasons, mixing medicine formulations for nebulisation
manufacturers because reconstituted CMS in saline is signif- should preferably be avoided unless they are needed to
icantly less stable [62]. Recently, the stability of obtain good adherence to the therapy. In the latter case,
reconstituted CMS for injection in sterile water was desired combinations need not only to be tested on chemical
investigated at different storage temperatures and it was and physical stability, but also on their aerosolisation per-
found that total colistin A and B formation at room tempera- formance in the nebuliser used for the administration. Fur-
ture in 24 h is less than 1 % [61]. thermore, mixtures should be made from preservative free
solutions and suspensions to avoid incompatibilities with
these additives.
6.6.4 Mixing of Formulations for Nebulisation
Most product information leaflets for nebulised medicine References

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Oropharynx
7
Suzy Dreijer - van der Glas
Contents dental gels. In this chapter the use, the design of formula-
7.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 tion and preparation method will be discussed.
In the formulation of preparations for the oropharynx,
7.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
taste and texture are features that are important for the
7.3 Biopharmaceutics and Side Effects . . . . . . . . . . . . . . . . . . . . . 133 acceptance by the patient. Pharmacy preparation can play
7.4 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 an important role, because of the advantage that
7.4.1 Liquid Preparations (Mouthwashes, Gingival Solutions preparations can be tailor made according to the specific
and Gargles) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 situation or taste of the patient. For instance, chemother-
7.4.2 Semisolid Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
7.4.3 Solid Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 apy and several other active substances, may cause dry
mouth and stomatitis, and mouthwashes or gels can
7.5.1 Liquid Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
relieve these problems. However, they should not cause
7.5.2 Semisolid Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 irritation and must be accepted by the patient. This has to
7.5.3 Solid Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 be kept in mind when choosing a vehicle, or the pH or the
7.6 Container, Label, Dosage Delivery Devices . . . . . . . . . . . . 136 osmotic value of a preparation.
7.7 Release Control and Quality Requirements . . . . . . . . . . . 137
Keywords
7.8 Storage and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Dental gel Mouthwash Oropharynx Formulation
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Preparation Muco-adhesive
7.1 Orientation
Abstract
Preparations for the oropharynx form a wide range, from Medicines that are meant for the oral mucosa are often
the classical gargles and lozenges up to modern muco- applied as a mouthwash, gingival solution or a semisolid
adhesive forms, based on polymer technology. This chap- mouthpaste. A mouthpaste will theoretically stay on the
ter deals with dosage forms intended for administration to mucosa for the longest time and it is useful in formulating
the oral cavity and the throat, or both, to obtain a local poorly water soluble ingredients. However viscous
effect. These dosage forms can be solutions such as mouthwashes and suspensions in water are easier to apply
mouthwashes and gingival solutions, or buccal tablets or to those parts of the oral cavity that are difficult to reach with
semisolid preparations such as oromucosal pastes and a (stiffer) mouthpaste [1]. Especially in the case of a painful
ailment prescribers and patients mostly prefer a mouthwash.
An example of this is the local application of corticosteroids
in oral lichen planus [2]. In such cases a (viscous) suspension
Based upon the chapter Mond en keel by Suzy Dreijer and Annick could be preferred to a solution in water to obtain the
Ludwig in the 2009 edition of Recepteerkunde. intended effect [1].
S.M. Dreijer - van der Glas (*) In patients undergoing chemotherapy or radiation therapy
Royal Dutch Pharmacists’ Association KNMP, The Hague, in the head and neck area saliva production is diminished,
The Netherlands and the immune system is weakened. For these reasons

132 S.M. Dreijer - van der Glas
mouthwashes are prescribed to prevent caries and sores or application the antibiotics were formulated in an adhesive
infections of the oral mucosa. For example chlorhexidine or paste. Other trials showed that prophylactic application of
hexetidine mouthwash or spray can be used instead of tooth- chlorhexidine in the mouth reduces the risk of ventilation
paste. Sometimes nystatin is added to the mouthwash, to associated pneumonia [6–8]. In these trials chlorhexidine
prevent Candida infections. Different forms of fluoride are mouthwash was replaced by a hydrophobic mouth paste,
used to prevent dental decay. since intubated patients are not able to rinse their mouth.
Not only chemotherapy, but some other medicines can Gargles with disinfecting active substances are still pre-
diminish saliva production. In these patients saliva scribed to soothe an irritated throat. But the tonsils, at the rear
substitutes are very popular to reduce mouth dryness. of the throat, are hardly reached by gargles. Lozenges, or
These are Over The Counter (OTC)-preparations with gargling with salted water are less irrational as an alternative
mucine or viscous solutions with electrolytes [3]. Examples and may be relieving. The effect of lozenges in the treatment of
are Xialine® and Saliveze®. The result of these preparations sore throats is possibly due to a mechanical effect, related to
is often no better than (sugar free) chewing gum. saliva production from sucking movements. Local anaesthetics,
Fluoride mouthwashes are examples of preparations for antiseptics and astringents do not add much to this effect. There
dental use. Dental solutions in general have the advantage is a wide variety in OTC lozenges for sore throat on the market.
that mouthwashes are easy to use by the patient. Semisolid Because of the risk of swallowing, mouthwashes and
dental gels can be applied to specific places on the teeth. gargles should only be used by adults and children older
Normally this is done by the dentist or dental hygienist. An than 6 years. Gingival solutions and oral gels or pastes can –
example is a hydrogel with phosphoric acid, used in etching with caution- be used in young children. These dosage forms
teeth enamel to facilitate composite restoration. can be applied at specific locations.
Oromucosal and gingival solutions are applied to local The advantages of preparations for the oropharynx are:
ailments in the oral cavity. They are administered with a local application directly to the lesions, which can be done
brush, a spatula or a cotton swab. by the patient. Adverse effects however may occur as well:
The pharmacy preparation of dosage forms for the oro- irritation, undesirable systemic effects after accidentally
pharynx can be customised by changing the strength, taste, swallowing and allergic reactions.
viscosity or volume according to the patient’s needs. Some
examples are shown below.
Solutions that are less concentrated than the licensed 7.2 Definitions
preparation reduce the risk of intoxications or adverse
reactions if the product is accidentally swallowed. The Ph. Eur. describes mouthwashes and gargles in the
OTC mouthwashes with chlorhexidine or fluoride often monograph on Oromucosal Preparations (Praeparationes
contain (red) dyes, which could be a problem in case of an buccales).
allergy. Mouthwashes are aqueous solutions intended for use in
Many cancer patients have disorders in the oral cavity contact with the mucous membrane of the oral cavity. They
after radiation or chemotherapy. They form a typical group are not to be swallowed. Mouthwashes may contain
that could benefit by care, attention and customised phar- excipients to adjust the pH which, as far as possible, are
macy preparations. Optimal oral hygiene can help to prevent neutral. Apart from these oromucosal solutions the Ph. Eur.
problems in these patients. lists oromucosal suspensions, drops and sprays.
Dental fluoride gels are normally acidic in order to obtain The Ph. Eur. specifies that gargles are aqueous solutions
a better effect. However, when the salivary glands are dam- intended for gargling to obtain a local effect and not to be
aged by radiation or chemotherapy, the acidic licensed swallowed. They may contain excipients to adjust the pH
preparations are often not tolerated, as they will be too irritant which should be neutral.
on the mucosa. A neutral dental fluoride gel, prepared in the Mouthwashes and gargles are supplied either as ready-to-
pharmacy, would be the medicine of choice. Formulations use or as concentrated solutions to be diluted. A well-known
containing ethanol can also irritate a damaged oral mucosa. example is hydrogen peroxide 3 %, which is normally
Tranexamic acid is used in dentistry as a 5 % mouth rinse diluted before use to 1,5 %. They may also be prepared
after extractions or surgery in patients on oral anticoagulant from powders or tablets to be dissolved in water before
therapy to prevent postoperative bleeding [4]. use, for instance powders with sodium perborate.
Decontamination of the oropharynx plays an important Semisolid preparations are hydrophilic gels or pastes
role in the prevention of hospital infections. In a large trial, intended for application in the oral cavity or a specific
selective decontamination of the oropharynx and the diges- location like the gums (gingival) or the teeth (dental).
tive tract, combined with intravenous antibiotics, reduced According to the Ph. Eur. these semisolid oromucosal
the rate of infections only slightly more than just decontam- preparations comply with the requirements for semisolid
ination of the oropharynx [5]. For the oropharyngeal preparations for cutaneous use.
7 Oropharynx 133
Lozenges and pastilles are solid, single-dose preparations 7.4.1 Liquid Preparations (Mouthwashes,
intended to be sucked to obtain a local effect in the oral cavity Gingival Solutions and Gargles)
and the throat. They contain one or more active substances,
usually in a flavoured and sweetened base. They are intended 7.4.1.1 Physico-chemical Properties of the Active
to dissolve or disintegrate slowly in the mouth when sucked. Substance
They have to comply with most of the requirements for Mouthwashes usually are solutions of active substances in
tablets. Lozenges are hard preparations, pastilles are soft. water or aqueous solvents; so the water soluble form of the
Buccal mucoadhesive tablets are mostly intended for active substance is chosen. For corticosteroids this would
systemic use, but adhesive tablets and semisolid forms can mean an aqueous solution of a phosphate ester. When rinsing
also be used to obtain a local effect. with such a solution the contact time would be too short to
obtain a sufficient therapeutic effect of the corticosteroid
[1]. As a viscous suspension sticks to the oral mucosa, the
An example is a mucoadhesive tablet with micona-
active substance can work for a longer period of time.
zole. With this dosage form higher saliva
Therefore a (viscous) suspension is to be preferred. In addi-
concentrations are obtained compared to an oral gel,
tion such a suspension has the advantage that the bitter taste
whilst no miconazole is detectable in blood plasma
PRODUCT DESIGN
of the corticosteroid is less pronounced. An example is a
[9]. Other examples are buccal films, in use for the
suspension with hydrocortisone acetate, lidocaine and
treatment of herpes labialis [10].
dexpanthenol (Table 7.1).
7.4.1.2 Vehicle
7.3 Biopharmaceutics and Side Effects Purified water is the first choice as a basis in mouthwashes
and gargles. Aqueous solutions of glycerine or sorbitol are
The oropharynx serves three purposes. In the first place food good alternatives. The use of high concentrations of glycer-
is taken in through this route, after chewing if needed. ine in mouthwashes is controversial. By dehydrating the
Secondly the oropharynx is one of the routes for air in- and mucosa these solutions would have the opposite effect to
exhalation. Third it plays an important role in speaking. that which they are meant to have [13].
The side effects of preparations for this route of adminis- Gingival solutions with antiseptics or local anaesthetics
tration are already mentioned in Sect. 7.1. Accidentally may also be formulated in mixtures of water and glycerine.
swallowing is one of the main causes of side effects in In this case glycerine serves the purpose of raising the
mouthwashes and gargles. As swallowing cannot be viscosity of the vehicle and improving adherence to the
excluded (especially in children), doses for local administra- mucosa. This is relevant because gingival solutions are
tion in the oropharynx have to be checked in the same way as used on local ailments in the oral cavity.
oral doses. When saliva production is insufficient, many different
Excessive use of dental sodium fluoride solutions may liquids can be used. They vary from glycerol with citric
cause coloured stains on the enamel. acid to the saliva substitutes already mentioned in
Chlorhexidine causes a reversible yellow discolouration Sect. 7.1. Citric acid stimulates the saliva production in the
of the teeth and the tongue, and sometimes taste disorders. salivary glands, and therefore raises the amount of saliva in
Too violent gargling may cause irritation of the pharyn- the mouth. If there is damage to the oral mucosa, it is best to
geal mucosa. Gargling with hydrogen peroxide may irritate avoid ethanol and propylene glycol, because these solvents
because of the itching effect of the active ingredient. Exces- may cause irritation, A German hospital developed an
sive use of 3 % hydrogen peroxide as a gingival solution
may cause painful blisters [11]. Table 7.1 Hydrocortisone Acetate Oral Suspension 0.5 % with Lido-
caine Hydrochloride and Dexpanthenol [12]
Extensive use of local anaesthetics in the oropharynx can
be hazardous because of impaired swallowing as long as the Hydrocortisone acetate 0.5 g
mucosa is numbed by the anaesthesia. Lidocaine hydrochloride 1g
Dexpanthenol 5g
Disodium phosphate dodecahydrate 0.05 g
Macrogolglycerol hydroxystearate 0.2 g
7.4 Product Formulation Peppermint oil 0.15 g
Propylene glycol 40 g
This section focuses on the design of the formulation of Water, purified 53.1 g
oromucosal preparations. Design and excipients are described, Total 100 g
in liquid, semisolid and solid dosage forms respectively.
Table 7.2 Lidocaine Hydrochloride Oral Gel 20 mg/ml [15] Table 7.3 Chlorhexidine Digluconate Mouthwash 0.2 % [16]
Lidocaine hydrochloride 2g Adapted for mouth
Disodium phosphate dodecahydrate 0.1 g FNA lesions
Glycerol (85 %) 20 g Chlorhexidine 10.65 g 10.65 g
Hypromellose 4,000 mPa.s 1.5 g digluconate
solution
Ethanol (96 % 70 g –
Peppermint oil 0.02 g
V/V)
Propyl parahydroxybenzoate 0.0125 g
Peppermint oil 3 dr 3 dr
Sorbitol liquid, 535 g –
Water, purified 81.2 g crystallising
Total 105 g (¼ 100 mL) Water, purified 493 g 986 g
Total 1,109 g (¼ 1,000 mL) 996.95 g (¼ 1,000 mL)
alcohol free formulation with benzydamine, especially for Table 7.4 Tetracycline Hydrochloride Mouthwash 5 % [17]
patients on chemotherapy or radiation treatment
Tetracycline hydrochloride 5g
[14]. Benzydamine is a NSAID with local anaesthetic and
antiseptic properties.
Propylene glycol 0.6 g
It is clear that surface tension and the viscosity of the Sodium citrate 6.5 g
vehicle will influence the effect of a mouthwash, but there is Sorbitol liquid, crystallising 65.5 g
still little investigated in this area. Tragacant 0.5 g
7.4.1.3 pH Total 118.2 (¼ 100 mL)
For reasons of taste mouth preparations should be slightly
acid or neutral. Instability or ineffectiveness of the active
Table 7.5 Citric Acid-Glycerol 1 % [18]
ingredient can make deviations in pH necessary. In Lidocaine
hydrochloride oral gel 20 mg/ml FNA the pH is adjusted to Citric acid, anhydrous 1g
6.8, because at that pH part of the lidocaine will be in the base Glycerol (85 %) 84 g
form (Table 7.2). Therefore, at that pH the numbing effect Orange essence (local standard) 0.01 g
will be much better than in an acid solution.
More information about the influence of pH on chemical Total 100 g
and physical stability of solutions and suspensions can be
found in Sect. 22.2.
7.4.1.6 Microbiological Stability (Preservation)
As most preparations for the oropharynx are aqueous
7.4.1.4 Osmotic Value solutions, growth of micro-organisms is possible. Therefore,
Mouthwashes need not be made iso-osmotic. But strongly the addition of a preservative is generally needed, except for
hyperosmotic solutions may hurt in case of lesions in the those preparations that have intrinsic preservative properties.
mouth. Sorbitol solution, because of its viscosity sometimes In this category there are many preparations with glycerol,
used as vehicle for suspensions, is strongly hyperosmotic. propylene glycol or ethanol, provided that these are present
For patients with lesions a formulation sometimes has to be in a sufficiently high concentration. See also Sect. 23.8. An
adapted. For instance many chlorhexidine mouthwashes example is glycerol with citric acid, see Table 7.5
contain sorbitol as a flavouring and ethanol as preservative. This solution contains so much glycerol that addition of a
In the following adapted version both are omitted (Table 7.3). preservative is not necessary. Zinc chloride and alumen
gargle FNA does not need preservation due to the low pH
(2.3–2.7) and the presence of salicylic acid Table 7.6.
7.4.1.5 Viscosity
In the preparation of viscous mouthwashes common viscosity
enhancers are used. Mostly cellulose derivatives are used, 7.4.1.7 Preservatives
such as hypromellose, but sometimes tragacanth is preferred. If a preservative is needed in a preparation for the orophar-
Nowadays tragacanth with a good microbiological quality can ynx the following considerations are important:
be purchased. The main advantage of tragacanth gels is their • Methyl parahydroxybenzoate and propyl parahydroxy-
resemblance to oral mucus, which makes flavouring easier. benzoate may cause an itching sensation on the tongue
An example is Tetracycline mouthwash 5 % FNA (Table 7.4). in some people.
7 Oropharynx 135
Table 7.6 Zinc Chloride-Alumen Gargle [19] Table 7.7 Tretinoine Oromucosal Paste 0.1 % [20]
Alumen 3.3 g Tretinoin 0.1 g
Zinc chloride 3.3 g Ethanol (96 %) 16 g
Peppermint oil 7 dr Hypromellose 4,000 mPa.s 16.78 g
Salicylic acid 1g Paraffin, white soft 67.12 g
Water, purified 995 g Paraffin, white soft q.s. for supplementing the evaporated
ethanol
Total 1,003 g (¼ 1,000 mL)
Total 100 g
• Sorbic acid is only effective in acid solutions.

• Chlorhexidine digluconate has an unpleasant taste and
with excessive use it may stain the teeth. Table 7.8 Metronidazole-Dental Gel 25 % [22]
In general methyl parahydroxybenzoate (sometimes com- Metronidazole 25 g
bined with propyl parahydroxybenzoate) or sorbic acid are Citric acid, anhydrous 0.07 g
chosen. For stability reasons the pH is adjusted to 5 by the Poloxamer 407 20 g
addition of potassium sorbate. If these substances cannot be Potassium sorbate 0.14 g
PRODUCT DESIGN
used, the organic solvents mentioned earlier (ethanol or Water for injections 54.79 g
glycerine) are an alternative to a preparation less susceptible Total 100 g
to microbial growth.
7.4.1.8 Taste, Smell and Colour Hydrophobe basisgel DAC). Plastibase® is a proprietary
Naturally taste and smell are very important in preparations mixture of 5 % polyethylene in liquid paraffin. The prepara-
for the oral cavity. Flavouring is frequently needed. To mask tion is difficult, and Plastibase® is on the market in
the unpleasant taste of chlorhexidine, sorbitol with pepper- Germany, but not in many other European countries. A
mint oil or raspberry essence are eligible. Lemon essence combination of Plastibase® with pectine, glycerine and
can be added to preparations with citric acid. carmellose sodium is marketed as Orabase® Although this
Simple syrup is inappropriate for mouth preparations preparation is originally meant for use on peristomal skin, it
because it lowers the pH in the mouth and thus may cause is often used in mouth disorders.
caries. Polyols like sorbitol or xylitol and glycerine are
considered safe for the teeth, as they do not lower the pH 7.4.2.3 Hydrogel Base
of the dental plaque. Xylitol would be the choice if sweet- Gels can be meant for application on the oral mucosa or on
ness is most important, because it is as sweet as saccharose. the teeth. When the active ingredient is intended for the teeth
Saccharin is not useful because of its bitter after taste. An the following points are important:
overview of flavourings can be found in Sect. 5.4.10. • The pH should be rather low to improve penetration of
the active ingredient in the enamel (for instance pH 4 in
OTC products with fluoride).
7.4.2 Semisolid Preparations • Surface tension and viscosity should be low for the same
reasons [21].
7.4.2.1 Active Substance • Because of the low pH carbopols are not suitable as
The aqueous solubility of the active substance is important viscosity enhancers (see Sect. 23.7.3.5). Cellulose
when choosing between an aqueous gel or a fatty mouth derivatives are a better choice.
paste or ointment. Lidocaine is used as the hydrochloride When the gel is intended mainly for the gums or the teeth
in lidocaine gels (see Table 7.2). Tretinoin may be pockets, a low pH is not needed. In this case poloxamers are
formulated in a hypromellose 20 % (adhesive) ointment, an alternative to cellulose derivatives. The thermoreversible
see Table 7.7. viscosity of poloxamer gels can be used in the preparation
and administration of a dental gel with metronidazole
7.4.2.2 Ointment Base (Table 7.8).
An ointment base containing 20 % hypromellose is often A special case is the use of an inorganic thickening agent
used in mouth pastes. The hypromellose, formulated in in a 35 (or 50) % phosphoric acid dental etching gel
white soft paraffin, has the purpose of making the paste (Table 7.9). In the strongly acidic environment of 35 %
adhere to the mucosa. Even better adherence can be obtained phosphoric acid only colloidal anhydrous silica can be used
by preparations in a hydrocarbon gel ointment (Plastibase®, as a viscosity enhancer.
Table 7.9 Phosphoric Acid Dental Gel for Etching [23] Table 7.10 Glycerated Gelatine Suppositories [24]
Phosphoric acid (85 %) 41.2 g Gelatin 2g
Glycerol (85 %) 15 g Glycerol (85 %) 5g
Methylthioninium chloride solution 10 mg/mL DAC 1g Water, purified 4g
Silica, colloidal anhydrous, compressed 7g
Total 100 g
7.5 Method of Preparation
7.5.1 Liquid Preparations

7.4.2.4 Microbiological Stability (Preservation)
The microbiological aspects of hydrogels are comparable
For the preparation of oromucosal solutions and gargles the
with those of aqueous solutions. So the same principles as active ingredients and the excipients are dissolved in the
for mouthwashes hold in mouth gels.
(mixture of) solvent(s) (see Sect. 5.5.2).
Oromucosal suspensions are prepared in the same way as
7.4.2.5 Scent and Colour suspensions for cutaneous use (see Sect. 12.7.3). So also for
Dental gels often contain a taste correction. An overview of in-process controls reference is made to those chapters.
flavourings can be found in Sect. 5.4.10.
In many dental gels a colouring agent is needed to obtain
a contrast between gel and teeth. For instance methylene 7.5.2 Semisolid Preparations
blue (methylthionine) is used in phosphoric acid gel
[23]. For an overview of water soluble dyes see Sect. 23.11. The preparation of semisolid oromucosal preparations is the
same as that of cutaneous preparations (see Sect. 12.6). The
same is true for the in process controls.
When preparing phosphoric acid gel, metallic utensils or
7.4.3 Solid Preparations homogenisers are not to be used, because they would be
tarnished/corroded by the acid.
As many aspects of solid preparations for the oropharynx are
similar to those of solid preparations for oral use, at first
reference is made to Chap. 4. Sweetening and flavouring 7.5.3 Solid Preparations
agents are important ingredients in lozenges. The active
substances may be formulated in hydrophilic bases with The preparation of tablets in general is dealt with in Sect. 4.9.3.
gelatin in glycerine, or a mixture of acacia gum (Arabic The preparation of lozenges with a gelatin base can be found in
gum) and sugar. Sect. 11.4.3 and other references about gelatin suppositories.
Lozenges are not to be swallowed. During the time that An example of such a base is in Table 7.10.
they stay in the mouth the active substance is released in a
certain period of time, to have a local effect. These lozenges
may contain antiseptics, local anaesthetics or antimycotics
(for instance Amphotericin B in Fungizone® lozenges). 7.6 Container, Label, Dosage Delivery
Lozenges should not disintegrate in contact with saliva: Devices
so they have to be formulated differently from tablets for
oral use. They may not contain disintegrants, but always Mouthwashes and gargles are packed in glass or plastic
contain flavouring agents, especially sweeteners. Tragacanth bottles, with a screw cap and a dosing cup.
(0.5–1 %) is a strong binder that is used in lozenges. It For dental sodium fluoride solutions a plastic bottle is
delays the disintegration of the tablet. Dextrose solutions preferable as sodium fluoride reacts with glass, the solutions
are also used as a binder to obtain firm tablets. Stearic acid may therefore be stored longer in plastic. Gingival solutions
delays disintegration because of its hydrophobic properties; are best supplied in a bottle with a brush or a spatula (see
therefore, it is a good lubricant for lozenges. Sect. 24.4.19.1).
Mucoadhesive tablets are prepared by compression of Fluoride dental gel may be packed in a coated aluminium
mono or multilayers. Usually they contain hydrophilic tube (see Sect. 24.4.8) or in a plastic bottle with a dosing
polymers, that form a flexible hydrogel after wetting by the pump or spraying device. For phosphoric acid gel a plastic
saliva. bottle with a dosing device or a syringe with a cap is the
7 Oropharynx 137
packaging of choice. Viscous gels should be avoided in most (see Sect. 22.7), because of the risk of contamination
babies, as they give a risk of suffocating even if the gel is by frequent opening of the package and possibly unhygienic
applied on the nipple of the mother. handling.
A dental syringe (with a hooked end) may help to apply For non-standardised formulas storage conditions, shelf
liquids in cavities in the mouth that are hard to reach. An life (of the unopened package) and usage period (after open-
alternative is chewing on a piece of cotton gauze, wetted ing) have to be assigned at the design phase of the product. If
with the liquid to be applied, e.g. hydrogen peroxide solu- not enough is known about the chemical, physical or
tion. Cotton swabs can be used to clean the tongue and oral microbiological stability, a beyond-use date of 1 month
mucosa when a tooth brush hurts too much. after preparation arbitrarily is maintained for preserved liq-
Dosage forms that are not to be swallowed by the con- uid dosage forms (see Sect. 22.7).
sumer (mouthwashes, solutions for dental or oromucosal
use, gargles and dental gels) have to be labelled accordingly.
Preferably the label should bear the text ‘mouthwash’, ‘solu-
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oromucosal use’. When these labels are not available, a strip 1. Ungphaiboon S, Maitani Y (2001) In vitro permeation of triamcin-
in a contrasting colour with the words ‘Not to be taken’
PRODUCT DESIGN
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about the dosage form and the manner of use will be Treatment of severe chronic oral erosive lesions with clobetasol
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tive randomized study of a 2-day regimen vs 5-day regimen to
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1054/ijom.2002.0414
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should be clear and should not contain a precipitate, sedi- Benus RFJ, van der Werf TS et al (2009) Decontamination of the
ment or (dust) particles. Gels for dental or oromucosal use digestive tract and oropharynx in ICU patients. N Engl J Med
should be checked before dispensing for appearance, texture, 360:20–31
6. Pitten F-A, Splieth CH, Kramer A (2000) Prophylactic and thera-
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Here the same requirements are valid as in gels for cutaneous 7. Koeman M, van der Ven AJAM, Hak E, Joore JCA, Kaasjager
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7.8 Storage and Stability 9. Petrou MA (2008) New miconazole mucoadhesive tablet to treat
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Nose
8
Suzy Dreijer - van der Glas and Anita Hafner
Contents Abstract
This chapter deals with preparations for nasal administra-
8.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
8.1.1 Local Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 tion, with a local or a systemic effect. Classical nasal
8.1.2 Systemic Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 preparations were always associated with local ailments,
8.1.3 Advantages and Disadvantages of Nasal Preparations . . . 141 but nowadays the interest in the nasal route for systemi-
8.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 cally acting substances and direct nose to brain delivery is
increasing. Fast absorption, the possibility of high blood
8.3.1 Anatomy and Function of the Nose . . . . . . . . . . . . . . . . . . . . . . . 141 levels and a patient friendly dosage form are the reasons.
8.3.2 Biopharmaceutical Aspects of Nasal Preparations . . . . . . . 143 Nasal administration of medicines with local effect is the
8.4 Adverse Effects and Toxicity of Nasal Drops first choice for the treatment of topical nasal disorders. It
and Sprays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 is also an attractive route for low dose active substances
8.5 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
with a systemic effect, such as peptides or
8.5.1 Liquid Preparations (Nasal Drops and Nasal Sprays) . . . . 145 benzodiazepines (e.g. midazolam). When compared to
8.5.2 Semisolid Preparations (Nasal Ointments and Gels) . . . . . 147 parenteral administration nasal administration is more
8.6 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 easily applied and causes less risk of infection.
8.6.1 Nasal Drops and Liquid Nasal Sprays . . . . . . . . . . . . . . . . . . . . 148 Nasal preparations can be formulated as liquid, semi-
8.6.2 Nasal Ointments and Nasal Gels . . . . . . . . . . . . . . . . . . . . . . . . . . 149 solid or solid preparations and can contain one or more
8.7 Containers and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 active substances. Whether intended for local or systemic
8.7.1 Packaging of Nasal Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 action, the mucociliary function of the nose should be
8.7.2 Packaging of Nasal Sprays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 disturbed as little as possible by the preparation However,
8.7.3 Packaging of Nasal Ointments and Gels . . . . . . . . . . . . . . . . . . 149
8.7.4 Labelling and Patient Counselling . . . . . . . . . . . . . . . . . . . . . . . . 150 it is well known that active substances as well as
excipients may have a negative influence on the
mucociliary clearance, in other words may be ciliotoxic.
8.9 Storage and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 In the formulation of nasal preparations one should take
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 into consideration the possible damage to the cilia in
relation to the indication and the period of use.
Within this chapter the emphasis is on dosage forms
that are prepared in the pharmacy and on forms that are
supplied by the pharmacy.
Keywords
Based upon the chapter Neus by Annick Ludwig and Suzy Dreijer in Ciliotoxic Mucociliary clearance Nasal preparation
the 2009 edition of Recepteerkunde. Local effect Systemic effect Preparation Formulation
S.M. Dreijer - van der Glas
The Netherlands
A. Hafner (*)
Department of Pharmaceutical Technology, University of Zagreb,
Zagreb, Croatia

140 S.M. Dreijer - van der Glas and A. Hafner
be transferred throughout the nasal cavity, whereas nasal

8.1 Orientation drops spread at the posterior part of the nose. Deposition of
the formulation in the anterior part of the nose provides
8.1.1 Local Action longer residence time and a longer period of contact between
active substance and mucosa. When the medicine is depos-
Active substances formulated as nasal preparations are tra- ited in the posterior part of the nose, mucociliary clearance is
ditionally used in the treatment of local ailments such as faster [4]. The permeability of the nasal mucosa however is
allergy, congestion and infections. Nasal preparations that better at the posterior part of the nasal cavity. Thus, active
are prepared in the pharmacy are mainly intended for the substances that are slowly absorbed should best be applied in
inner part of the nose. In addition nasal drops are often the anterior part, while substances that are intended to act
applied in diseases of the middle ear, in order to keep the fast should be applied in the posterior part of the nose. This
Eustachian tube open (see Sect. 9.1). should be kept in mind when choosing a dosage form (nasal
In the treatment of local impairments mainly aqueous drops, spray or gel) [3, 5, 6]. In allergic rhinitis nasal sprays
solutions of decongestants or sodium chloride are used, or with corticosteroids are the most widely used. In the treat-
(micro)suspensions of poorly water-soluble active ment of nasal polyps, which are mostly located at the poste-
substances (levocabastine hydrochloride or beclomethasone rior part of the nose, nasal drops would give a better contact
dipropionate) [1]. with the mucosa than nasal sprays. In some countries nasal
Aqueous nasal drops as well as sprays are suitable for self drops with fluticasone propionate are authorised especially
administration. Viscous solutions are best avoided, as they for nasal polyps, the spray for allergic rhinitis.
make less contact with the nasal mucosa. To clear a The ciliary epithelium cannot perform its transport func-
congested nose the patient can also sniff a salt solution tion if it is covered by lipophilic vehicles (e.g. liquid paraf-
(half a teaspoon of salt in a glass of lukewarm water) four fin). The use of soft fatty nasal ointments or creams is only
to six times a day. The benefit of the addition of sodium appropriate in disorders of the vestibulum nasi, because in
hydrogen carbonate for a so-called alkaline nasal wash has the anterior part of the nose, cilia are absent (see Sect. 8.3.1).
not been demonstrated [2]. Nasal gels are normally hydrogels, and as such less toxic
Nasal sticks and so called inhalation ointments with vol- for the cilia than nasal ointments, more efficient in applying,
atile ingredients such as menthol and eucalyptol are mainly and they remain longer on the mucosa [3]. However, the
used in self-care. The same is true for vapours. cellulose thickening agents in these hydrogels form a crusty
Nasal powders for insufflation (i.e. with corticosteroids) layer (xerogel) on drying, that may irritate. The addition of a
are on the market as an alternative to sprays, but powders humectant (glycerine, sorbitol) should prevent drying out
seem to give more risk of irritation and bleeding [3]. and irritation, but generally patients do not appreciate nasal
In general, retention of the product within the nasal cavity gels. As a consequence, very few nasal gels with a local
will be attained if the vast majority of the particles or action are on the market. A nasal gel can however be a good
droplets are larger than 10 μm. The deposition site of the choice for short term use. Chlorhexidine nasal gel is used in
formulation is important and therefore also the container and the prevention of ventilation associated pneumonia in Inten-
dosing device and the way of administration. When using a sive Care patients [7].
spray the solution is finely distributed in the anterior part of Examples of nasal preparations with local action are
the nose and mucociliary clearance causes the formulation to given in Table 8.1.
Table 8.1 Nasal preparations with local action (examples)

Active substance Physical form Indication/therapeutic class Preparation
Azelastine HCl Solution Allergic rhinitis/antihistamine Allergodil®, Allergocrom®,
Cromohexal®
Levocabastine HCl Microsuspension Allergic rhinitis/antihistamine Livocab®, Livostin®
Oxymetazoline HCl Solution Nasal decongestion/vasoconstrictor Afrin®, Dristan®, Nasivin®, VicksSinex®
Beclomethasone Suspension Allergic rhinitis/corticosteroid Beconase®, Nasobec®,Qnasl® and
diproprionate generics
Fluticasone propionate Suspension Allergic rhinitis and nasal polyps/corticosteroid Nasofan®, Flixonase®, Flonase® and
generics
Momethasone furoate Suspension Allergic rhinitis and nasal polyps/ corticosteroid Nasonex®, Mommox®
Budesonide Suspension Allergic rhinitis, rhinitis and nasal polyps/ Rhinocort® spray
Powder corticosteroid Rhinocort® turbuhaler
8 Nose 141
Table 8.2 Nasal preparations for systemic purpose (examples)

Active substance Physical form Indication/therapeutic class Preparation
Desmopressin Solution Central diabetes insipidus/derivative of the antidiuretic hormone DDAVP, Minrin®
Nafarelin acetate Solution Endometriosis/agonist of gonadotropin-releasing hormone Synarel®
Oxytocin Solution Gynaecological hormone (uterotonic, uterostiptic) Syntocinon®
Sumatriptan Solution Migraine/antimigraine agent Imigran®, Imitrex®, Rosemig®
Fentanyl citrate Solution Chronic pain/opioid analgesic Instanyl®a, PecFent®a
a
Approved for use in the European Union
8.1.2 Systemic Action are usually iso-osmotic and may contain excipients, for
example, to adjust the viscosity, to adjust or stabilise the
Nasal administration of medicines is an effective way of pH, to increase the solubility of the active substance or to
systemic delivery of active substance, alternative to oral stabilise the preparation.
and intravascular delivery. Advantages of nasal systemic Nasal preparations are supplied in multidose or single-
delivery include relatively large surface area available for dose containers, provided, if necessary, with a suitable
PRODUCT DESIGN
absorption, rapid onset of therapeutic action, avoidance of administration device, which may be designed to avoid
first-pass metabolism (see Sect. 16.2.6), non-invasiveness of contamination.
application of the active substance, resulting in patient com- The Ph. Eur. lists
fort and compliance [8]. • Nasal drops and liquid nasal sprays
Generally speaking active substances with a systemic • Nasal powders
therapeutic action can be formulated as nasal preparations • Semisolid nasal preparations (nasal ointments and gels)
under the following conditions: high water-solubility • Nasal washes
(required dose must fit in 25–150 microlitres vehicle), suffi- • Nasal sticks
cient chemical stability, no unpleasant smell or taste, Nasal drops and liquid nasal sprays are solutions, emulsions
favourable nasal absorption parameters, minimal nasal irri- or suspensions intended for instillation or spraying into the
tation and clinically important properties such as fast onset nasal cavities. Nasal powders or nasal insufflation powders
of therapeutic action, low dosage (normally less than 25 mg are intended for insufflation into the nasal cavity by means of
per dose), and no toxic metabolites [3, 8]. a suitable device. The size of the particles are such as to
In preparations intended to obtain a systemic effect a localise their deposition in the nasal cavity. In nasal sticks
spray solution is the favourite dosage form, because it and so-called inhalation ointments mostly volatile active
enables accurate dosing. Examples of nasal preparations substances are formulated in a fatty base. Nasal washes are
for systemic purpose are listed in Table 8.2. Examples of generally aqueous iso-osmotic solutions intended to cleanse
licensed preparations are nasal sprays with buserelin, fenta- the nasal cavity. If they are intended for application on
nyl and vaccines (e.g. against airway infections) [8]. injured parts of the mucosa, or prior to a surgical operation,
they have to be sterile. Nasal powders and nasal sticks are
not very common in pharmacy practice. Therefore they are
8.1.3 Advantages and Disadvantages of Nasal not discussed in this chapter.
Preparations
The advantages and disadvantages of nasal preparations are 8.3 Biopharmaceutics

summarised in Table 8.3.
8.3.1 Anatomy and Function of the Nose
8.2 Definitions The nostril, the vestibulum nasi, is covered by hairy skin for
1–1.5 cm inward. The nose skin is not different from the rest
The European Pharmacopoeia (Ph. Eur.) defines nasal of the skin, and can suffer from the same disorders. Further
preparations as a liquid, semisolid or solid preparations inward the skin is replaced by the nasal mucosa, which is
intended for administration to the nasal cavities to obtain a covered by cilia (see Fig. 8.1).
local or systemic effect. They contain one or more active The nasal epithelium contains cells with or without cilia,
substances. Nasal preparations are as far as possible mucous cells and basal cells. The submucosa contains glands
non-irritating and do not adversely affect the functions of that produce mucus and an aqueous secretion. Nasal mucus
the nasal mucosa and its cilia. Aqueous nasal preparations consists of 95 % of water and contains 2 % mucine, 1 %
Table 8.3 Advantages and disadvantages of nasal preparations. + the advantage applies for this type of preparation, the disadvantage applies
for this type of preparation
Nasal preparations with Nasal preparations with
local effect systemic effect
Advantages
Administration by patient, at home + +
Good adherence + +
Accurate dosing possible + (only for sprays) +
Little risk of overdosing + (except for sprays in +
young children)
High absorption, pharmacokinetic profile comparable with intravenous injection – + (for lipophilic
substances)
Fast absorption, onset of therapeutic effect within 30 min – + (for lipophilic
substances)
Possible direct pathways to the CNS, bypassing the blood–brain barrier [5, 8, 9] – +
Possible alternative for active substances with low biological availability caused by – +
insufficient absorption or extensive first-pass metabolism
Possible induction of systemic or local immune response without injection (vaccines) – +
Disadvantages
Ciliotoxicity and nasal irritation by active substances or excipients
Fast clearance (15–20 min) of liquids and powders due to activity of mucociliary apparatus
Variablility in mucociliary clearance related to patient condition and environmental factors
(moisture, temperature)
Variability in absorption and therapeutic effect related to the nature of the active substance
and condition of the patient
Nasal absorption of systemically acting substances resulting in a profile with ups and downs – (when an even profile
is needed)
Limited volume that can be administered per nostril (25–200 microlitres) ()
Accurate dosing not possible (nasal drops) –
Low biological availability of hydrophilic substances, such as peptides with a high –
(>1,000 Da) molecular weight
Enzymatic degradation or metabolism on the mucosa –
nasal mucosa
frontal sinus
upper nasal concha
sphenoid sinus
middle nasal concha
middle nasal passage
lower nasal concha

upper nasal passage
lower nasal passage

Eustachian tube
vestbulum nasi
Fig. 8.1 Schematic cross section of the nose. Source: Recepteerkunde 2009, #KNMP
8 Nose 143
inorganic salts, 1 % proteins (albumin, immunoglobulines, 8.3.1.2 Ciliary Beat

lysozyme) and less than 1 % of lipids. Mucus comes from A well operating ciliary epithelium is important in preven-
the chalice-shaped mucous cells and the submucosal tion as well as cure of many diseases of the airways. The
glands. The mucus layer (thickness 5 μm) actually consists activity of the cilia depends on a number of factors, includ-
of two layers. The lower part is a aqueous layer, in which ing temperature and humidity of the air, pH and viscosity of
cilia move. The upper layer is a discontinuous viscous the mucus layer. Besides pathological conditions (allergic
mucus layer resting on the cilia, which is passed on by the diseases, sinusitis, measles) also chemical influence may
cilia in the direction of the pharynx. The viscosity of this inhibit the action or even destroy the ciliary epithelium.
aqueous layer (sol layer) and gel layer, respectively, has This is called ciliotoxicity. Ciliotoxicity is an important
influence on the mucociliary clearance. In the case of reason to restrict the period of use of nasal preparations.
rhinitis the sol layer is so thick that the cilia cannot reach The inhibiting effect of anaesthetics on the ciliary epithe-
the upper layer (gel layer) to transport it to the pharynx. If lium is supposed to be an important cause of respiratory
the upper layer becomes too viscous due to dehydration, the infections following surgery [12].
cilia do not have sufficient power to move and clear it. The The rate of mucociliary clearance differs between
mucus layer has several different functions: it covers and individuals (fast and slow movers), but it does not depend
PRODUCT DESIGN
protects the mucosa physically and by the action of on gender or age [11].
enzymes, it has a capacity for water retention, allows the
transfer of warmth and moves particles down to the naso-
pharynx [10, 11]. 8.3.2 Biopharmaceutical Aspects of Nasal
The thin, porous and highly vascularised nasal epithe- Preparations
lium has a high total blood flow, which facilitates fast
absorption of substances. Direct transport to the systemic Section 16.2.6 discusses biopharmaceutics of nasal
circulation or the central nervous system makes it possible preparations from a general biopharmaceutics viewpoint.
to obtain a rapid therapeutic effect. The intranasal absorp- This subsection adds some more specific details, first on
tion depends on the mucociliary clearance, pathological the nasal absorption and then on the many investigations
conditions such as infections, allergy and obstruction, on absorption enhancing substances. The interest for nasal
mucus secretion, moisture content, enzymatic degradation, absorption is predominantly raised by the desire to find an
and blood flow. It should be remembered that the blood alternative administration route for systemically acting
flow can be affected by either locally or systemically active active substances.
substances. These phenomena can determine the nasal
absorption of substances. Oxymetazoline and clonidine
reduce the blood flow, while phenylephrine and salbutamol 8.3.2.1 Intranasal Absorption
raise it. The mucociliary clearance rate may influence the intranasal
absorption of systemically active substances. Pathological
conditions and an accelerated rate of mucociliary clearance
8.3.1.1 Mucociliary Clearance shorten the contact time between active substance and the
The function of the nose is, besides being the olfactory absorbing mucosa. A delayed mucociliary clearance will
organ, to prepare the air in such a way that the airways and have the opposite effect. Nasal hypersecretion dilutes the
the lungs will not be damaged. In the nasal cavity the air is medicine solution and delays passive absorption. In addition
warmed up and moisturised before reaching the lungs. it may lead to a local loss of some of the medicine due to a
Coarse dust particles are held back by the hairs at the washout effect. A change in pH of the mucus layer may have
entrance of the nose, while smaller particles and micro- consequences on the ionisation of some substances, and thus
organisms can pass this first barrier, but are retained in the on their absorption [11].
mucus layer. The cilia show a coordinated movement in
wave-like patterns. By these movements the mucus with all 8.3.2.2 Absorption Enhancers
the retained particles (dust, bacteria, powders, oil droplets) is Three ways exist to improve limited nasal absorption of
drained to the pharynx, where the soft palate conducts it to systemically acting substances:
the oesophagus by the swallowing movement. The coordi- • Using substances enhancing absorption through the
nated movement (phase and frequency) is necessary for an mucosa
efficient mucociliary clearance [11, 12]. • Using enzyme inhibitors to reduce degradation of active
More detailed information about the anatomy of the nose substances
and the properties and functions of the nasal mucosa can be • Using mucoadhesive polymers, to make the preparation
found in the literature [3, 8, 11–15]. stay in the nasal cavity for a longer time
Any substance added to improve absorption should be commercially developed (i.e. cyclopentadecalactone,
pharmacologically inert, with no taste or smell, alkylsaccharides, chitosan, low methoxylpectin, hydroxyl
non-allergenic, non-irritating, non-toxic, affecting the fatty acid ester of polyethylene glycol) and have been
structure of the mucosa and the mucociliary clearance reviewed in the literature [22]. Low methoxylpectin is
only in a reversible way [11, 12]. Examples of already used in PecFent®, an intranasal preparation with
mucoadhesive polymers are carbomers, chitosan and fentanyl (Table 8.2). It contains the PecSys® delivery sys-
carmellose. They lengthen the residence time of nasal tem, an in situ gelling system that gels due to interaction
powders or suspensions in the nasal cavity [13, 16–18]. In with calcium ions in the nasal fluid [29].
addition to that carbomers bind in a reversible way with
the tight junctions of the epithelium, thus facilitating
8.3.2.3 Local Effect
paracellular transport [11, 12, 19–21]. Using cell culture
Not much is known about the biopharmaceutics of nasal
and animal models, the mechanism of absorption enhance-
preparations with a local effect. Dosing is done on a thera-
ment of chitosan was also shown to be the transient opening
peutic result basis. What is known is that bioavailability and
of the epithelial tight junctions combined with the
residence time are influenced by:
mucoadhesion [22]. However, more research has to be
• The position of the head during administration
done on the effects of chronic use of mucoadhesive
• The droplet size, which depends on different factors,
polymers in nasal preparations.
including the interfacial tension of the solution and the
Absorption enhancers such as cyclodextrins can enhance
dropper
the biological availability of intranasally administered
• The pattern of atomisation, that depends on the properties
medicines [23]. Research has mainly been focused on the
of the nozzle
influence of these excipients on systemic availability, but an
• The viscosity of the solution
enhanced local effect seems possible as well.
• The administered volume (number of drops or spray
In short term studies cyclodextrins caused less histologi-
volume)
cal changes of the nasal epithelium in rats than for instance
• The site of deposition (anterior or posterior part of the
benzalkonium chloride [24]. Other studies in rats showed
nasal cavity)
that dimethyl betacyclodextrin, methylated betacyclodextrin
• Pathological situations and the condition of the mucosa
and hydroxypropylbetacyclodextrin are safe and efficient
(cold or flu, nose congestion, runny nose, nasal polyps,
enhancers of nasal absorption [8, 25, 26]. These results
etc.), which affect absorption and mucociliary clearance
suggest that cyclodextrins (see also Sect. 18.1.4) can
be used in nasal preparations, but more research is still
needed.
Surfactants are also used to promote penetration of 8.4 Adverse Effects and Toxicity of Nasal
ingredients with systemic activity through the nasal mucosa. Drops and Sprays
Their mechanism of action is based on a change of the
permeability by disturbing (reversibly or irreversibly) the As the mucosa is highly sensitive to irritation, nasal toxicity
structural integrity of the mucosa. Polysorbate 80, for of active substances and excipients is an important issue in
instance, has a strong negative effect on the cilia, which is formulating nasal preparations, especially when they are
however reversible. intended for treatment of chronic diseases [11]. Nearly all
More information about absorption enhancers is to be substances used in nasal preparations have a negative influ-
found in literature [3, 11, 12, 27, 28]. ence on the ciliary beat, and are therefore ciliotoxic. The
A range of nasal peptides such as desmopressin, influence may vary from a temporary (reversible) effect up
buserelin, nafarelin and oxytocin, have been formulated to an irreversible inhibition of the ciliary beat [30]. In many
into licensed nasal products. However, none of them nasal drops and nasal sprays preservatives cause the toxic
contains a nasal absorption enhancer. Even though these effect on cilia [31], but the active substance itself may also
nasal products are characterised by low peptide bioavailabil- have a negative influence on the ciliary epithelium. Nasal
ity they are efficacious, as low systemic levels are needed to drops with decongestants have been shown to exhibit rela-
exert a therapeutic effect. However, developing of novel safe tively low ciliotoxicity (e.g. Xylometazoline nasal drops
and efficient nasal absorption enhancers is of great interest to 0.025 %, 0.05 % and 0.1 % (see Table 8.4) as well as a
improve bioavailability of presently marketed peptides and number of licensed preparations) [32].
to provide sufficient nasal permeability of less potent A review of the ciliotoxicity of other active substances
biologicals [22]. that are used in nasal preparations, including local
Several novel nasal absorption enhancer systems with anaesthetics, antibiotics, antihistamines and corticosteroids
promising preclinical or clinical data or both are now being can be found in the literature [12].
8 Nose 145
Table 8.4 Xylometazoline Nasal Drops/Spray, Solution 0.025 % [33]

8.5 Product Formulation
Xylometazoline hydrochloride 0.025 g
Benzalkonium chloride 0.01 g
8.5.1 Liquid Preparations (Nasal Drops
and Nasal Sprays)
Sodium chloride 0.8 g
Sodium dihydrogen phosphate dihydrate 0.15 g 8.5.1.1 Physico-chemical Properties of the Active
Water, purified ad 100 mL Substance
A water soluble form of the active substance is preferred.
The administration of nasal drops or sprays may some- This may bring about oxidation or hydrolysis reactions (see
times cause temporary irritation of the nasal mucosa. Sys- Sect. 22.2). Common sympathomimetics such as
temic (side) effects, e.g. of decongestants, may be seen as a naphazoline, oxymetazoline and xylometazoline may
result of absorption by the nasal mucosa and the gastrointes- hydrolyse in aqueous solution, but this happens only at a
tinal tract. Problems of this kind can be avoided, if the pH higher than what is normal for nasal preparations, or at a
patient carefully follows the instructions for use, the quantity higher temperature than what is normal for the storage of
these preparations.
PRODUCT DESIGN
to be administered and the duration of the therapy.
Especially in young children the use of nasal drops or In preparations for intranasal administration for systemic
sprays should be restricted. An overdose administered in the purposes, the aqueous solubility of the substance must be
nose (e.g. by too high concentration) will more quickly lead sufficient to make administration of the desired dose in a
to intoxication in young children than in adults, as the small volume possible. The volume that can be administered
absorption surface of the mucosa compared to body weight per nostril is 25–150 microlitres at the time, with a maxi-
in children is larger than in adults. In using nasal sprays, the mum of 200 microlitres.
contact absorption surface is larger than for nasal drops, so Lipophilic substances are absorbed better, but the water
overdosing is more likely to occur. Due to the ease with solubility may be the limiting factor. For insoluble active
which nasal sprays can be administered there is a real risk of substances, such as many corticosteroids, a suspension is the
overdosing in children. This risk led to the removal of the most suitable form. In that case the particle size of the raw
indication of primary nocturnal enuresis (PNE) in 2007 from material should be less than 90 μm. Beside particle size,
all desmopressin nasal spray products, due to increased risk polymorphism is another influencing factor [3, 8]. See also
of hyponatremia and other adverse effects compared with Sect. 18.4.2.4.
the oral formulation [34]. For the formulation of a homogeneous, readily dispers-
In children under about 2 years of age there is the risk of a ible suspension reference is made to Sect. 5.4.6 about oral
life-threatening laryngospasm. The nasal mucosa after a suspensions.
mechanical stimulus or a stinging smell can show a reflex Tables 8.1 and 8.2 give some examples of nasal
apnoea or a spasm of the vocal cords. Menthol is a notorious preparations, solutions as well as suspensions. Note that all
example, but other volatile substances might cause the same licensed preparations for systemic therapy are solutions, as
reflex action. shown in the second column of Table 8.2.
In this section focus lies on the design of the formulation
of nasal preparations, first for liquids and then for semisolid
forms. 8.5.1.2 Vehicle
In addition to the active substance, nasal preparations Properties of the vehicle which influence the effectiveness of
often contain a number of excipients, including vehicles, a nasal solution include pH, buffer capacity, osmolarity,
buffers, preservatives, tonicity adjusting agents, solubilising stability, influence on normal mucus viscosity, compatibility
agents, humectants, viscosity enhancing substances and pos- with active substance and compatibility with ciliary func-
sibly antioxidants. In the design of a nasal preparation, great tion. Water is chosen as the solvent, because most other
care is needed when choosing a vehicle and other excipients. solvents will have a negative influence on the ciliary func-
The integrity of the mucosal epithelium, the overall ciliary tion. A buffer solution may be needed for stability reasons.
function and the mucus production should be retained as Propylene glycol is strongly ciliotoxic, as it causes imme-
much as possible after administration. Otherwise the physi- diate paralysis of the cilia, it is also hypertonic and it
ological function, and thus the protective action, of the nose dehydrates the mucosa. It may also change the rheological
will be disturbed. In many cases there will be a need to properties of the mucus. However propylene glycol may be
compromise between physiological requirements and necessary to bring an active substance into solution,
restrictions with regard to the stability and pharmacological e.g. midazolam nasal spray [35]. In a preparation for inci-
activity of the active substances. dental use, e.g. as an emergency medication in people
suffering from epilepsy, ciliotoxicity could be acceptable, is needed, phosphate (pH 6.8–8.5) and trometamol
more than in a nasal spray against chronic rhinitis. (pH 7.2–8.5) buffers are suitable. Citrate buffers should be
Fatty vehicles, such as (vegetable) oils, have the disad- avoided because of their ciliotoxic effect and possible irrita-
vantage that they do not mix with the mucus layer. In that tion of the nasal mucosa. Borate buffers are ciliotoxic and
situation there would be little contact of an oil soluble active badly tolerated [10]. The nasal drops in the Dutch formulary
substance with the nasal mucosa and that oily substances are (weakly) buffered with a mixture of sodium mono hydro-
would rapidly pass on to the nasopharynx. gen phosphate and sodium dihydrogen phosphate, see
Table 8.4.
8.5.1.3 pH and Buffer Capacity In medicines with intended systemic action a certain pH
The pH of the nasal formulation is a very important parame- may be necessary to guarantee sufficient absorption of the
ter which can be set to avoid irritation of the nasal mucosa active substance. In that case a buffer with high capacity is
and influence on physiological ciliary movement, to ensure chosen, although it will have a negative effect on cilia. The
active substance solubility or availability in unionised form more pH deviates from the physiological value, the more
suitable for absorption, to prevent growth of pathogenic irritation will be felt. An example is a licensed nasal spray
bacteria or to maintain functionality of preservatives with the peptide buserelin in a citrate buffer (pH 5.5–6). Its
[36]. The pH of physiological normal nasal liquid is 6–8 Summary of product characteristics (SPC) says nasal irrita-
[37]. The health condition of the patient is one of the factors tion may occur, sometimes leading to epistaxis or hoarse-
that influence the pH. A physiological pH is necessary for a ness, as well as changes in taste and smell.
normal mucociliary clearance and minimal nasal irritation.
A pH outside these limits will have a negative influence on 8.5.1.4 Osmotic Value
the activity of the cilia. Deviations in the alkaline region are Nose drops and sprays that are not iso-osmotic have a nega-
better tolerated than acid solutions. After the introduction of tive influence on the ciliary epithelium. Hypo-osmotic
a solution of pH 5.8, the mucosa will react by increasing the solutions however are more ciliotoxic than hyper-osmotic
production of bicarbonate containing mucus [37]. For this ones [32]. Again the requirements should be more strict than
reason the pH of nasal drops and sprays should be not far for eye drops, because the diluting effect of the nasal liquid
below the physiological value. The Ph. Eur. does not set is much smaller than that of tears. Nasal drops are made
limits for the pH of nasal preparations, but requires they will iso-osmotic with sodium chloride, or in case of incompat-
not have a negative influence on the functioning of the nasal ibilities with glucose or mannitol. More information about
mucosa and the cilia. A pH between 6.2 and 8.3 is generally osmotic pressure and tonicity, and the calculation of the
considered safe for the cilia. (A pH > 8.3 and <10 would osmotic value of solutions, is given in Sect. 18.5.
perhaps not affect the cilia much, but may cause an unpleas-
ant taste after administration). The safe range for the pH of 8.5.1.5 Viscosity
nasal drops is narrower than for eye drops, because the In many licensed medicines viscosity enhancers and
buffering and diluting effect of the nasal liquid is less than surfactants are added to stabilise suspensions. In such cases
that of tears. This means that a formulation for eye drops it is important to avoid too high concentrations of these
cannot always simply be used for nasal drops. excipients, in order to avoid too much negative influence
The ciliotoxicity of some substances depends on the pH on the mucociliary clearance.
of the solution. For instance when benzalkonium chloride is Also solutions are sometimes made viscous to prevent
used as preservative, the pH of the preparation should be >5 them from flowing out of the nose, for example nasal drops
to reduce the ciliotoxicity. Preservative efficacy can also be with 0.9 % or 1.5 % sodium chloride (Table 8.5), but there
dependent on pH of the formulation. For instance, antimi- are doubts whether this will help.
crobial activity of benzalkonium chloride occurs between Opinions on the use of viscosity enhancers in nasal sprays
pH 4 and 10, and methyl parahydroxybenzoate exhibits are not uniform. Firstly, the residence time of viscous nasal
antimicrobial activity over the pH range of 4–8 [38,
39]. See also Sect. 23.8.2.
In other cases the stability or solubility of the active Table 8.5 Sodium Chloride Nasal Drops, Viscous Solution 0.9 % [40]
substance requires a pH deviating from the physiological Sodium chloride 0.9 g
one. Midazolam nasal spray has pH 4, in order to keep the Benzalkonium chloride 0.01 g
active substance in solution [35]. Disodium phosphate dodecahydrate 0.025 g
Buffers are included to maintain a desired pH throughout Hydroxyethylcellulose 400 mPa.s 0.5 g
the shelf life of the preparation. As the nasal liquid has only Water, purified 88.35 g
limited buffering effect, it is important for the buffer capac- Total 100 g
ity of the preparation to be as low as possible. When a buffer
8 Nose 147
sprays within the nasal mucosa is somewhat longer. Sec- morphology of the mucosa [24]. In addition, benzalkonium
ondly, non-viscous sprays may be nebulised to smaller chloride safety has been reviewed on the basis of 14 in vivo
drops, which enlarges the contact surface. In addition, during and 4 in vitro studies [46]. It has been concluded that intra-
its residence time a viscous liquid will stay on top of the nasal products containing preservative benzalkonium chlo-
viscous mucus, and therefore be passed on easily. A ride appear to be safe and well tolerated for both long- and
non-viscous solution will have better contact with the nasal short-term clinical use.
epithelium. Disodium edetate, normally the second component in
When surface-active viscosity enhancers are used, the preserving solutions with benzalkonium chloride, has lim-
surface tension will influence the droplet size of the ited intrinsic antimicrobial efficacy and a relatively small
nebulised solution. A lower surface tension will lead to effect on the cilia.
smaller drops, and thus a larger contact surface. For instance Balancing advantages and disadvantages the combination
nasal sprays with corticosteroids often contain carmellose. of benzalkonium chloride 0.01 % and disodium edetate
When a nasal spray is supplied in a squeeze bottle instead 0.1 % is the preferred preservative for nasal drops and
of one with a pump atomizer, a viscous spray might be sprays. Second choice would be methyl parahydroxy-
difficult to nebulise. So, in the design of a spray formulation, benzoate 0.1 %. Detailed information about the efficacy of
PRODUCT DESIGN
viscosity has to be considered together with the intended preservatives in nasal preparations can be found in [47].
type of container and atomising device.
Nasal suspensions can be characterised by thixotropic 8.5.1.7 Appearance, Smell and Taste
properties [41]. Nasal sprays containing triamcinolone When used correctly, nasal drops and sprays will not come
acetonide or mometasone furoate showed time-dependent, into contact with the taste buds, but nevertheless they can
reversible loss of viscosity under shear (shaking or give a sensation of taste [23]. This is easy to understand, as
spraying,) flowing more freely. Recovery of viscosity after the olfactory organ plays an important role in the experience
application is likely to inhibit suspension flowing out from of taste. The clearance through the nasopharynx can be
the nasal cavity [42, 43]. another cause, as a bitter taste is mainly observed at the
rear of the tongue. Usually nasal preparations do not contain
8.5.1.6 Preservation any flavouring agents. A side effect of especially nasal
Aqueous nasal drops and nasal sprays are preserved when sprays may be a change in the users sensation of smell and
they are supplied in multidose containers. In order to get a taste. Examples are nasal sprays with fluticasone and with
low level of microbiological contamination at the start, the buserelin (Suprefact®).
use of sterilised water or sterilised solutions of preservatives
as primary materials is recommended.
Benzalkonium chloride is so far the most widely used
preservative, but thiomersal, chlorobutanol, phenylethanol, 8.5.2 Semisolid Preparations (Nasal
and parabens can also be found in nasal formulations. Ointments and Gels)
Mercury compounds, such as phenylmercuric borate and
thiomersal, can lower the ciliary beat frequency fast and 8.5.2.1 Active Substance
irreversibly and, therefore, should be avoided, if their use Active substances may be incorporated as a solution or as a
is not already limited because of environmental reasons suspension. More information about this choice can be found
[44]. See also Sect. 23.8.4. Chlorobutanol inhibits the ciliary in Sect. 5.4.2.
beat very fast, but provided the contact time is short, the
ciliary movement will recover after some time. Parabens 8.5.2.2 Ointment Base
also have proved to be able to inhibit the ciliary movement The choice of an ointment base depends on the site of
(in vitro studies) [45]. application. In the anterior part of the nose, where cilia are
Benzalkonium chloride in vitro has a ciliotoxic effect, absent, and in rhinitis sicca or in atrophic rhinitis, a fatty
which develops slowly, but is irreversible. Benzalkonium ointment base is used. An example is Menthol-paraffin nasal
chloride slows down the ciliary movement and disorganises ointment 0.6 % (Table 8.6). When the nasal mucosa does not
the mucus layer. This structure change is supposed to be the function, as in atrophic rhinitis, possible ciliotoxicity of the
result of an interaction of anionic substances in the mucus
with the cationic benzalkonium. The ciliotoxic effect of Table 8.6 Menthol-Paraffin Nasal Ointment 0.6 % [48]
benzalkonium chloride increases when pH is lowered from Menthol, racemic 0.6 g
7 to 5. Therefore nasal drops preserved with benzalkonium Paraffin, liquid 49.4 g
chloride should preferably have a pH around 7. In vivo Paraffin, white soft 50 g
however, long-term use of benzalkonium chloride 0.02 % Total 100 g
did not change the rate of mucociliary clearance and the
ointment base is less relevant. The same applies to the Table 8.7 Base for Hydrophilic Nasal Gel [7]
treatment of vestibulitis nasi, because of the absence of Benzalkonium chloride 0.01 g
cilia in that part of the nose (see also Sect. 8.1). Disodium edetate 0.1 g
In diseases of the vestibulum nasi soft ointment or emul- Glycerol (85 %) 10 g
sion bases are often used. Examples of ointments are Hydroxyethylcellulose 400 mPa.s 4g
Hydrophobes Basis gel DAC (see Sect. 12.7.6), with added Water, purified 85.89 g
wool fat or a similar w/o emulsifier. Sometimes part of the Total 100 g
white soft paraffin in these ointments is replaced by liquid
paraffin or triglycerides, to make them softer and easier to
apply in the nose. 8.5.2.4 pH
In nasal gels pH should be in the range 6.2–8.3, as in nasal
drops. Values outside these limits may be necessary for
Alternatively w/o emulsion bases are used in practice,
reasons of solubility, stability or efficacy of the active sub-
such as hydrophobic creams:
stance. Preferably nasal gels are not buffered, but when for
1. Glycerol 85 % – White soft paraffin – Water –
instance the stability of the active substance demands a
Wool fat (33.3 % - 33.3 % - 8.3 % - 25 %)
certain pH, phosphate or trometamol buffers are used.
2. Anhydrous Eucerinum® – Propylene glycol –
Sodium chloride – Water – Refined Olive oil
8.5.2.5 Preservation
(23 % - 10 % - 1 % - 46 % - 20 %)
When preservation of a nasal gel is needed, like in nasal
None of them has been officially published
drops the combination of benzalkonium chloride and
however.
disodium edetate (0.01 % and 0.1 % respectively) is pre-
ferred. According to the NRF the concentration of
benzalkonium chloride should preferably be doubled to
0.02 %, because the antimicrobial action is not always suffi-
8.5.2.3 Hydrogel Base
cient in the presence of viscosity enhancers [50]. Methyl
Theoretically a hydrogel is safer for the cilia than a nasal
parahydroxybenzoate is the second choice.
ointment with fatty components. Compared to nasal drops
the application of a hydrogel is more efficient, and it stays
longer on the mucosa, thus raising the chances for absorption
of the active substance. Gels containing humectants (glyc- 8.6 Method of Preparation
erol, sorbitol and mannitol) are supposed to diminish the
irritation caused by some active substances. 8.6.1 Nasal Drops and Liquid Nasal Sprays
There are however a number of restrictions to the formu-
lation of a nasal gel. Carbomer gel is not acceptable, because 8.6.1.1 Sterile Vehicles
of the incompatibility with substances such as sodium chlo- In order to get a low degree of microbiological contamina-
ride, chlorhexidine digluconate and other ionogenic tion at the start, the use of sterilised water or sterilised
substances that are often incorporated in this dosage form. solutions of preservatives as primary materials is
A hydrogel with a cellulose derivative leaves a crusty layer recommended. A Dutch example is Benzalkonium Sterile
after drying, which may irritate. This effect is more obvious base solution 0.1 mg/ml (Table 8.8).
for high molecular derivatives than for those with lower For nasal drops as a suspension, or when viscous nasal
molecular weight. Uncharged cellulose derivatives show drops are needed, the combination of equal parts of
least ciliotoxicity. Suitable cellulose derivatives for nasal hypromellose-benzalkonium solution (Table 8.9) and
preparations are hypromellose 4,000 mPa.s (2–6 %) and benzalkonium base solution 0.1 mg/ml (Table 8.8) may be
hydroxyethylcellulose 300–560 mPa.s (3–6 %). The addi- used.
tion of a humectant (e.g. glycerol 85 %) is necessary in order Both preservative solutions can be sterilised by steam and
to soften the crusty layer that will be left, thus lessening stored in bottles of borosilicate glass (Type I glass see Sect.
irritation. The addition of such a humectant will however 24.2.1).
cause hyperosmosis, which is not desirable regarding the
ciliary function. A suitable hydrophilic gel base might be 8.6.1.2 Preparation Method
the formula given in Table 8.7 that has been used clinically In the preparation of nasal drops and liquid nasal sprays the
according to [7]. It is based upon the formula of active substances are dissolved or suspended and the
Hydroxyethylcellulose gel DAB [49], but with the combina- excipients are dissolved in the preservative solution or
tion of benzalkonium and disodium edetate as preservative. sterilised water. For viscous nasal drops the components
8 Nose 149
Table 8.8 Benzalkonium Sterile Base Solution 0.1 mg/ml [51] brown glass. Also an opaque white plastic bottle (high den-
Benzalkonium chloride 0.01 g sity polyethylene bottle) generally gives sufficient protection
Disodium edetate 0.1 g from light.
Water, purified ad 100 mL Nasal drops can be supplied in a multidose bottle with an
integral dropper or with a dropper applicator. From a
microbiological point of view an integral dropper may
offer better protection, but for practical reasons a dropper
Table 8.9 Hypromellose-benzalkonium Sterile Base Solution [52] applicator is often preferred. It makes dosing easier for the
patient and so prevents overdosing (see Sect. 24.4.19.9). The
Hypromellose 4,000 mPa.s 1g disadvantage of a separate dropper for the administration of
Disodium edetate 0.1 g nasal drops is that mucus with bacteria from the nose can get
Water, purified ad 100 mL into the liquid. This can be avoided if patients are instructed
to keep squeezing the rubber balloon until the dropper tip has
been removed from the nostril. In any case the dropper
should be cleaned with warm water each time it has
PRODUCT DESIGN
may be dissolved or suspended in a standard base solution been used.
such as the benzalkonium base solution 0.1 mg/ml of Preservative free nasal drops should be supplied in single-
Table 8.8. This solution or suspension is then diluted with dose containers (see Sect. 24.4.14).
hypromellose-benzalkonium base solution (Table 8.9).
8.6.1.3 In-process Controls 8.7.2 Packaging of Nasal Sprays

In the preparation of nasal drops and nasal sprays the fol-
lowing in-process controls are important: Nasal sprays can be supplied in containers with some form
• Writing down the tare or calibrating utensils in case a of atomiser. There are two possibilities: plastic (high
final addition to weight or volume is required density polyethylene) squeeze bottles with an atomiser and
• Measuring of temperature, for instance during dissolving glass bottles with a pump atomiser (see Fig. 24.14 in
under heating of thermolabile substances, and after Sect. 24.4.19.9). In the first type, dosing is done by squeez-
cooling down ing the bottle; in a pump atomiser, by pumping. Dosing with
• pH a pump atomiser is more accurate than by squeezing, which
• Clarity after each dissolution step makes the pump atomiser more suitable for highly active
• Absence of particles in solutions by visual inspection substances, such as corticosteroids [7].
• Homogeneity and absence of lumps in suspensions To avoid contamination with nasal liquid, the squeeze
• Total weight or total volume or the yield. bottle should be kept pressed in until it is removed from the
nose. This is not needed with the pump atomiser. Both
devices have to be cleaned by rinsing or wiping.
8.6.2 Nasal Ointments and Nasal Gels In some licensed nasal sprays dosage delivery devices are
used that make it possible to deliver doses free from micro-
8.6.2.1 In-process Controls organisms and at the same time maintain sterility of preser-
The In-process controls of nasal ointments are the same as vative free solutions. The manner of construction is claimed
those of similar cutaneous preparations (see Sect. 12.6.4). to prevent environmental air coming into contact with the
For the preparation and in-process controls of nasal gels (sterile) content in the reservoir. Examples are the
see Sect. 12.7.11. COMOD® system and the Freepod® pump system. These
systems are not available for pharmacy preparations.
8.7 Containers and Labelling

8.7.3 Packaging of Nasal Ointments and Gels
8.7.1 Packaging of Nasal Drops
Nasal ointments and gels are supplied in tubes. Eye ointment
Containers for nasal drops usually should protect their con- tubes are often chosen, not only for their application tip, but
tent from light, as many nasal preparations show degradation also because, usually, small quantities are dispensed, for
on exposure to light. Dropper bottles are therefore made of short term treatments (see Sect. 24.4.9).
8.7.4 Labelling and Patient Counselling
Nasal drops should be dispensed in a container with a label

saying “nasal drops” or “for nasal use”. Nasal sprays and
nasal gels and ointments can be labelled as such. When
labels with that specific indication are lacking, the label
should at least make clear that the medicine is not for oral
use. When the container is dispensed in a secondary packag-
ing, this should be labelled also. The label should comply
with the requirements mentioned in Sect. 37.3.
For suspension nasal drops the label should bear the
warning “Shake well before use”. This applies also to the
many licensed suspension nasal sprays that are on the mar-
ket. For these preparations it is important to shake first and
only then start pumping. Doing this in the right order
prevents clogging of the tube of the atomiser. Thixotropic
suspension nasal sprays should be shaken vigorously in
order to transform a thick suspension into liquid as it will
spray only when it becomes liquid.
When dispensing nasal preparations the patient should
receive all relevant information, oral as well as written. Fig. 8.2 Position of the head during the administration of nasal drops.
In using nasal drops, the method of instillation is impor- Source: Recepteerkunde 2009, #KNMP
tant to obtain the required effect [5, 6]. After blowing the
nose nasal drops are usually instilled with the head tilted
period (usually 7 days or more), ‘re-priming (pumping the
forward or backward. A disadvantage of a backward tilted
spray several times) is needed until a fine mist is produced.
head is that the nasal drops will flow across the bottom of the
The number of priming and re-priming actuations is usually
nose to the nasopharynx, and hardly come into contact with
recommended in the labelling.
the mucosa where they are to act. For this reason several
When using a nasal spray, the tip of the atomiser is
different positions of the head have been suggested, but the
brought into each nostril respectively, while pumping once
identification of a single ‘best technique’ appears not to be
and inhaling through the nose. The nozzle of the squeeze
realistic. Lying head back (with the head just off the bed) or
bottle or the pump atomiser should be cleaned by rinsing and
lateral head low (bent down forward and at the same time
wiping, taking care that water is not sucked up.
sideward, see Fig. 8.2) gave slightly better results than head
Patients should be advised that nasal products are for one
bent down forward (so called Moffat position) [53].
patient only and should not be passed around since the risk of
An individual approach seems more appropriate. During
inter patient contamination by nasally administered products
the administration, the drops should be gently inhaled,
is very high.
keeping the other nostril closed. The teat should remain
pressed until it has been removed from the nostril. Rinse
and wipe the dropper after use.
When using a nasal spray, the position of the body is 8.8 Release Control and Quality
much less important. After blowing each nostril, the spray Requirements
can be nebulised with the head in upright position. Plastic
squeeze bottles demand short and firmly squeezing, and Nasal drops and sprays are to be checked before release on
keeping the bottle pressed until it is drawn back. When appearance, packaging and labelling. Solutions should be
using a pump atomiser for the first time, pumping several clear and free from (dust) particles. Suspensions should be
times (‘priming’) is needed, until an even mist is produced. checked on homogeneity and resuspendability.
Priming is needed to displace air that might be present in the Specifications for nasal drops are (see Table 32.2):
dip tube. Only then the desired dose will reach the nose • Identity
[54]. In addition, preparing the spray for use should not • Appearance (clarity, no precipitate, sediment or dust
include shaking it unless specified by the manufacturer, as particles)
this can affect the dose. Patients can also be advised to keep • Content (of active substances)
the bottle upright to reduce the risk of air bubbles getting • pH
into the dip tube. If the spray has not been used for a certain • Microbiological quality
8 Nose 151
• For preparations in single-dose containers: uniformity of chemical, physical or microbiological stability, arbitrarily
mass (solutions) or uniformity of content) a shelf life of 1 month at 25 C (not in a freezer) is
• In some cases: uniformity of dosage units advised (Sect. 22.7.1). For preservative free nasal drops,
Nasal sprays with a declared amount of active substance sprays and hydrophilic nasal gels a shelf life of 2 weeks
for each puff (so called metered-dose sprays), should comply refrigerated (2–8 C) is recommended. In containers with
with the requirements on the variation in this amount. In the special systems COMOD® or Freepod® preserva-
practice, this is only seen in licensed medicines. For tive free preparations the Companies give a shelf life of
solutions the test for uniformity of mass is sufficient. 2–3 years and a beyond-use after opening date of several
Suspensions should comply with the test for uniformity of months.
dosage units (see Sect. 32.7.2.4), or, where justified and
authorised, with the test for uniformity of delivered dose.
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Ear
9
Suzy Dreijer - van der Glas and Monja Gantumur
Contents Abstract
This chapter deals with formulation and preparation of
9.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
ear drops for application to the external auditory canal as
9.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 well as those intended for the middle ear. Creams and
9.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 ointments for the ear are similar to semisolid preparations
9.3.1 Anatomy of the Ear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 for cutaneous use.
9.3.2 Passing the Eardrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
The most used ear drops prepared in pharmacies are
9.4 Ototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 discussed for their formulation (solvent, pH, osmotic
9.5 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 value, preservation), method of preparation, packaging,
9.5.1 Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 storage and methods of administration.
9.5.2 Chemical Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 The formulation of ear drops, especially the choice of
9.5.3 Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
9.5.4 pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
the vehicle, depends on the site of action: the external
9.5.5 Osmotic Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 auditory canal or the middle ear. When ear drops get to
9.5.6 Viscosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 the middle ear, they may come into contact with the inner
9.5.7 Preservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 ear and so cause ototoxicity. Because of the ototoxicity of
9.5.8 Preservatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
9.5.9 Method of Sterilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
active substances, non-aqueous vehicles and many other
excipients, special precautions are needed in formulations
that should, or may accidentally, come into contact with
9.6.1 Non-sterile Ear Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
9.6.2 Sterile Ear Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 the middle ear. Preparations intended for the middle ear
are aqueous, sterile and preferably iso-osmotic. When
9.7 Containers and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.7.1 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 non-aqueous vehicles are used in ear drops for the exter-
9.7.2 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 nal auditory canal, it depends on the state of the patient’s
ear drum whether they will reach the middle ear.
9.9 Storage and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Keywords
9.9.1 Non-sterile Ear Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.9.2 Sterile Ear Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Formulation Preparation Ear drops Ototoxicity
Vehicles
9.10 Administration and Dosage Delivery Devices . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.1 Orientation
Based upon the chapter Oor by Annick Ludwig and Suzy Dreijer in the
2009 edition of Recepteerkunde.
For the treatment of diseases of the external auditory canal
and the auricle non-sterile ear drops or semisolid bases are
S.M. Dreijer - van der Glas (*)
normally used. In the case of ear drops non-aqueous
The Netherlands preparations are preferred, due to the possibility of microbial
e-mail: [email protected] growth in a moist environment caused by aqueous vehicles.
M. Gantumur Therefore in external otitis non-aqueous vehicles are the
Children’s Hospital, University Hospital Center Rijeka, Rijeka, Croatia

154 S.M. Dreijer - van der Glas and M. Gantumur
ones of choice, except for those situations where the skin Table 9.2 Aluminium Acetate Ear Drops, Solution [2]
would be excessively irritated. Aluminium sulfate 22.5 g
Ear drops that have to act in the middle ear have to be Acetic acid (30 %) DAC 25 mL
sterile, aqueous and preferably iso-osmotic. They are applied Calcium carbonate 10 g
to the auditory canal and reach the middle ear via the ear- Tartaric acid 4.5 g
drum, which, in the diseased state, is usually permeable by Water, purified 75 mL
perforation.
The requirements for sterility, aqueous vehicle and
osmotic value also apply to eardrops that are placed directly These bacteria usually originate from the external ear canal
in the middle ear during surgery, and to eardrops that are and contaminate the middle ear [6].
used for the external auditory canal, but can easily reach the For ear drops that are given to reduce pressure in the
middle ear. This is the case for a “clean” perforated eardrum middle ear, as is often the case in inflammations, glycerol
because if not clean the debris will normally block the is used as the solvent, provided the eardrum is not
entrance to the middle ear anyway. Most non-aqueous perforated. A disadvantage of this kind of ear drops is that
solvents and many active substances are ototoxic (see they make it difficult for the physician to clearly view the
Sect. 9.4). Thus the choice of the vehicle depends on the eardrum.
type of treatment and the site of application. For the auditory
canal glycols (such as propylene glycol or glycerol) are There are many different treatments for cleaning the
preferred, provided they do not irritate. Ear drops for the external auditory canal or softening hard plugs of
treatment of infections in the external auditory canal usually earwax. Some of them may be prescribed as a phar-
contain antibiotics or corticosteroids or both, in a macy preparation. These remedies vary from peanut
non-aqueous vehicle. For example eardrops with acetic oil or almond oil (of pharmacopoeia quality, not ordi-
acid and hydrocortisone (Table 9.1) have propylene glycol nary vegetable oil) to solutions of sodium carbonate in
as the solvent. They have the purpose of reducing the mixtures of glycerol and water. There are different
swelling of the auditory canal in acute external otitis. opinions on the best way to soften earwax. Good
In the case of an acute weeping otitis the cooling effect of research on the rationality of the different remedies
water can be advantageous as in eardrops with aluminium is lacking. According to a Cochrane review, it is
acetate and tartrate (Table 9.2). They are applied on a piece uncertain if one type of drop is better than another,
of gauze or an ear tampon, which should be changed at least although the use of any kind of drop is better than no
every 24 h. In the acute phase the ear tampon often is chosen. treatment [7].
The treatment is then continued with acid ear drops com-
bined with a corticosteroid.
In the case of a perforated eardrum propylene glycol
should not be used because of the possible ototoxicity. In
the aqueous ear drops (Table 9.2) the concentration of alu- Theoretically, preparations with a fatty base are the first
minium acetate or acetotartrate may be too high. Therefore a choice in dry external otitis. But because of practical
tenfold dilution is normally used as a matter of precaution. problems in applying ointments and creams in the ear, ear
The antibacterial action of acetic acid in these drops are often preferred. Some guidelines recommend
preparations is due to a specific effect of acetic acid as applying the ear drops, cream or ointment on an ear tampon
well as the lowering of the pH. There are two benefits, that can be placed in the external auditory canal [8].
namely that acetic acid is bactericidal to Pseudomonas In the NRF ear drops with the antimycotic clotrimazol in
aeruginosa, the major pathogen isolated from otorrhoea, peanut oil are included [Table 9.3]. This vehicle could be an
and that it also suppresses several fungi [3–5]. In chronic alternative when propylene glycol would excessively
suppurative otitis media (CSOM), the most common organ- irritate.
ism is P. aeruginosa, followed by Staphylococcus aureus. Chronic as well as acute inflammations of the middle ear
are treated with sterile, aqueous ear drops with antibiotics,
sometimes in combination with a corticosteroid. Normally
Table 9.1 Acetic Acid with Hydrocortisone 1 % Ear Drops, Solution [1] these are short-time treatments. Many medicines of this kind
Hydrocortisone (micronised) 1.0 g are commercially available.
Acetic Acid (30 %) DAC 2.4 g Ear drops have the following advantages and
Propylene glycol 96.6 g disadvantages:
Total 100 g Advantages:
• Simple application
9 Ear 155
Table 9.3 Clotrimazole Ear Drops, Solution 1 % [9] administration device which may be designed to avoid the
Clotrimazole 1g introduction of contaminants.
Arachis oil, refined 99 g Unless otherwise justified, aqueous ear preparations sup-
Total 100 g
plied in multidose containers contain a suitable antimicro-
bial preservative at a suitable concentration, except where
the preparation itself has adequate antimicrobial properties.”
An example of this is Bacicoline B®. These ear drops
• Local application enables much higher tissue
contain a borate buffer, but no preservative. This was
concentrations than would be possible with systemically
accepted by the licensing authorities because borate buffers
administered medicines.
have some antimicrobial properties and because the beyond-
• Low risk of systemic adverse effects.
use date is 10 days after opening.
• Due to the higher tissue concentrations development of
In the monograph Ear Preparations of the Ph. Eur. the
resistance against antibiotics is (at least theoretically) less
following categories are distinguished:
likely [10]
• Ear drops and sprays
Disadvantages:
• Semisolid ear preparations
• Ototoxicity of many active substances, non-aqueous
PRODUCT DESIGN
• Ear powders
vehicles and other excipients.
• Ear washes
• For short term use only.
• Ear tampons
• Risk of contact allergy.
• Assessment of the eardrum may be difficult due to
residues from ear drops.
9.3 Biopharmaceutics
Ear drops are not the only dosage form for treatment of
diseases of the ear. Nose drops with decongestants are used
9.3.1 Anatomy of the Ear
to keep the Eustachian tube open to relieve the pressure and
pain in otitis media, although the effect is not proven. In
Looking from the outside to the inside the ear consists of the
diseases of the middle ear nasal drops can be used
auricle, the external auditory canal, the middle ear and the
For the local administration of medicines in the inner ear
inner ear (Fig. 9.1).
and the cochlea highly sophisticated systems are used, like
The middle ear is connected to the nasal pharynx by the
microcatheters, osmotic and peristaltic pumps. Current
Eustachian tube and to the inner ear via the oval and the
research on repairing patients hearing includes gene therapy,
round window.
administration of neutrophins and stem cells [11, 12].
The inner ear consists of the cochlea and the labyrinth,
organs for hearing and balance respectively, with the eighth
cranial nerve. This nerve has an auditory and a vestibular
9.2 Definitions portion. The inner ear is filled with liquid. When sound
waves strike the eardrum, between the external canal and
The Ph. Eur. states that Ear preparations (Auricularia) are the middle ear, this causes movements of the ear bones
“liquid, semisolid or solid preparations intended for instil- (hammer, anvil and stirrup). These movements are trans-
lation, for spraying, for insufflation, or application to the ferred into vibrations of the liquid in the inner ear, where
auditory canal or as an ear wash. Ear preparations usually the hair cells convert the movements to nerve impulses. The
contain 1 or more active substances in a suitable vehicle. signals are sent to the brain through the auditory nerve.
They may contain excipients to adjust tonicity or viscosity, More information about the anatomy and the physiology
to adjust or stabilise the pH, to increase the solubility of the of the inner ear can be found in [11].
active substances, to stabilise the preparation or to provide
adequate antimicrobial properties. The excipients do not
adversely affect the intended medicinal action of the prepa- 9.3.2 Passing the Eardrum
ration, or, at the concentrations used, cause toxicity or local
irritation. In external otitis, and, less often, for diseases of the middle
Preparations for application to the injured ear, particu- ear, local application of medicines – i.e. in ear drops, may be
larly when the eardrum is perforated, or prior to surgery are necessary. Pharmacokinetic data of substances after admin-
sterile, free from antimicrobial preservatives and supplied in istration to the middle ear have been reported in the
single-dose containers. literature [11].
Ear preparations are supplied in multidose or single-dose Administration of preparations in the external auditory
containers provided, if necessary, with a suitable canal means that (theoretically) there is a chance that some
stirrup
pinna semicircular canals
hammer anvil
vestibular and cochlear nerve
eardrum
cochlea
oval window
round window
Eustachian tube
auditory canal
middle ear inner ear
Fig. 9.1 Anatomy of the ear. Source: Recepteerkunde 2009, #KNMP
substances will pass the eardrum and thus may damage the presence of a tympanostomy tube without inflammation, or
hearing organ. To be ototoxic a substance has to reach the other ailments where the middle ear is accessible, but not
inner ear. To do this from the external canal, first the ear- affected, are examples of this situation. In infections of the
drum has to be passed, and secondly from the middle ear the middle ear the inner ear cannot easily be reached, and
round or oval window. All of these membranes appear to be eardrops may be used. Aqueous preparations are then pre-
more or less permeable for the ingredients of ear drops ferred, and the period of use should preferably not exceed
[13]. Factors affecting permeability include the thickness 10 days.
of the membrane, concentration of the solution, electrical It has been explained (Sect. 9.3.2) that the chance of
charge, and facilitating agents (prostaglandins, leukotrienes, passage of substances to the hearing organ is at the greatest
staphylococcal and streptococcal exotoxins) [14, 15]. when the middle ear is ‘clean and healthy’. Theoretically all
Factors that make the passage more difficult are active substances and excipients that can reach the middle
contaminating substances in the external canal, and a ear and subsequently diffuse into the inner ear may be
swollen mucosa or purulence in the middle ear. ototoxic. There are a few exceptions, like azole antimycotics
Especially in the case of a perforated eardrum that show no ototoxicity [13, 17].
preparations for the external auditory canal could acciden- There is discussion in literature [13, 18] on the serious-
tally reach the middle ear and thus the inner ear. Still, in ness of the ototoxicity of aminoglycosides (e.g. neomycin,
acute situations treatment can be necessary, even when the gentamycin). In clinical practice ototoxicity is seldom seen
condition of the eardrum is not known. Use of ear drops [18], but loss of hearing has been reported [11]. In the
should then be restricted to a couple of days. treatment of some forms of external, otitis, omitting
Preparations intended for the middle ear are aqueous and aminoglycosides may be more harmful than a short term
sterile. They are mostly used in middle ear infections, treatment with this kind of antibiotic, as secretion of puss
because in that condition the drops will be unlikely to may also be ototoxic [18]. Fluoquinolones, mostly consid-
reach the inner ear. ered as a standby medication, are less ototoxic than
aminoglycosides. In some parts of the world (USA,
Australia) ear drops with fluoquinolones are commercially
9.4 Ototoxicity available. Where this is not the case, as in many European
countries, eye drops with ofloxacin or ciprofloxacin are
Ototoxicity may be caused by the active substance, the prescribed for use as ear drops.
excipients or the solvent [11, 13, 16]. The risk of ototoxicity Vehicles such as propylene glycol and macrogol (poly-
as a result of the use of ear drops can be limited by not giving ethylene glycol) not only are ototoxic, but they can also
ear drops when the middle ear (and thus also the inner ear) is enhance the passage of their solutes through membranes.
easily accessible. A traumatic eardrum perforation, the The longer substances are in contact with the middle or
9 Ear 157
inner ear, the greater is the chance of damage. Shortening the 9.5.3 Solvents
period of contact may thus limit the risk.
The choice between an aqueous or non-aqueous solvent has
already been explained in Sect. 9.1. Glycerol, propylene
glycol and macrogol 400 are used as non-aqueous solvents.
Propylene glycol is the most used. It is less hygroscopic than
glycerol and less easily oxidised compared to macrogol 400.
It has preservative properties in concentrations >15 %.
The application of glycerol is based on the hygroscopic
Ear drops are usually solutions of active substances in water
properties. The suggested pharmacotherapeutic action is by
or non-aqueous solvents, depending on the kind of treat-
the lowering of the pressure in the middle ear by dehydra-
ment. Solutions are to be preferred to suspensions, as it is
tion. Glycerol has preservative properties at concentrations
easier to control their homogeneity. In Acetic acid with
>30 %.
hydrocortisone ear drops, solution (Table 9.1) hydrocorti-
Hypromellose 0.5 % is a suitable viscosity enhancer
sone is present as such, so not as the more common hydro-
when a viscous aqueous vehicle is required, for instance in
cortisone acetate, because the acetate is insoluble in
PRODUCT DESIGN
the formulation of a suspension of slightly soluble
propylene glycol. For the same reason of solubility micona-
corticosteroids.
zole base instead of the nitrate is chosen for miconazole ear
drops 2 % in Table 9.4.
When a (water) soluble form of the active substance is
9.5.4 pH
lacking, a suspension has to be prepared.
A change of pH in the external auditory canal can be very
important for the pathogenesis of both acute and chronic
9.5.2 Chemical Stability external otitis [20].
Drops with an acidic pH have the theoretical advantage of
Chemical stability (in general) is discussed in Chap. 22 and restoring the external auditory canal environment to normal
storage in Sect. 9.9.1. For formulation of ear drops it is and may contribute to the treatment of external otitis.
relevant to consider hydrolysis reactions as being likely Aqueous ear drops intended for the middle ear should
with phosphate esters of corticosteroids, such as predniso- have a pH between 6 and 8. However a different pH may be
lone sodium phosphate or dexamethasone sodium phos- needed because of stability, efficacy or tolerability of the
phate. These hydrolysis reactions are catalysed by active substances. When the pH of the vehicle is not 7.4, the
hydrogen ions. Therefore the vehicle should be neutral or buffer capacity should be as low as possible. These
slightly alkaline. Oxidation of dexamethasone sodium phos- requirements are similar to those for eye drops, but they
phate can be prevented by adding disodium edetate, which are more strict, as there is no physiological correction by
binds the catalysing metal ions. tears. Thus, formulations of eye drops are not always suit-
In Acetic acid with hydrocortisone 1 % ear drops, solu- able for the middle ear.
tion (Table 9.1) the acetic acid content decreases by esterifi- Strongly acidic or alkaline solutions may be unpleasant or
cation with propylene glycol. Degradation of hydrocortisone irritate. This applies in the external auditory canal as well, as
occurs by a non-oxidative reaction. Also triamcinolone this is comparable with the skin. The acceptable range for
acetonide shows degradation in the acetic acid –propylene the pH is much broader than for the middle ear however, see
glycol vehicle. For these reasons these ear drops are kept the examples of ear drops with acetic acid or sodium car-
refrigerated and the storage period is limited. When reasons bonate in Sect. 9.1. Again, care should be taken when such
of stability make it necessary to keep ear drops refrigerated, ear drops are used in situations where the middle ear is easily
the solubility of the active substance in the chosen vehicle accessible.
must be sufficient in order to prevent crystallisation at this
storage temperature.
9.5.5 Osmotic Value
Table 9.4 Miconazole Ear Drops, Solution 2 % [19] Ear drops for the middle ear should preferably be
Miconazole 2g iso-osmotic, or at least between the osmotic value of
Propylene glycol 98 g 260 milliosmols and 460 milliosmols (a 0.8 % and a 1.4 %
solution of sodium chloride). Substances used to adjust the
Total 100 g
pH or the osmolarity are the same as those used in eye drops.
These excipients are dealt with in Sect. 10.6.1. To adjust pH penetration of the ear drops into the middle ear. Besides,
boric acid or sodium tetraborate can be used, or dilute the period of use should be restricted to a maximum of
hydrochloric acid or sodium hydroxide solution. The sys- 2 weeks. Taking into account the short period of use and
temic exposure to boric acid by the use of ear drops will not the low concentrations, the risk of possible side effects of
be relevant, because of the low concentration and the short preservatives is considered acceptable. This applies even
period of use [21]. more when the active substances of the ear drops are oto-
toxic themselves. In practice sterile ear drops are packed in
multidose containers, and preserved.
9.5.6 Viscosity
Viscosity is to be considered when using topical agents 9.5.8 Preservatives

[10]. Theoretically, the more viscous a preparation, the
more difficult it will pass through a tympanostomy tube or In aqueous solutions intended for the external auditory canal
a drum perforation and enter the middle ear. A higher vis- or the middle ear, where the active substance has no preser-
cosity could also help to prevent ear drops flowing from the vative properties, the combination of benzalkonium chloride
auditory canal. 0.01 % and disodium edetate 0.1 % is the first choice; the
second choice is methyl parahydroxybenzoate 0.1 %. They
are dealt with in Sect. 23.8. Phenylmercuric salts are not
9.5.7 Preservation used in ear drops anymore, as the use of mercury and its salts
is discouraged for reasons of protection of the environment
Ear drops for the external canal in non-aqueous vehicles and possible toxic effects.
(glycerol, propylene glycol or macrogol) do not need to be
sterile. As the water activity in these solvents is very low, the
addition of a preservative is unnecessary. Water is the sol- 9.5.9 Method of Sterilisation
vent in the ear drops with aluminium acetate or acetotartrate
(Table 9.2). The active substance in this concentration has Aqueous ear drops can be sterilised in the same ways as eye
such strong antimicrobial properties, that the formulation drops (see Sect. 10.7.1). Sterilisation in the (final) container
complies with the test on the efficacy of microbial preserva- for 15 min at 121 C is to be preferred. Preparation in a
tion of the Ph. Eur. without an additional preservative controlled, clean environment combined with a heat treat-
[22]. However in the tenfold diluted ear drops (used if ment of 30 min at 100 C (in streaming steam) is an alterna-
physicians want to avoid the risk of ototoxicity at all) the tive for preserved ear drops, when steam sterilisation is not
preservative properties are insufficient, due to the low con- possible due to instability. In formulations with substances
centration. Therefore the shelf life as well as the usage that cannot tolerate heating at all, aseptic preparation is the
period are much shorter than for the undiluted only possibility left.
preparation [23].
Ear drops that may, or should reach the middle ear are
sterile aqueous solutions, with a preservative added when 9.6 Method of Preparation
they are supplied in multidose containers. The monograph
Ear Preparations of the Ph. Eur. states that ear drops that may 9.6.1 Non-sterile Ear Drops
or should reach the middle ear, should be sterile and free
from antimicrobial preservatives. That sterility is required The active substances and the excipients are dissolved in the
seems clear, as the solvent in ear drops intended for the vehicle (see Sect. 29.5).
middle ear is water, and the middle ear has little defence When glycerol is used as the solvent, care should be taken
because of its low blood flow. When preservatives are not to that it attracts as little moisture as possible, for instance by
be used, such ear drops should be supplied in single-dose working in a closed vessel. For non-sterile ear drops the
containers, unless otherwise justified. following in-process controls are important:
There is little chance that the sterile ear drops that are • Writing down the tare or calibrating utensils in case a
normally used, will actually reach the middle ear. These ear final addition to weight or volume is required
drops are applied for indications where the drops only theo- • Measuring of temperature, for instance during dissolving
retically may reach the middle ear, such as (impending) under heating of thermolabile substances, and after
chronic otitis media with effusion, or when a glue ear cooling down
develops in a patient with grommet. A swollen middle ear • pH in aqueous ear drops
mucosa or a glue ear greatly reduces the chance of • Clarity after each step of dissolution
9 Ear 159
• Homogeneity after mixing of liquids to room temperature (with the hand) before use (see
• Absence of particles in solutions by visual inspection Sect. 9.10).
• Total weight or total volume or the yield
9.6.2 Sterile Ear Drops 9.8 Release Control and Quality

Requirements
For the preparation of sterile ear drops sterilised and pre-
served base solutions for eye drops (for instance those of Ear drops are to be checked before dispensing for appear-
Table 10.9) should preferably be used. When a preservative ance, packaging and labelling.
free preparation is needed, sterilised water is the alternative. Solutions should be clear and free from (dust) particles.
The active substance is dissolved in the eye drop base Suspensions should be checked on homogeneity and
solution or the sterilised water. Details about the preparation resuspendability.
process can be found in Sect. 10.7. Specifications for ear drops are (see Table 32.2):
The in-process controls for sterile ear drops are the same • Identity
as for non-sterile ear drops, with extra controls for the • Appearance (clarity, no precipitate, sediment or dust
PRODUCT DESIGN
microbiological quality. These could be the bubble point particles)
test on filters and parameters of the sterilisation process. • Content (of active substances)
• pH
• Microbiological quality
• Sterility if applicable
And for ear drops in single dose containers:
• Uniformity of content of single-dose preparations or
9.7.1 Containers
• Uniformity of mass of single-dose preparations
According to the Ph. Eur. ear drops are usually supplied in
multidose containers of glass or suitable plastic material that
are fitted with an integral dropper, or with a screw cap of 9.9 Storage and Stability
suitable materials incorporating a dropper and a rubber or
plastic teat. Alternatively, such a cap is supplied separately. Ear drops are best stored at room temperature, provided the
Non-sterile ear drops are dispensed in a bottle of 10 or chemical and microbiological stability permit this. The rea-
20 mL with an integral dropper or with a dropper applicator son is that administration of cold drops may cause dizziness
(see Sects. 24.4.2 and 24.4.19.4). The bottle with screw cap (see Sect. 9.10). Ear preparations should only be stored
and dropper applicator is preferred, because it is easier for refrigerated when this is absolutely necessary.
the patient in measuring the prescribed quantity before
administration.
The requirements for the packaging of sterile ear drops
are the same as for eye drops. That is why they are supplied 9.9.1 Non-sterile Ear Drops
in similar bottles (see Sect. 24.4.2). These may contain at
most 10 mL. Sterile aqueous ear drops may also be supplied For chemically stable ear drops a maximum shelf life of
in a single-dose container. Plastic materials should, prefera- 2 years at 25 C, not refrigerated, is generally considered
bly, be polyolefins, that means, polyethylene (PE) or poly- acceptable (see Sect. 22.7). For standard ear drops that are
propylene (PP) because these are free from harmful not chemically stable, the maximum shelf life is specific and
phthalates. validated, and should be indicated in the relevant monograph
in the formulary. The maximum shelf life is to be used only
for the unopened container. Once opened, the usage period
9.7.2 Labelling for patients may be arbitrarily set at 6 months at 25 C, not
refrigerated, provided that the end of this period is not
Ear drops should be dispensed in a container with a label that beyond the expiry date.
says ‘ear drops’. The same applies to a secondary packaging. Aqueous solutions for the external canal that do not
The label should comply with the requirements mentioned in contain a preservative are an exception. They get a shelf
Sect. 37.3. life of 2 weeks at 2–8 C (refrigerated). An example is
For ear drops that are kept refrigerated by the patient, the tenfold diluted Aluminium-acetate or -acetotartrate ear
label should mention a warning to warm the drops to at least drops (see also Sect. 9.5.7).
9.9.2 Sterile Ear Drops auditory canal. Ear drops are used for 2–5 days, depending
on how serious is the disease. For antimycotic drops a longer
Sterile ear drops may also have a shelf life of 2 years (see treatment may be needed. Sometimes the advice is to con-
Sect. 22.7), but only if they have been sterilised by steam tinue use for 3 days after disappearance of the symptoms.
sterilisation (15 min at 121 C). Ear drops that are only In external otitis the physician can reduce the swelling in
subjected to a heat treatment at 100 C are best stored the external canal by placing an ear tampon or a gauze,
refrigerated (2–8 C), and for aseptically prepared ear which is drenched in aqueous Aluminium acetate or
drops an additional security against any microbial growth -acetotartrate ear drops or Acetic acid ear drops
may be obtained by freezing at least 15 C, for a maximum (in propylene glycol) with a corticosteroid (Tables 9.2 and
of 6 months, provided the closure/container security at this 9.1). The gauze or tampon should be kept moist by repeated
temperature has been suitably validated. instillation of the ear drops 6–8 times a day. For aqueous
Ear drops that have been stored in a freezer should be Aluminium acetate or -acetotartrate ear drops application on
swirled until clear during thawing. a tampon or gauze is absolutely necessary, because other-
For sterile aqueous preserved ear drops the usage period wise crystals can be formed on the eardrum. When the ear
is set at maximum 1 month after opening. tampon has been removed, mostly after 24 h, the patient has
For preservative free preparations intended for the middle to continue treatment with non-aqueous Acetic acid ear
ear the in-use expiry date is 24 h after opening; possibly drops (often with a corticosteroid).
longer if the solution is known to have preservative
properties. An example is Bacicoline B® (see Sect. 9.2).
For preparations with uncertain or unknown chemical or References
physical stability, arbitrarily a shelf life of 1 month at
25 C, not refrigerated, is advised. For preparations liable 1. Zure oordruppels met hydrocortison 1 % FNA. Jaar 2009.
to degradation a shorter period and refrigeration may be Formularium der Nederlandse Apothekers. Den Haag: Koninklijke
necessary. See Sect. 22.7 for more information. 2. Aluminium Acetate Ear Drops. British Pharmacopoeia 2014. The
As many preparations will show degradation under the Stationary Office, London
influence of (day) light, most ear drops should be kept away 3. Thorp MA, Kruger J, Oliver S, Nilssen EL, Prescott CA (1998) The
from light. In some cases the protection against light by a antibacterial acidity of acetic acid and Burow’s solution as topical
otological preparations. J Laryngol Otol 112:925–928
brown bottle will not be enough, for instance for 4. Goycoolea MV, Jung TK (1991) Complications of suppurative
chloramphenicol. otitis media. In: Paparella MM, Shumrick DA, Gluckman JL,
Meyerhoff WL (eds) Otolaryngology, vol 2. WB Saunders,
Philadelphia, pp 1381–1403
The stability of some ear drops may be such that they 5. Glassman JM, Pillar J, Soyka JP (1978) Otitis external: comparative
have a more practical shelf life when stored in vitro sensitivities of clinical isolates of bacteria and fungi to
refrigerated than at 25 C. So the pharmacy stock nonantibiotic and antibiotic otic preparations. Curr Ther Res Clin
Exp 23:S29–S38
will be refrigerated and that will be indicated on the 6. Brook I, Finegold SM (1979) Bacteriology of chronic otitis media.
label. It is preferable for the patient to store such ear JAMA 241:487–488
drops at room temperature, as the period of use will 7. Burton MJ, Doree C (2009) Ear drops for the removal of ear wax.
normally be much shorter than the shelf life. This must Cochrane database of systematic reviews issue 1. Art. No.:
CD004326. DOI: 10.1002/14651858.CD004326.pub2. Accessed
be remembered when dispensing the ear drops, so the 15 Mar 2013
patient label will not mention the warning “keep 8. Farmacotherapeutisch Kompas. Aandoeningen van de uitwendige
refrigerated”. gehoorgang www.fk.cvz.nl. Accessed 15 Mar 2013
9. Ölige Clotrimazol-Ohrentropfen 1% NRF 16.4. Fassung 2010.
Neues Rezeptur-Formularium. GOVI-Verlag Pharmazeutischer
Verlag GMBH, Eschborn. Deutscher Apotheker-Verlag, Stuttgart
10. Dohar J (2004) Eardrops for Otorrhoea. In: Alper CM, Bluestone C,
9.10 Administration and Dosage Delivery Dohar JE, Mandel EM, Casselbrant ML (eds) Advanced therapy of
Devices otitis media. BC Decker Publications, Hamilton, pp 246–253
11. Swan EEL, Mescher MJ, Sewell WF, Toa SL, Borenstein JT (2008)
Inner ear drug delivery for auditory applications. Adv Drug Deliv
Ear drops should be slightly warmed in the hand before Rev 60:1583–1599
administration, to avoid dizziness after instillation of a cold 12. Richardson RT, Wise AK, Andrew JK, O’Leary SJ (2008) Novel
liquid. Dizziness can develop as a result of a thermic effect drug delivery systems for inner ear protection and regeneration
after hearing loss. Expert Opin Drug Deliv 5:1059–1076
on the organ of balance. 13. Haynes DS, Rutka J, Hawke M, Roland PS (2007) Ototoxicity of
The patient should lie down after the administration, with ototopical drops – an update. Otolaryngol Clin North Am
the treated ear upside, to make the drops go down the 40:669–683
9 Ear 161
14. Goycoolea MV (2001) Clinical aspects of round window perme- 19. Miconazol oordruppels 2% FNA. Jaar 2009. Formularium der
ability under normal and pathological conditions. Acta Otolaryngol Nederlandse Apothekers. Den Haag: Koninklijke Nederlandse
(Stockh) 121:437–447 Maatschappij ter bevordering der Pharmacie (KNMP)
15. Goycoolea MV, Muchow D, Schachern PA (1988) Experimental 20. Kim JK, Cho JH (2009) Change of external auditory canal pH in
studies on round window membrane structure function and perme- acute otitis externa. Ann Otol Rhinol Laryngol 118(11):769–772
ability. Laryngoscope 98(Suppl. 44):1–20 21. Horikx A (2005) Boorzuur in oogdruppels ook beneden 3 jaar.
16. Guthrie OW (2008) Aminoglycoside induced toxicity. Toxicology Pharm Weekbl 140:82
249:91–96 22. Aluminiumacetotartraatoordruppels 12% FNA. Jaar 2009.
17. Munguia R, Daniel SJ (2008) Ototopical antifungals and Formularium der Nederlandse Apothekers. Den Haag: Koninklijke
otomycosis: a review. Int J Pediatr Otorhinolaryngol 72:453–459 Nederlandse Maatschappij ter bevordering der Pharmacie (KNMP)
18. Van der Hulst RJAM (2001) Ototoxiciteit van oordruppels. 23. Aluminiumacetotartraatoordruppels 1,2% FNA. Jaar 2009.
Het standpunt van de KNO-vereniging. Pharm Weekbl Formularium der Nederlandse Apothekers. Den Haag: Koninklijke
136:495–497 Nederlandse Maatschappij ter bevordering der Pharmacie (KNMP)
PRODUCT DESIGN
Eye
10
Annick Ludwig and Holger Reimann
Contents Abstract
In this chapter several aspects of ocular dosage forms are
10.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
discussed with emphasis on eye drops, eye lotions and
10.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 eye ointments prepared in pharmacies. Their formulation,
10.3 Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 method of preparation, packaging, storage and methods
10.3.1 Structure of the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 of administration are also discussed.
10.3.2 Tear Film and Lachrymal Secretion . . . . . . . . . . . . . . . . . . . . . 166
The availability of medicines in ocular dosage forms is
10.4 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 low due to the efficient barrier function of the cornea,
10.4.1 Lipophilicity and Ionisation of Active Substance . . . . . . . 168 lachrymation, tear turn over and drainage. Formulations
10.4.2 Active Substance Concentration, Drop Size, Surface
Tension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 should take into account these constraints. The vehicle
10.4.3 Dilution and Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 and excipients selected should improve the permeation of
10.4.4 Viscosity of the Tear Film . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 the active substances in the eye or the residence in the
10.4.5 pH Value and Buffer Capacity of the Solution . . . . . . . . . . 169
conjunctival sac and consequently the therapeutic effects,
10.4.6 Osmotic Value of the Preparation . . . . . . . . . . . . . . . . . . . . . . . 169
but also minimise irritation. Tolerance of the preparation
10.5 Adverse Effects and Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 is of utmost importance.
10.6 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 When formulating aqueous ophthalmic preparations
10.6.1 Eye Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 attention should be given to osmolality, pH, solubility,
10.6.2 Eye Lotions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
chemical interactions, stability of the active substance,
10.6.3 Eye Ointments and Eye Creams . . . . . . . . . . . . . . . . . . . . . . . . . 177
together with viscosity and the choice of a preservative.
10.7 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Sterility is of critical importance and therefore the most
10.7.1 Eye Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
10.7.2 Eye Lotions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 appropriate sterilisation method must be chosen.
10.7.3 Eye Ointments and Eye Creams . . . . . . . . . . . . . . . . . . . . . . . . . 182 Besides pharmaceutical factors, the correct adminis-
10.8 Release Control and Quality Requirements . . . . . . . . . . 183
tration of the eye drops is an important factor. Therefore,
clear instructions to the patients about eye drop instilla-
10.9 Administration of Ophthalmic Preparations . . . . . . . . . 183
tion and correct storage of the medicine is essential. It
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 will add to the success of pharmaceutical care and patient
compliance.
Keywords
Eye Eye drops Eye ointment Eye lotion Eye cream
Based upon the chapter Oog by Adriaan van Sorge en Annick Ludwig Formulation Preparation Tear film
in the 2009 edition of Recepteerkunde. Biopharmaceutics Osmotic value Lachrymal secretion

A. Ludwig (*)
Department of Pharmaceutical Sciences, University of Antwerp,
Antwerp, Belgium
H. Reimann
Laboratories DAC/NRF, Govi-Verlag Pharmazeutischer Verlag,
Eschborn, Germany

164 A. Ludwig and H. Reimann
In order to improve bioavailability, active substance

10.1 Orientation targeting and patient compliance new dosage forms with
controlled release have been developed: colloidal carriers,
Eye medication is intended for local use on or into the eye. implants, inserts, plugs, active substance eluting contact
Eye drops and semisolid preparations are usually applied lenses and iontophoresis [3–6].
topically, in the lower conjunctival sac. Absorption of active In community pharmacies contact lens solutions are
substances into the ocular blood vessels and also into the delivered to customers as medical devices. It is noteworthy
systemic circulation occurs at the conjunctiva and nasal to mention that many contact lens wearers do not clean their
mucosae. Due to absorption, systemic side effects could lenses properly. The careless use of their lenses can result in
appear after instillation. eye infections. During application of medicated eye
After permeation through the cornea, active substances preparations contact lenses should not be worn.
reach the anterior chamber and afterwards the posterior In some countries eye preparations are prepared in
chamber and vitreous. With cases of external infections pharmacies for the special needs of animals. E.g. some
absorption should not happen, because the active substance breeds of dogs frequently suffer from dry eyes or vascular
needs to be present in therapeutic concentrations at the keratitis. Formulas for veterinary use generally do not differ
cornea and conjunctiva. An example of a targeted local eye from those designated for human use.
preparation are erodible inserts, the active substances diffuse
slowly from the matrix at the ocular surface.
Some ocular diseases require specific treatment given via 10.2 Definitions
intravitreal or periocular injection into the eye.
The sensitivity of the eye requires that the formulation The description of eye preparations to be used as medicinal
and sterility of ocular medication are of critical importance. products is similar in the European, British, Japanese and
An inappropriate formulation can cause irritation or disrup- US-American Pharmacopoeias. Several categories may be
tion of the mechanisms responsible for the protection of the distinguished:
eye. Contaminated ophthalmic preparations could, espe- • Eye drops
cially in the case of an injured eye, cause infections or • Eye lotions
exacerbate the infection. • Powders for eye drops and powders for eye lotions
The preferred route of administration depends on the • Semisolid eye preparations (ointments, creams and gels)
location of the disease (Table 10.1; [1, 2]). • Ophthalmic inserts
Eye preparations are also employed for diagnostic pur- Eye drops are sterile aqueous or oily solutions, emulsions
pose or in connexion with surgery. Combinations of fluores- or suspensions of one or more active substances intended for
cein with oxybuprocaine, proxymethacaine or lidocaine are administration upon the eyeball or instillation into the
applied for the measurement of intra-ocular pressure with conjunctival sac.
tonometry, diagnosis of corneal defects and choice of size Eye lotions are sterile aqueous solutions intended for use
and control of hard contact lenses. Strips with fluorescein are in rinsing or bathing the eye or for impregnating eye
used to examine the integrity of the tear film. In some dressings in order to cover the eye.
countries they are considered medical devices. Sodium Semisolid eye preparations are sterile ointments, creams
hyaluronate eye drops, other eye drops which relieve the or gels intended for application to the conjunctiva or to the
symptoms of dry eyes by increasing the viscosity of the eyelids. They contain one or more active substances
tear film or eye preparations in the context of contact lenses dissolved or dispersed in a suitable base. They have a homo-
are generally regarded as medical devices. geneous appearance.
Table 10.1 Location and preferred routes of administration

Location Route of administration
Conjunctiva External
Cornea External
Internal eye Intravitreal Subconjunctival External
Intracameral
Eyelids External
Orbita Oral Parenteral Retrobulbar
Retina Intravitreal Oral Parenteral
Lachrymal apparatus Oral Parenteral External
10 Eye 165
Fig. 10.1 Schematic conjunctiva

representation the human eye and
the structure of the cornea [77] vitreous body
sclera
anterior
chamber choroid
(chorioidea)
tear film
retina
cornea
lens
iris posterior
chamber
PRODUCT DESIGN
Meibomian corneal
gland endothelium
tear film Bowman’s Descemet’s

membrane membrane
corneal stroma
epithelium
Ophthalmic inserts are sterile, solid or semisolid with immunological and antimicrobial properties of the
preparations of suitable size and shape, designed to be lachrymal fluid [5, 7–10].
inserted in the conjunctival sac, to produce an ocular effect.
They generally consist of a reservoir of active substances
embedded in a matrix or bounded by a rate-controlling 10.3.1 Structure of the Eye
membrane. The active substance, which is more or less
soluble in the lachrymal liquid, is released over a determined Figure 10.1 shows schematically the structure of the human
period of time. Ophthalmic inserts are individually eye. In detail the structure of the cornea is given. The cornea
distributed into sterile containers. separates the aqueous humour from the lachrymal fluid and
These pharmacopoeial general monographs on eye protects the delicate internal structures of the eye from exter-
preparations do not comprise parenteral preparations to be nal influences. The cornea is a clear, avascular tissue to which
administered in the eye. nutrients and oxygen are supplied by the lachrymal fluid and
the aqueous humour. It is composed of five layers: a lipophilic
multilayered epithelium, Bowman’s membrane, a hydrophilic
stroma, Descemet’s membrane and a lipophilic endothelium.
10.3 Anatomy and Physiology The epithelial cells are closely packed together like a
pavement, forming not only an effective barrier to most
Anatomical characteristics and physiological mechanisms micro-organisms, but also for active substance absorption.
protect the eye against toxic external effects. These The low permeability of the cornea is due to the presence of
mechanisms include the specific structure of the cornea, tight junctions between the epithelial cells. The superficial
blinking, baseline and reflex lachrymation, drainage, tear corneal epithelial cells are exfoliated from the ocular sur-
film composition and the corneal sensitivity. The combina- face, their average life is 4–8 days.
tion of all mechanistic, anatomical and physiological The cornea is highly innervated with sensory nerves,
characteristics maintains the integrity of the eye, together which serves important sensory and reflex functions.
The eyeball has a wall consisting of three layers: the outer 10.3.2 Tear Film and Lachrymal Secretion
coat or the sclera and cornea, a middle layer or uveal coat
and the inner coat or retina. The lachrymal glands secrete lachrymal fluid, which spreads
The cornea has no blood vessels and the sclera only a few, on the exposed part of the eye forming the precorneal tear
consequently the supply of immunoglobulins to these tissues film. An intact film protects the ocular surface from desicca-
is limited. Therefore the treatment of infections is difficult. tion. The tear film results from the lachrymal functional unit
The conjunctiva is a thin transparent membrane, which [8] which consists of the:
lines the inner surface of the eyelids and is reflected onto the • Lachrymal glands
globe. The conjunctiva consists of three parts: bulbar on the • Ocular surface
eye surface (sclera), fornix or conjunctival sac and palpebral • Sensory nerves involved
on the inner side of the eyelids. The bulbar conjunctiva lies The tear film is a mixture of several excretion products:
upon the sclera and only attaches to the sclera on the limbus. • Aqueous fluid (95 % of water, salts, glucose, urea,
The structure resembles a palisade and is more permeable proteins) secreted by the lachrymal glands
than the cornea. • Soluble mucins produced by the goblet cells present in
the conjunctiva
• Lipids from the Meibomian glands embedded in the tarsal
The high corneal sensitivity is due to the specific plate of the eyelids
innervation of the eye. The corneal surface possesses The lipid composition is kept within physiological limits by
the highest nerve density of all organs in the human androgens [17]. The decrease of their secretion in elderly
body: about circa 7,000 nociceptors per mm2. The people is one of the reasons for development of dry eye
nerve endings are located only one layer below the syndrome. Patients with Meibomian gland dysfunction
corneal surface. Consequently they are very sensitive show a high tear film evaporation rate and a high tear
and active substances elicit reflex blinking. Three osmolality [18, 19].
types of stimuli are responsible for pain perception:
mechanical, physico-chemical and temperature gradi-
ent dependent. The distribution of the various kinds of The structure of the tear film
nerves and receptor is functional heterogeneous: 20 % According to the “three layers theory” the tear film
mechanical, 70 % physico-chemical and 10 % tem- consists of a superficial lipid layer, the central aqueous
perature (cold) sensitive. The sensitivity of the cornea layer and an inner mucus layer.
and conjunctiva seems to be dependent on the colour No clear separation exists between the aqueous
of the iris, age and gender [11, 12]. Pathophysiological layer and the mucus layer because mucins are
processes, long term use of ocular medication could dissolved in the aqueous layer (see Fig. 10.2).
influence the corneal sensitivity [13, 14]. To maintain the integrity of the tear film is of
The high corneal sensitivity serves to protect the utmost importance during the administration of eye
eye. Reducing pain perception is dangerous. Patients drops. The role of the glycocalyx is essential. The
should be warned of the danger of anaesthesia glycocalyx consists of anionic membrane-spanning
dolorosa due to repeatedly instillation of local or membrane-associated mucins secreted by corneal
anaesthetic eye drops. Welding without protection or and conjunctival epithelial cells [20, 21]. Due to its
snow blindness due to excessive exposure to UV light moisture binding characteristics it stabilises the tear
can cause photoelectrical keratitis, which is a very film (see Fig. 10.2). Moreover the superficial lipid
painful condition [15]. Administration of local layer prevents evaporation of the central viscous aque-
anaesthetics will be recommended. It is true that ous layer.
local anaesthetics reduce corneal sensitivity but they
delay the renewal of corneal epithelium layers with About 1.2 microlitres of lachrymal fluid is secreted per
nerve endings. Repeated instillations of anaesthetics minute. The functions of the lachrymal fluid are:
result in the duration of action being shortened • Improvement or maintenance of the optical quality of
resulting in pain breakthrough and are responsible for vision (homeostasis)
the serious condition where the stroma melts away • Lubrication of the eyeball
[16]. Therefore, local anaesthetics should only be • Elimination of foreign bodies
delivered in single-dose containers and their use • Supply of nutrition to the ocular surface
should be limited. • Defence against infection (viral and bacterial)
• Oxygen transport to the avascular corneal epithelium
10 Eye 167
superficial 10.3.2.1 Tear Film Stability

lipid layer
The tear film is only temporarily stable. The time period of
aqueous layer
stability of an intact tear film is named the tear film break up
time (TFBUT) [28]. TFBUT is measured using fluorometry
[29]. Tear film stability is reduced by tensioactive
preservatives, which solubilise the superficial lipid layer.
The example is the preservative benzalkonium chloride.
mucus layer
Reduction of stability causes an increase in blinking fre-
quency [30]. The tear film breaks up after 10–20 s and dry
spots form on the corneal surface (dewetting of the cornea).
epithelium These dry spots irritate the corneal nerve endings and acti-
with associated vate the lachrymal functional unit, which triggers the blink
glycocalyx reflex. During eyelid opening a new protective film spreads
over the ocular surface. Patients suffering from dry eye
syndrome exhibit formation of dry spots even when eye
PRODUCT DESIGN
drops without benzalkonium chloride are instilled. The
reduced film stability can be due to lower lipid-, tear- or
conjunctival epithelium corneal epithelium
(goblet cells and (microvilli and membrane mucin production [31].
secreted mucus) associated mucus)
Fig. 10.2 Schematic representation of the tear film structure [77] Improvement of the Diagnosis of Dry Eye
Syndrome
The Ocular Protection Index (OPI) was proposed to
The secreted lachrymal fluid is spread over the ocular
get a better insight into the uncomfortable condition,
surface by the eyelids (precorneal tear film) and distributed
dry eye syndrome [32]. To obtain an optimal hydration
to the conjunctival sac during blinking. Meanwhile the tears
of the corneal epithelium the ratio between the time
are swept to the medial canthus and drained through puncta,
period of an intact tear film and the time between two
canaliculi, lachrymal sac and nasolachrymal duct which
reflex blinks must be greater or equal to 1 (OPI 1).
opens into the inferior nasal passage. The volume of the
Investigation of tear film stability using sodium fluo-
precorneal tear film amounts to about 7 microlitres. The
rescein improves the diagnosis of dry eye syndrome
conjunctival sac can accommodate about 30 microlitres,
when 1–5 microlitres solution is used instead of larger
but in some persons only 20 microlitres or even less
volumes [33]. As a result the certainty of diagnosis is
[22]. The tear film evaporates at a rate of 6–12 microlitres
increased. However, the use of small drop volumes has
per hour [23].
not yet been introduced, as this technique is insuffi-
ciently developed.
Immunological and Antibacterial Mechanisms
of the Eye
The ocular surface is the domain of the mucosa-
bonded immune system [24]. This system plays an
important role in combating infections by killing
micro-organisms. It consists of the lachrymal gland, Improvement of Tear Film Stability
conjunctiva and related structures. Besides immuno- Patients suffering from dry eye syndrome complain
globulins, enzymes and bactericidal components are about tear film instability. Stability can be improved
present: IgA, lysozyme, lactoferrin, lipocalins, by increasing the viscosity of the tear film (see also
cathelicidine and probably beta-defensins [25]. Sect. 10.4.4) [34]. Viscoelastic polymers increase vis-
Lipocalin is considered the most important component cosity but also possess elastic properties. During
in eliminating toxic (phospho)lipids and fatty acids blinking sodium hyaluronate (Na-HA) exhibits a kind
from the ocular surface [26]. Elimination is necessary, of cushioning action and induces improved protection
otherwise only partial hydration of the corneal epithe- of the ocular surface compared to classical
lium will occur, which could result in ulceration [27]. pseudoplastic viscosity enhancing polymers.
(continued)
R-NH+ R-N+H+ lachrymal fluid

Consequently the movement of the eyelids during
epithelium
blinking is smoother. Na-HA is effective in providing
relief to dry eyes. R-NH+ R-N+H+
Other viscosity enhancing polymers are natural
stroma
anionic polysaccharides such as gellan gum (E-418)
and xanthan gum (E-415). These macromolecules are R-NH+ R-N+H+
used as gelling agents. Artificial tears may contain endothelium
dextran, hypromellose and carbomer sometimes with
R-NH+ R-N+H+ aqueous humour
or without polyvinylalcohol and povidone. Unfortu-
nately the ideal non crust forming and stability Fig. 10.3 Transport of dissociated active substances through the cor-
improving gelling agent has not yet been developed. nea. Source: Recepteerkunde 2009, #KNMP
It seems that hydroxypropyl-guar possess more spe-
cific adhesive properties to injured ocular surfaces
[35–37]. The degree of lipophilicity and ionisation of the active
substance determines the extent of corneal permeation.
Many examples are reported in the literature [41, 42].
However, recent research proved the presence of a num-
10.4 Biopharmaceutics
ber of transporters in the cornea and conjunctiva such as
amino acid/peptide, nucleoside, organic anionic and organic
After administration active substances should reach their
cationic. These systems will influence the absorption of
target tissue. Therefore eye drops should fulfil certain
active molecules. Moreover active substance efflux pumps
requirements. The following properties are important:
at the cell surface could restrict active substance penetration
• The lipophilicity of the active pharmaceutical ingredient
into ocular tissues [5].
(active substance)
• Active substance concentration
• Dilution by the lachrymal fluid and drainage
• Viscosity of the tear film 10.4.2 Active Substance Concentration,
• pH value and buffer capacity of the preparation Drop Size, Surface Tension
• Osmotic value of the preparation
First the absorption of the active substances through the The amount of active substance applied to the eye depends
cornea is discussed and afterwards how the previously men- not only on the concentration but also on the drop size,
tioned factors will influence the absorption. which is influenced by the surface tension of the solution.
The design, dimensions of the dropper tip, the cross-
sectional surface area on which the drop is formed and the
dispensing angle at which the patient manipulates the bottle
10.4.1 Lipophilicity and Ionisation of Active
influence the drop volume instilled [43].
Substance
As shown in Fig. 10.2 the cornea consists of various layers.

The permeation of the active substances occurs transcellular Drop size Variation
or paracellular. Lipophilic, non-ionised molecules will dif- Research performed in the eighties in the USA showed
fuse via the transcellular pathway, while ionised, hydrophilic that most dropper containers delivered drop volumes
molecules pass through the paracellular space (tight between 25 and 75 microlitres [44]. A similar study
junctions). The pore size at the corneal surface is about performed about 10 years later demonstrated that drop
6 nm (60 Å). The lipophilic epithelium prevents the passage volume of products on the market had decreased
of 90 % of the hydrophilic active substance dose, but only [45]. This trend will continue as production techniques
10 % in the case of a lipophilic active substance [38]. Most of dropper tips became more precise.
ophthalmic active substances are salts of weak bases, which
are completely dissociated at a low pH value. The contrary is
true in the case of most NSAIDs. The permeation of pilocar- Active substances such as antazoline and tetracaine
pine [39] and some mydriatics [40] is higher when the reduce the surface tension. Eye drops with a surface tension
molecule is not dissociated, resulting in a higher therapeutic below 35 mN/m (normal surface tension of lachrymal fluid is
effect compared to the protonated molecule (see Fig. 10.3). 40–46 mN/m) are painful and uncomfortable [30].
10 Eye 169
10.4.3 Dilution and Drainage increase residence time in the eye but are generally less
successful. The use of viscous ophthalmic gels is under
The maximum volume of solution the lower conjunctival discussion. Xerogel forming polymers such as cellulose
sac can accommodate is about 30 microlitres. After instil- derivatives are in theory able to block for example puncta
lation the normal volume of the precorneal tear film on the eyelids and canaliculi when used in high concentra-
(7–10 microlitres) is established again due to drainage of tion and after desiccation. Carbomer, which does not form
the extra volume of fluid present. The drainage rate is xerogels, used in the concentration 2 mg/mL, improves the
directly proportional to the volume of ophthalmic solution availability and the prolonged activity of some active
instilled. A high percentage of hydrophilic active substances substances. No blurred vision was reported [51].
are eliminated and lost to the eye. The drained active sub-
stance reaches, via the nasolachrymal duct, the nasal
mucosae and after absorption enters the systemic circulation.
10.4.5 pH Value and Buffer Capacity
As lipophilic substances are absorbed much more rapidly,
of the Solution
these systemic effects are less prominent.
If the decision is taken to administer very small volumes
The pH value of the lachrymal fluid is about 7.4. Due to
PRODUCT DESIGN
(1–10 microlitres) of concentrated active substance solutions
evaporation of CO2 from the tear film when the eyes are
in order to compensate for dilution in the tear film, irritation
open, the pH value increases to 8 and even higher values
becomes a problem. Consequently excessive lachrymation,
[52]. Three buffer systems are present in tear fluid:
drainage and wash out will occur, resulting in low active
bicarbonate-carbonate, mono-dibasic phosphate and ampho-
substance availability. To avoid irritation the surface ten-
teric proteins; the buffer capacity is low [53]. The acid-
sion, osmolality, pH and buffer capacity should be within
neutralising capacity of the tear fluid of one eye is equal to
certain limits (see Sects. 10.4.5 and 10.4.6).
about 8–10 microlitres 0.01 M NaOH.
Tolerance and availability of ophthalmic preparations are
The pH value influences the active substance availability
closely related [46]. The condition being treated can also
from an ophthalmic preparation in two ways:
play a role: i.e. the drainage rate in Sjögren’s patients is
• A pH value outside the physiological range causes extra
slower than in healthy people [47].
lachrymation and reduces the residence time of the active
Administration of more than one eye drop makes no
substance on the ocular surface.
sense. The second drop or a drop of double volume will be
• The pH value influences the permeation of the active
drained almost immediately. The availability could only be
substance through the cornea (see Sect. 10.4.1).
improved by lengthen the residence time of the preparation
Solutions with pH values below 5.0 and above 8.5 are
in the lower conjunctival sac. Closing the puncta by applying
uncomfortable and not well tolerated [54]. The intensity and
pressure with the thumb or fingers, but also closing the
the duration of pain sensation after instillation are related to
eyelids for approximately three minutes, increases the resi-
the acidity (pH) and buffer capacity of the eye drop.
dence time and decreases the drainage of the ophthalmic
solution to the nasal mucosae [48].
Animal experiments evaluating drop size and percentage
of drained active substance demonstrated that after instillation 10.4.6 Osmotic Value of the Preparation
of a 50 microlitres solution more than 50 % was lost [49].
When three drops of flurbiprofen (0.3 mg/mL) were instilled Eye drops should be in principal iso-osmotic with lachrymal
in rabbits, one drop every 30 min, a 2–3 times higher concen- fluid, which means the NaCl concentration 9 mg/mL or
tration was measured only in the corneal tissues [50]. approximately 0,9 % (280 mosmol/L). This value
corresponds to the tear fluid of patients suffering from con-
junctivitis. In healthy persons the osmolarity of the lachry-
10.4.4 Viscosity of the Tear Film mal fluid equals 290–310 mosmol/L, but varies during the
day [55]. Tears of keratoconjunctivitis sicca and Sjögren’s
To improve the therapeutic effect of a medicine, one should patients show higher values (343 mosmol/L) [56]. Therefore
try to increase the absorption of the active substance. Eye these patients welcome hypotonic eye drops [57].
ointments and eye creams stay much longer in the conjunc- Almost no pain sensation occurs within the range
tival sac and on the ocular surface than eye drops. Conse- 0.5–2 % NaCl [58]. Strong hypo-osmotic solutions could
quently the active substance is delivered during a longer damage the corneal epithelium. This should not happen
period of time to the eye. Ointments or creams could be during normal application of eye drops, because one minute
considered as prolonged release dosage forms (depot after instillation of distilled water the baseline osmolarity of
preparations) for ophthalmic use. Viscous eye drops can the tear film is restored.
After administration of eye drops, chloramphenicol

10.5 Adverse Effects and Toxicity appeared to disappear very rapidly from the tear film and
aqueous humour contrary to the prolonged concentration
The irritating properties of substances have been after administration of the ointment [64, 65].
investigated using the Draize irritating test on rabbit eyes
[59]. This method was used to test many different substances
and resulted in serious consequences for the rabbit eye.
Nowadays the test is performed according to contemporary 10.6 Product Formulation
acceptable procedures. The redness and its rate of develop-
ment are an indication of the irritating potential of the A reliable source of information concerning this section can
substance examined. No satisfactory alternative method is be found under “Codex der Augenarzneistoffe und
available. Caution should be taken regarding interpretation Hilfsstoffe” published in Ophthalmika [66]. The pharmaceu-
of the observations collected. For example the frequency of tical, physico-chemical and pharmacological properties of
(reflex) blinking influences the results obtained after appli- many active substances used for the preparation of eye drops
cation of ophthalmic preparations. The frequency differs are described.
between rabbit and human being. The rabbit blinks about Initially the formulation of eye drops will be discussed
every 20 min, while humans every 10 s. This difference in followed by eye lotions, eye ointments and eye creams.
blinking frequency is relevant during investigation of vis-
cous solutions.
Alternative in vitro or ex vivo methods have been 10.6.1 Eye Drops
developed and validated for assessing ocular irritation
[60, 61]. 10.6.1.1 Choice of Active Substance
Ophthalmic preparations should not contain substances, A soluble active substance is preferred when eye drops are
which could mechanically injure the eye during the blinking being formulated. When the active substance prescribed is
of the eyelids (see also Sect. 10.8). The cornea is extremely not (or not sufficiently) aqueous soluble, a suspension will
sensitive to solid particles especially when larger than be prepared.
50 μm. Particles of 20–25 μm could, depending on their Active substances employed in suspension eye drops are
shape, irritate the eye. Due to the induced lachrymation the usually micronised. Polysorbate 80 or 20 may be used for
active substance will be washed away rapidly. wetting of the powdered active substances.
Even if eye drops are applied topically, undesirable sys- Hydrocortisone eye drops (see Table 18.12) is an exam-
temic side effects could occur after absorption [43, 62]. The ple of a suspension formulation, where micronised raw
effects could be dangerous to life. Administration of scopol- material is used. Povidone is used mainly as wetting
amine eye drops in children resulted in a toxic coma [63]. A agent for an effective dispersion of the hydrocortisone
substantial amount of active substance administered is acetate. This improves the settling behaviour (see also
drained through the nasolachrymal tube, reaches the nasal Sect. 18.4.2.2).
mucosae and will be absorbed in the systemic circulation. Precipitation or opalescence could occur when the con-
The correct instillation of eye drops reduces the risk of centration of one of the formulation components is near to
drainage to the nose but this cannot be completely its limit of solubility or due to an incompatibility between
eliminated. The correct methodology for instilling eye two formulation components. The appropriate choice of
drops will be discussed under Sect. 10.9. excipients can solve these problems. For example, the
A special mention concerns the use of chloramphenicol in addition of citrate to an eye lotion containing zinc
ointment and eye drops, see also Sect. 22.2.4. Chloramphen- sulphate prevents precipitation of zinc hydroxide (see
icol is degraded by light. During preparation and storage the Table 10.2).
degradation product 4-nitrobenzaldehyde is formed by pho- Borax in aqueous solution associates to form a 2:1 com-
tolysis. This degradation should be avoided because plex with chloramphenicol. Therefore, chloramphenicol
4-nitrobenzaldehyde is responsible for a non-dose dependent 0.5 % eye drops could be prepared with the pH value of
aplastic anaemia, which condition is rare but lethal. This the solution adjusted to 7 (see Table 10.3).
photochemical reaction can also occur on the ocular surface Frequently the active substance is not or not readily
and skin. Therefore it may be better to apply chlorampheni- available for pharmacy preparation. Then a sterile licensed
col as eye ointment at night instead of eye drops at daytime. pharmaceutical preparation must be used as starting mate-
This might be anyway as effective as the general recommen- rial. Usually powder for solution for injection (i.v.) is used,
dation of 0,5 % eye drops 3 times a day. sometimes solution for injection, powder for bladder
10 Eye 171
Table 10.2 Zinc Sulphate Eye Lotion [67] necessary to adjust the pH of the tear film to 7.4 should be
Zinc sulfate heptahydrate 0.25 g less than 25 microlitres 0.01 M NaOH per dose. Sometimes
Borax 0.53 g even the equivalent of 10–15 microlitres 0.01M NaOH may
Boric acid 1.15 g be uncomfortable.
Phenylmercuric boratea 0.0045 g The volume of 0.01 M NaOH needed depends on the
Sodium citrate 0.5 g acidic ingredients, including the buffer. In simple cases
Water, purified ad 100 mL knowledge of the pKa value and the molar concentration of
a
Phenylmercuric borate is no longer available for pharmacy the active substance or the buffer substances enables the
preparation estimation of the pH of the solution (see Sect. 18.1.1).
Information on the maximum acceptable amount of H+
Table 10.3 Chloramphenicol Eye Drops, Solution 0.5 % [68] ions at a pH > 7.4 is not available and of less relevance.
Chloramphenicol 0.5 g
Borax 0.3 g
A drop of 1 % pilocarpine HCl solution has a pH
Boric acid 1.5 g
value of about 5.5, which after instillation must be
Thiomersal 0.002 g
adjusted to 7.4 by the lachrymal functional unit. 2 %
PRODUCT DESIGN
Water for injections 97.7 g
and 4 % pilocarpine HCl solutions exhibit a pH value
Total 100 g
of 5.3 and 4.0 respectively, and more NaOH will be
required to compensate for the pH difference. If the
amount of NaOH needed is higher than the
neutralising capacity of the tear fluid, instillation will
Table 10.4 Ciclosporin Eye Drops, Oily Solution 1 % [70]
be painful. The choice of a different salt of the active
Ciclosporin 1g substance can potentially reduce the irritation caused
Castor oil, refined 9.9 g
by ophthalmic preparations. E.g. epinephrine HCl eye
Triglycerides, medium chain 89.1 g
drops are less painful compared to epinephrine
Total 100 g bitartrate.
irrigation or other products. The active substances comprise For example, pilocarpine HCl, phenylephrine HCl and
the range of antifungals (e.g. fluconazole, voriconazole, lidocaine HCl solutions in concentrations higher than
amphotericin B), antibiotics (e.g. vancomycin hydrochlo- 10 mg/mL possess such a high buffer capacity that during
ride, cefuroxime sodium, tobramycin, bacitracin) or others, administration substantial pain is experienced resulting in
e.g. mitomycin. Detailed information is necessary about the lachrymation and wash out of the eye drop. This is due to
overage with respect to the labelled value, the quantity of their high therapeutic concentrations and their pKa values in
excipients, the resulting pH and osmolality. Suitability of the the neutral or slightly acidic range. Therefore, the pH value
reconstituted solution for intravenous injection does not of these eye drops should be adjusted as near as possible
necessarily mean suitability for topical ophthalmic use. to 7.4.
The pH value of pilocarpine solutions on the market is
4 and is irritating due to the low buffer capacity of the tear
10.6.1.2 Vehicle
fluid. Therefore the LNA formulated pilocarpine eye drops
Usually eye drops are formulated as an aqueous solution. If
with a pH value of 6.5, this improves the tolerance of the
an oil is employed medium chain triglycerides [69] are
preparation [71].
suitable as a vehicle along with refined castor oil, refined
When the pH value of the eye solution deviates from 7.4,
peanut oil, refined sesame oil or mixtures of triglycerides
it will take time to get the normal pH restored in the tear
(see Table 10.4 and Sect. 23.3.5).
fluid. The greater the buffering capacity is, the longer it will
take [72]. Therefore, it is advisable not to use buffering
10.6.1.3 pH and Buffer Capacity solution outside the pH range 6.5–8.5.
The buffer capacity (see Sect. 18.1.1) of the tear film is low. In order to obtain well tolerated eye drops, the pH of the
Consequently the buffer capacity of eye drops should be as active substance solution is measured and if necessary a
low as possible. The acid neutralising capacity of tear fluid combination of excipients is added to adjust to the required
of one eye is about 8–10 microlitres 0.01 M NaOH (see value (see Table 10.5).
Sect. 10.4.5). In order to avoid eye irritation the following Addition of the excipients mentioned in Table 10.5
rule of thumb is used. The volume of 0.01 M NaOH increases the osmotic value of the preparation. Due to
Table 10.5 Combination of excipients used to adjust the pH value of 10.6.1.5 Viscosity Enhancing Polymers
eye drops In Table 10.6 the characteristics of most frequently used
Decreasing pH Increasing pH viscosity enhancing polymers are reviewed. More informa-
Boric acid Borax (Na2B4O7.10H2O) tion is available in literature [77] and Sect. 23.7.
Sodium dihydrogen phosphate dihydrate Disodium phosphate Apart from the polymers mentioned in Table 10.6 some
(NaH2PO4.2H2O) dodecahydrate authorised medicines contain other viscosity enhancing
(Na2HPO4.12H2O)
agents such as dextran, hydroxyethylcellulose, hyaluronic
Citric acid, anhydrous; citric acid, Sodium citrate
monohydrate acid and hydroxypropylguar gum (HP-guar; Systane®) [36,
Acetic acid Sodium acetate trihydrate 37, 57]. Hyaluronic acid possesses good adhesive properties.
In situ-gelling systems, such as gellan gum, are used in order
to increase the precorneal residence time of the eye drop and
incompatibility or a high osmotic value of the active sub- to obtain a sustained active substance release [78, 79].
stance solution, the substances cannot be always employed. Nowadays interest in poloxamers has increased [77,
In these cases a diluted HCl or NaOH solution is 80]. Their solution viscosity increases at body temperature,
recommended. The disadvantage is of course that an amount however poloxamers are not added frequently to artificial
of solution instead of solid powder must be weighed or tears. Excellent overviews of non-ionic poloxamers and
measured. A pH increase can also be carried out with surface active substances can be found in literature [81].
trometamol (pKa > 8).
Exact buffer compositions and osmotic values are 10.6.1.6 Preservatives
reported in [66]. During the development of an eye preparation whose formu-
It is preferable to use a boric acid-borax buffer, because lation contains an antimicrobial preservative, the necessity
this buffer system has a very low buffer capacity at the pH for and the efficacy of the chosen preservative must be
value of the tear film and at any lower pH. Boric acid is a demonstrated. The effectiveness of the preservative in the
weak acid. Boric acid-borax buffer solutions reacts neutral final preparation is tested according to the Ph. Eur. Efficacy
to weakly basic. of antimicrobial preservation (see Sect. 32.8).
Boric acid and borax are regarded as reproductive
toxicants. The use of boric acid in eye drops for children Testing of Antimicrobial Activity
younger than 3 years old is not recommended, but it is The methodology used to test the antimicrobial activ-
permitted since a clarification in 2003 [73]. Boric ions do ity is still under debate.
not permeate through the intact corneal epithelium [74]. A high storage temperature could reduce the antimi-
The EMA’s committee for medicinal products for human crobial activity as seen during the use of a new contact
use (CHMP) considered that the benefits of phosphate- lens solution ReNu with moistureLoc® formulated with
containing eye drops outweigh their risks, but that in very a new preservative alexidine [85]. The use of this com-
rare cases patients with significant damage to the cornea may mercial product caused a Fusarium keratitis epidemic
develop corneal calcification during treatment with eye worldwide. Research at room temperature and at high
drops that contain phosphate [75]. temperature (60 C) has shown, contrary to other
preservatives, that alexidine loses its antimicrobial
activity at higher temperature. The cold supply chain
10.6.1.4 Viscosity of the product is of primary importance. The possible
The mean viscosity of tear fluid is between 1.3 and 5.9 mPa∙s contribution to the development of the biofilm on the
[76]. As expected, increasing the viscosity of eye drops contact lens surface was also investigated, but was not
increases the residence time in the conjunctival sac considered to have contributed to the problem [86]. The
[77]. Not only the viscosity, but also tensioactive properties, researchers concluded that temperature control during
adhesion on the ocular surface and interactions with mucins production, storage and transport is of utmost impor-
play a role in increasing residence time. tance. Examination of possible biofilm formation was
Viscosity enhancing agents intended for use in eye drops relevant, because other studies investigated this phe-
must fulfil several requirements. Their chemical and physi- nomenon as possible origin of infections. In general,
cal characteristics must be stable during and after attention is drawn during antimicrobial efficacy tests to
sterilisation. Sterilisation induces an important viscosity planktonic free moving bacteria contrary to
decrease for some polymers. Moreover viscous polymer microorganisms fixed in biofilm structures. Nowadays
solutions should be free of particles, colourless, be optically interest in biofilm formation (see also Sect. 19.3.5) has
clear and have a refractive index comparable to tear fluid increased, because bacteria associated with such
( η20
D ¼ 1.336–1.338). The concentration used should not systems are more difficult to kill [87].
cause discomfort and irritation.
10 Eye 173
Table 10.6 Overview of viscosity enhancing agents used in eye drops preparations (see also 23.7)
Carbomer Carbomer is a viscosity enhancing polymer used in eye gels. Its activity is based on an
interaction with mucins. The interaction is the most effective when flexible and
mobile polymer chains entangle and interact with mucins present at the conjunctiva
[20, 77]
Hyprolose (hydroxypropylcellulose, HPC) Hyprolose is used in the production of inserts, such as Lacrisert®. The
macromolecules can adhere to the eyelashes, they glue them together
Hypromellose (hydroxypropylmethylcellulose, HPMC) Hypromellose is a non-ionic cellulose polymer. Hypromellose is a component of the
4,000 mPa∙s; 0.125–0.5 % or 1.25–5 mg/mL viscous vehicle hypromellose-benzalkonium solution (see Table 10.10). The
concentration is % (10 mg/mL), but as it will be diluted 1:1 during preparation of
viscous eye drops, the final concentration will be 0.5 % (5 mg/mL). Hypromellose
solutions are not always well tolerated because of surface tension reduction of the tear
film [30]. The antimicrobial activity of benzalkonium chloride is only slightly
influenced by hypromellose [82]
Methylcellulose (MC) 4,000 mPa∙s; 0.5–1.25 % or Methylcellulose is a non-ionic cellulose polymer. The high viscosity types of
5–12.5 mg/mL methylcellulose are employed, because at low concentration solutions are viscous
enough and the refractive index is only slightly changed
As with all cellulose ethers, methylcellulose increases the residence time of the
PRODUCT DESIGN
preparation. In addition, methylcellulose possesses wound healing properties.
Therefore the polymer is suitable as a tear substitute for dry eye especially for those
with punctate lesions. A disadvantage are irritating insoluble cellulose particles
present in methylcellulose. The amount of insoluble particles depends on the quality
of the product
Carmellose (carboxymethylcellulose sodium, Na CMC) The adhesion of carmellose to the ocular mucosa is less than carbomer. The solubility
of the polymer depends on the degree of substitution. The viscosity decreases during
heating and at a pH value lower than 5
Poly(vinyl alcohol) (PVA) 1.4 % or 14 mg/mL The viscosity and surface tension depend on the degree of polymerisation of the PVA
selected. PVA is often a component of artificial tears and contact lens solutions. PVA
solutions (viscosity ¼ 25 mPa∙s) sometimes irritate, because of its inherent surface
active properties [30]
Povidone (polyvidone, PVP) K 30 Povidone is used in the preparation of suspensions in order to facilitate
resuspendability of the sediment on shaking. Complex formation between PVP and
methyl parahydroxybenzoate or propyl parahydroxybenzoate is possible
If eye drops do not contain antimicrobial preservatives Table 10.7 Tetracaine hydrochloride Eye Drops, Solution 1 % [83]
(Tables 10.7 and 10.8) they are supplied in single-dose Tetracaine hydrochloride 1g
containers or in multidose bottles preventing microbial con- Borax 0.01 g
tamination of the content after opening. Sodium chloride 0.7 g
Antimicrobial preservatives should be omitted in eye Water for injections ad 100 g
drops intended for use in surgical procedures. Tetracaine
hydrochloride eye drops (Table 10.7) comply with the Table 10.8 Indometacine Eye Drops, Solution 0.1 % [84]
Ph. Eur. efficacy of antimicrobial preservation.
With Without a
The use of preservatives is not possible when the patient
thiomersal preservative
is sensitive or allergic to the preservative or if eye drops will
Indometacin 0.1 g 0.1 g
be administered just before, during or after surgery, because Borax 0.3 0.3 g
of its toxicity. Commercial ophthalmic products without Disodium phosphate 3g 3g
preservatives are popular because of their better tolerance dodecahydrate
and lower irritancy potential [88–90]. Sodium dihydrogen phosphate 0.25 g 0.25 g
The preference is given to the combination of dihydrate
benzalkonium chloride and sodium edetate (EDTA). Edetate Mannitol 1.6 g 1.6 g
is added in order to improve the activity of benzalkonium Thiomersal 0.002 g –
chloride against Pseudomonas aeruginosa. Water for injections 94.75 g 94.75 g
Total 100 g 100 g
Table 10.9 Possible combinations of excipients for basic ophthalmic

Benzalkonium Chloride / Edetate and Active solutions
Substance Effect pH-modifying osmotic active
Could the combination of benzalkonium chloride and Preservative excipient excipient
edetate present in so many ophthalmic solutions influ- Benzalkonium chloride Boric acid/borax; Boric acid/borax
0.1 g/L + (citric acid/citrate; (NaCl, KNO3,
ence the therapeutic activity of the active substance?
Na edetate 1 g/L phosphates; HCl, mannitol,
In the case of an intact cornea a higher active sub- NaOH) glycerol)
stance availability is assumed because benzalkonium Chlorhexidine Acetic acid/acetate; Mannitol; boric
chloride acts as a penetration and solubility enhancer digluconate 0.1 g/L or boric acid/borax acid/borax
increasing passive diffusion of the active substances Chlorhexidine diacetate
0.1 g/L
through the corneal epithelial cells (transcellular path-
Thiomersal 0.2 g/L Borax; phosphates Mannitol
way). Additionally, edetate is a penetration enhancer,
active at the tight junctions between cells, and has an
effect on intercellular passive diffusion. Research
performed using ketorolac eye drops on rabbits with Table 10.10 Preserved base solutions and concentrates of FNA
intact and de-epithelialized corneas [91] demonstrated and NRF
that the availability of ketorolac in the case of intact Preservatives and concentrations Properties pH
corneal epithelium was similar after application of Benzalkonium chloride solution Non iso-osmotic; 4.9
drops with or without benzalkonium chloride and 0.1 g/L + Na edetate 1 g/L (FNA) vehicle
edetate, whilst in the case of the injured cornea a Benzalkonium chloride solution Non iso-osmotic; 4.8
lower availability was measured in the presence of 1 g/L + Na edetate 10 g/L (NRF) concentrate
benzalkonium chloride. The researchers speculate Boric acid – Benzalkonium chloride Iso-osmotic; vehicle 4.6
solution 0.1 g/L + Na edetate 1 g/L (FNA)
that the non-irritating ketorolac formed an irritating
Hypromellose – Benzalkonium chloride Non iso-osmotic, 5.1
combination with benzalkonium chloride resulting in solution 0.1 g/L + Na edetate 1 g/L (FNA) viscous; vehicle
lachrymation (active substance wash out) and lower Chlorhexidine diacetate solution 1 g/L Non iso-osmotic; 7
availability. Combination of edetate with boric acid (NRF) concentrate
and an experimental active substance in an ophthalmic Thiomersal solution 0.2 g/L (NRF) Non iso-osmotic; 7
solution seems to exhibit permeation increasing concentrate
properties ex vivo on intact rabbit cornea [92]. The Hypromellose 4,000 mPa.s is used in the concentration 10 g/L if added
for increasing viscosity
results of both studies do not provide sufficient infor-
mation to draw a meaningful conclusion as to whether
benzalkonium chloride and edetate influence the avail-
to the right osmotic value. Table 10.10 shows how these
ability of ophthalmic medicines.
possibilities have led to standard basic solutions (vehicles)
for eye drops and concentrates for further dilution.
An overview of preservatives is given in Sect. 23.8. More
When the combination of benzalkonium chloride and information concerning specific preservatives suitable for
edetate cannot be used because of incompatibilities, ophthalmic preparations can be found in the literature [66,
thiomersal sodium can be used. Phenylmercuric borate is 72, 88, 93, 94]. Benzalkonium chloride is the most fre-
not available anymore because of toxicological problems to quently used preservative in ophthalmic products. However
the environment. its use is under discussion, because of its toxicity in chronic
A third preservative is chlorhexidine in the form of chlor- treatment [95, 96]. Therefore new preservatives are used in
hexidine acetate or chlorhexidine digluconate at a concen- the development of licensed products [94, 97–100].
tration of 0.1 mg/mL. However, chlorhexidine induces many The efficacy of a preservative is pH dependent. Therefore
chemical incompatibilities (see Sect. 23.8). the pH value of the ophthalmic solution determines the
The preservative selected reduces the choice of other choice of the preservative. Sorbic acid and benzoic acid
excipients required to adjust pH and osmotic values. present in other dosage forms are active at a pH value
Table 10.9 shows the possible combinations of lower than 5, and therefore unsuitable in most ophthalmic
preservatives, pH modifiers and excipients that can add up solutions.
10 Eye 175
10.6.1.7 Sterility
Phenylethanol alone is not routinely used as preser- Sterility is the most important requirement concerning oph-
vative in eye drops due to too low an antimicrobial thalmic preparations. A diseased or injured eye is extremely
activity especially against gram-positive bacteria. sensitive to infections with catastrophic consequences. Pseu-
Moreover phenylethanol cannot be combined with domonas aeruginosa is the most feared organism due to the
other preservatives because of its potential to irritate organism causing serious and difficult to treat corneal ulcer-
the eye [101]. Hydroxybenzoic esters are also reported ation, which can result in rapid loss of vision. Other bacteria
to cause a high incidence of eye irritation. Thiomersal such as Bacillus subtilis, Staphylococcus aureus and
is not routinely used due to low antimicrobial activity, Haemophilis influenzae as well as yeasts and moulds such
allergic reactions and penetration of mercury into the as Aspergillus fumigatus, Fusarium species and Candida
eye. The same is also true but to a much lesser albicans (or non-albicans) are responsible for serious eye
extent for phenylmercuric salts [102–104] (see also infections.
Sect. 23.8.4). Therefore ophthalmic preparations must be sterile when
dispensed to the patient, and this sterility must be guaranteed
throughout storage. When using single-dose packaging for
The preservative should remain effective throughout the
PRODUCT DESIGN
eye drops, no issues with sterility should occur. When
period of use by the patient. The substance should be chemi-
multidose packaging is chosen, the risk of contamination
cal stable, even after heat sterilisation. Moreover the preser-
should be reduced by the following measures:
vative should be physically stable during preparation and
• Preservation
storage. The preservative should be compatible with the
• Adequate design of primary packaging
other ingredients of the preparation, filters and packaging.
• Adequate instructions to the patient concerning correct
Significant adsorption can reduce the antimicrobial efficacy
application technique and hygiene
partially or completely [105, 106].
• Limited storage time once the container is opened
Organic phenylmercuric derivates and thiomersal are
• Refrigeration once the container is opened
known for their strong adsorption onto rubber and various
The probability of eventual growth of bacteria
plastics such as low density polyethylene (LDPE).
contaminating the preparation depends on:
Benzalkonium chloride and chlorhexidine are also
• Presence of a preservative
adsorbed onto plastics and rubber, but to a lesser extent.
• pH value of the preparation
Chlorobutanol is not recommended because of the
• Adequate antimicrobial properties of the active substance
relative strong adsorption on and permeation through the
or the excipients
packaging material, degradation by heat, relative low
• Presence of water and water activity (see Sect. 19.2.2)
dissolution rate and the chemical instability of the raw
• Temperature
material.
Chlorhexidine degrades during heating but not to such an
extent that autoclaving is impossible. The degradation prod- Literature reports are published on a regular basis
uct 4-chloraniline and related substances are formed. The concerning ophthalmic preparations which have been
degradation is strongly dependent on the pH of the solution. contaminated during use, even when the solution
The lower the pH the lower the decomposition, with maxi- complies with the criteria of the antimicrobial efficacy
mum stability at pH 5–6. During autoclaving the concentra- test of the Ph. Eur. After 4 weeks of use caps, dropper
tion of 4-chloraniline is less than 0.125 % (pH range 5–8). tips or even solutions can be contaminated. The
According to the Ph. Eur. monograph the maximum tolera- reasons are: careless administration, transfer of tear
ble values are 0.25 % chloraniline and 3 % related fluid into the dropper tip at instillation, cross-
substances for the chlorhexidine raw material (see also contamination in hospitals and nursing homes and resis-
Sect. 23.8.7). tance of (gram-negative) bacteria against preservatives
As already mentioned for contact lens solutions (see box [107–109]. This phenomenon is underestimated and is
Testing of Microbial Activity in Sect. 10.6.1.6) storage one of the reasons why after opening the contents of the
temperature also influences the preservation of eye drops. container must not be used for longer than 4 weeks
At room temperature a solution of borax, boric acid and (unless otherwise justified). To reduce cross-
edetate exhibit an effective antimicrobial activity but not at contamination patients should be instructed how to
4 C. Non preserved pilocarpine-hypromellose eye drops correctly instil eye drops (see Sect. 10.9) and snap-cap
can be used for a longer period of time when stored at containers (see Sect. 24.4.2.3) should be selected.
room temperature compared to storage in the refrigerator.
10.6.1.8 Osmotic Value Hydrolysis and oxidation play an important role in the
The osmotic value (see Sect. 18.5) of ophthalmic solutions stability of ophthalmic preparations. Degradation can be
should be in the range equivalent to 0.5–2 % sodium chlo- maintained within acceptable limits when an appropriate
ride solution in order to avoid pain sensation. However, in pH is selected and by addition of antioxidants if necessary.
practice the upper limit should be set to 1.6 % NaCl to make Degradation is also reduced by a lower sterilisation temper-
sure the eye drops are well tolerated by all patients. ature, a lower storage temperature or a shorter shelf life.
Isotonicity of eye drops is obtained by adding boric acid, Non-preserved aqueous eye drops sterilised by
borax or a combination thereof. If their use is not possible autoclaving may be stored in unopened containers for a
due to chemical incompatibilities, sodium chloride solution maximum of 1 year in Redipac plastic tubes and 2 years in
can be employed. Other tonicity substances are mentioned in dropper bottles. After opening of the container storage
Table 10.9. should not exceed 28 days in the case of preserved solutions,
eye drops with adequate antimicrobial properties imparted
10.6.1.9 Container and Labelling by the active substance, and oily eye drops. But for use on
A review of ophthalmic dropper packaging is given under wards, 1 week is considered more appropriate.
Sect. 24.4.2. In community pharmacies glass containers with The storage of aseptically prepared eye drops without
dropper tips are usually used to dispense multidose preservative may be at maximum 6 months at –15 C. If no
preparations. Polyethylene containers are becoming more freezer is available, the preparation should only be stored for
popular. Chloro-or bromobutyl rubber teats should not be 1 week in the refrigerator. After opening of the container
used with oily eye drops and with iodinated povidone only if there is no storage in the narrower sense, because
previously tested, well defined and standardised cases. The non-preserved eye drops must be packaged in single-use
dropper tip and the cap should be made of polypropylene. containers. This must be strictly observed without exception
Packaging should protect the eye drops against exposure to when application to different patients cannot be excluded or
light. If impossible the preparation must be placed into a with immunosuppressive eye drops. In practice storage and
protecting secondary packaging, e.g. a carton. application on one and the same patient within some hours
The label (see also Sect. 37.3) should mention the storage after opening of the container occurs frequently and is
conditions, shelf life of unopened containers and for widely accepted. When justified the period of use after
multidose bottles and the in-use shelf life after which the opening is always a maximum of 24 h and the volume of
contents must be discarded. This period must not exceed the preparation should be adjusted. When the patient‘s eye is
4 weeks. In order to guarantee sterility during use, the injured or infected a shorter time limit should be considered.
Ph. Eur. requires that multidose preparations are supplied Research has demonstrated that some non-preserved
in containers containing at most 10 mL solution. preparations are not easily contaminated. If this is the case,
The use of tamper-evident packaging makes it clear to the a period after opening of longer than 24 h may be acceptable.
patient that he is the first person to open the container.
Non preserved ophthalmic solutions are preferably deliv-
ered in single-dose packaging such as Redipac® plastic
10.6.2 Eye Lotions
tubes. In pharmacy preparation alternatives may be:
• 1 mL syringes (Luer) with stopper
Eye lotions are defined as aqueous solutions. Thus active
• 10 mL polyethylene dropper bottles filled to only
substances must be soluble at the concentration needed. Eye
250 microlitres or maximum 1 mL
lotions must be sterile. According to Ph. Eur. eye lotions
Multidose containers could be used if sterility during storage
intended for use in surgical procedures or in first-aid treat-
and in use has been proven and guaranteed. Research on the
ment do not contain an antimicrobial preservative and are
storage of non-preserved eye drops delivered in Gemo-type
supplied in single-dose containers, see for example an eye
containers with snap-cap (see Sect. 24.4.2.2) has been
lotion with iodinated povidone (Table 10.11).
undertaken. In the case of acetylcysteine 5 % eye drops
integrity during storage of the containers was guaranteed
from a microbiological point of view, even after freezing
and thawing [110]. Whether non-preserved eye drops sup- Table 10.11 Iodinated Povidone Eye Lotion 1.25 % [111]
plied in this packaging could be administered for longer than Povidone, iodinated 1.25 g
24 h, was not investigated. Disodium phosphate dodecahydrate 0.25 g
10.6.1.10 Storage and Stability Water for injections 97.7 g
A general discussion concerning stability and assignation of Total 100 g
storage times is provided in Sect. 22.7.
10 Eye 177
Table 10.12 Disodium Edetate Eye Lotion 2 % [115]

Disodium edetate 2g precipitation at the ocular surface due to complexation
Benzalkonium chloride 0.01 g of calcium ions released from the damaged cells with
Borax 0.95 g phosphate ions. Physiological saline solution exhibits
Sodium chloride 0.15 g the same effect as tap water. Without debate, the
Purified Water ad 100 mL hypertonic eye lotions showed the best results. The
use of hypertonic rinsing solutions prevents the devel-
opment of corneal oedema. The amphoteric molecule
Antiseptic eye lotions frequently used pre-, intra- and diphoterine neutralises acids and bases and prevents
postoperatively at eye surgery may contain polihexanide chemical wounds. If only tap water is available, it
(PHMB), iodinated povidone or chlorhexidine salts. should be used immediately but there is the risk of
If a preservative is required for multidose containers, corneal swelling. The dilution of the chemical sub-
sterile and preserved vehicles can be used (see Table 10.10). stance by tap water will reduce pain until a more
The same considerations regarding the use of preservatives suitable eye lotion is available, but rinsing as soon as
in eye drops apply to eye lotions. possible is of utmost importance [113, 114].
Compared to eye drops a higher volume of eye lotion will
PRODUCT DESIGN
be in contact with the eye. Therefore the pH value should be
adjusted very close to 7.4. If this is not possible, the buffer
capacity of the solution must be low in order not to cause 10.6.2.2 Packaging and Labelling
discomfort and pain. Irritation is a great challenge in the case High volume eye lotions prepared in pharmacies may be
of eye lotions. The results of a German study evaluating eye packed in sterile, clean polypropylene bottles with an appro-
lotions are surprising and showed that about 16 % of the priate closure. Also type I glass bottles can be used. The
commercial products showed a pH value outside the range volume is a maximum of 200 mL, except if the solution is
6.4–8.0 [112]. intended for first-aid treatment where a dispensed volume of
1,000 mL is more appropriate. Aseptically prepared eye
10.6.2.1 Osmotic Value lotions should be packed in sterilised containers.
As high volumes of eye lotions are applied, the product must An example of an eye lotion prepared in pharmacies is a
be isotonic to avoid irritation. However, eye lotions intended low volume antiseptic solution for eye surgery. The lotion is
to treat ocular oedema should be hypertonic. As discussed filled in sterile injection vials, polyethylene dropper bottles
under Sect. 10.6.1 the tonicity of eye drops is frequently or other suitable single-dose containers. If eye lotions do not
adjusted with boric acid, borax or a combination thereof. contain antimicrobial preservatives they must be supplied in
The same is valid for eye lotions. If these excipients are single-dose containers too.
chemically incompatible, or as an alternative, sodium chlo- The label states:
ride can be used (see Tables 10.11 and 10.12). Suitable • Where applicable, that the contents are to be used on one
excipients adjusting tonicity are summarised in Table 10.9. occasion only
• For multidose containers - the period after opening after
which the contents must be used or discarded: this period
Hypertonic Eye Lotions to Prevent Oedema should not exceed 4 weeks
Research on the use of eye lotions to treat chemical According to national legislation the label mentions the
burns noted the importance of hypertonicity. In vitro dosage form (eye lotion), the route of administration (ocular
and ex vivo (rabbit and pigs eyes) a 2 M NaOH use), the patient information for the intended use. If neces-
solution was applied resulting in tissue damage. The sary an eye cup should be supplied. The patient should be
pH value of the aqueous humour increased by 5 pH instructed as to the proper use of the eye lotion and eye cup,
units, the increase being quickest in eyes that were not the contact time of bathing the eye and cleaning of the eye
rinsed. The rinsing solutions examined were: tap water cup. The device should be thoroughly rinsed and cleaned
(hypotonic), phosphate buffered saline solution (PBS, before and after use.
isotonic), physiological saline solution (0.9 % NaCl,
isotonic), saline in hypertonic borate buffer solution
and a hypertonic saline solution with an amphoteric
chelator. Immediately after chemical burning, inten- 10.6.3 Eye Ointments and Eye Creams
sive rinsing for 15 min was carried out, according to
American guidelines. PBS induces calcium phosphate Apart from eye ointments and eye creams also eye gels could
be seen as semisolid eye preparations. But many of the so
(continued)
Table 10.13 Erythromycin Eye Ointment 0.5 % [116] Table 10.15 Chloramphenicol Eye Ointment 1 % [118]
Erythromycin, anhydrous 0.5 g Chloramphenicol microcrystalline 1g
Cetostearyl alcohol 2.5 g Eye ointment base FNAa 99 g
Paraffin, liquid 39.8 g Total 100 g
Paraffin, white soft 51.2 g
a
Wool fat 6g For eye ointment base FNA see Table 10.16
Total 100 g
Table 10.16 Eye ointment base [119]
Cetostearyl alcohol 2.5 g
Paraffin, liquid 40 g
Table 10.14 Sodium Chloride Eye Ointment 5 % [117]
Sodium chloride 5g Wool fat 6g
Cetostearyl alcohol 1.9 g
Total 100 g
Wool fat 4.5 g
Water, purified sterile 20 g Table 10.17 Emulsifying Eye Ointment [120]
Total 100 g Cholesterol 1g

Paraffin, liquid 42.5 g
called eye gels are not actually semisolid but they are high- Total 100 g
viscous liquids (see Sect. 10.6.1).
10.6.3.2 Vehicle
10.6.3.1 Choice of the Dosage Form The base must be non-irritant to the conjunctiva.
The choice of the type of dosage form will depend on the salt Non-aqueous lipophilic ointment bases consist of a mixture
form, particle size and solubility of the substance. In princi- of white or yellow soft paraffin, liquid paraffin and lipophilic
pal there are three categories of semisolid eye preparations: surfactants, such as cholesterol or wool fat.
• The active substance is dissolved in a lipophilic ointment Triglyceride-based vehicles may also be suitable and
base. advantageous in respect to their dissolving power for active
• The aqueous active substance solution is emulsified in the substances (see also Sect. 10.7.3).
lipophilic ointment base (resulting in an eye cream). Wool fat or cholesterol in an eye ointment emulsify with
• The active substance is dispersed in the ointment base. lachrymal fluid resulting in a water-in-oil emulsion-type
The first ointment type is applicable for only a few active cream. Cetostearyl alcohol is not a muco- or bioadhesive
substances dissolved in the non-aqueous ointment bases. To substance.
date, almost only paraffin-based lipophilic ointments are Common eye ointment bases are given in Tables 10.16
used for semisolid ophthalmic products. An example of and 10.17.
this type of preparation is eye ointment with 0.5 % erythro-
mycin (Table 10.13). Suitable triglyceride-based vehicles
may lead to more solution-type eye ointments (see 10.6.3.3 Preservatives
Sect. 10.7.3). Micro-organisms are not able to grow in ointments, as no
The second category of semisolid eye preparations is a water is present. Therefore, the addition of a lipophilic
lipophilic cream: the active substance is dissolved in water preservative to a non-aqueous ointment makes little sense.
or a (preserved) aqueous vehicle and emulsified in the oint- However for lipophilic eye creams the addition of a preser-
ment base. An example to mention is a sodium chloride 5 % vative to the aqueous phase is recommended.
eye cream (Table 10.14). The strong hypertonic aqueous phase of sodium chloride
The most common category of semisolid eye preparations 5 % eye ointment FNA (Table 10.14) prevents bacterial
is a suspension ointment as in chloramphenicol 1 % eye growth.
ointment (see Table 10.15). A microfine powdered chloram-
phenicol substance is used as starting material. The particle 10.6.3.4 Packaging and Labelling
size of the powder to be dispersed must comply with Ph. Eur. Eye ointments are packed in small, clean, sterilised collaps-
requirements (see Sect. 10.8). ible tubes fitted or provided with a sterilised cannula (see
10 Eye 179
Sect. 24.4.9). According to Ph. Eur. the tube contains a other ingredients will be dissolved in these vehicles. When
maximum of 10 g of the preparation. viscous eye drops are prepared, the viscous hypromellose
Eye ointments and eye creams are applied in the same stock solution containing the preservative (see Table 10.10)
manner as eye drops: in the lower conjunctival sac and after is always diluted 1:1 with a stock solution containing the
administration the eyelid is pulled forward. Due to body same preservative. Vehicles for eye drops prepared on stock
temperature the ointment melts and is spread by the eyelids often show a weak acidic reaction. Benzalkonium chloride
over the ocular surface during blinking. When the eye is solutions with high pH values, containing alkaline
injured the ointment is applied on the eyelid rim, not in the substances such as borax, attack glass material, i.e. the boro-
conjunctival sac. Ointments and creams are not well silicate glass (type I) of Schott Duran bottles (see also Sect.
tolerated, because they produce a film over the eye and 24.2.1).
thereby blur vision [121]. Therefore, application in the even- In-process control of the dissolution of the active
ing is preferred. substances may include pH measurement of the bulk solu-
Patients should be instructed to the proper use and admin- tion immediately before filtration to confirm that the correct
istration of eye ointments and eye creams. It is important to ingredients and vehicles have been used.
avoid contamination by contact with the skin or surface of
PRODUCT DESIGN
the eye. Consequently, one preparation should be used only
10.7.1.2 Filtration
by one patient. The same tube can eventually be used by care
Foreign particles can be removed by (pre)filtration over a
providers for several persons, however, nursing home staff
membrane filter (1.2 μm pore size). The use of this filter
should be aware of the contamination risk.
reduces the initial viable contamination as well. When
According to national legislation the label mentions the
autoclaving or steam sterilisation is not suitable for the
dosage form (eye cream or eye ointment), the route of
product in order to remove viable contamination,
administration (ocular use), the intended use, the storage
i.e. bacteria, the solution is passed through 0.2 μm mem-
conditions, the expiry date and, for multidose containers,
brane which will retain all bacteria. In practice a one-step
the beyond-use date after which the opened preparation
procedure is preferred using only one membrane filter with a
must not be used. This period should not exceed 4 weeks.
nominal pore size of 0.2 μm. For use in pharmacies this type
If necessary the label also bears warnings and mentions
is readily available.
that the contents should be brought to room temperature
before administration if the tube is stored in the
refrigerator. Polyethersulfone (PES) material for the membrane
filter is preferred because of low active substance
adsorption and superior filtration. It is unclear whether
10.7 Method of Preparation PES filters are suitable for oily eye drops. Usually
fluoropolymer filters are used in these cases.
The preparation process for eye drops, eye lotions, eye A viscous benzalkonium chloride solution, for
creams and eye ointments will be described subsequently. instance with 0,5 % hypromellose 4,000 mPa∙s, is
filtered through a membrane with pore size 1.2 μm
to eliminate non dissolved hypromellose fibres. The
10.7.1 Eye Drops solution is too viscous to be forced through a 0.2 μm
membrane filter. When eye drops are prepared by
Eye drops are prepared using materials and methods dissolving a dry powder in a container with the sup-
designed to ensure sterility and to avoid the introduction of plied vehicle, the solution obtained should be with-
contaminants and the growth of micro-organisms as also drawn using a 5 μm filter needle to remove any
stated by the various Pharmacopoeias. The preparation undissolved powder particles [122].
method consists of several steps: dissolution of the
ingredients, (sterile) filtration, filling and packaging and The integrity of membrane filters with a pore size of 0.2
(when possible) heat sterilisation. and 1.2 μm should be verified using a bubble-point test after
use as an in-process control. During this test a 0.2 μm mem-
10.7.1.1 Dissolution of the Ingredients brane filter should resist the air pressure produced by moving
For the dissolution process see Sect. 29.5. For small-scale the plunger over 80–85 % of the total syringe volume and in
preparation of preserved eye drops the use of autoclaved the case of a 1.2 μm membrane filter over 50–60 % without
stock solutions may be convenient. They contain a preserva- continuous bubble formation on the opposite of the mem-
tive and often boric acid and borax (see Table 10.5). The brane (see also Sect. 30.6.5).
Table 10.18 Conditions for the preparation of preserved aqueous eye drops
Method Filtration Other characteristics
Steam sterilisation 15 min 121 C Membrane filtration 1.2 μm Terminal sterilisation
Heating 30 min 100 C (over boiling water) + membrane Membrane filtration 1.2 μm Sterile vehicle
filtration + preservative Class A workbench
Sterile container
Filtration Membrane filtration 0.2 μm Sterile vehicle (recommended)
Class A workbench (recommended)
Sterile container
Filtration into final container
Aseptic handling – Sterile vehicle
Sterile products
Sterile equipment
Class A workbench
Sterile container
10.7.1.3 Sterilisation 10.7.1.4 Aseptic Handling

Sterilisation is generally dealt with in Chap. 30. The pre- Aseptic handling in clinical practice often occurs when
ferred method is a 15 min steam sterilisation at 121 C of the licensed parenteral medicines are used off-label for eye
active substance solution filled into the final container. disorders, i.e. amphotericin B, fluconazole, mitomycin, and
Sterilisation in the final container is however not always voriconazole [123–126]. A sterile product with the active
feasible because the container is not heat resistant or the substance (i.e. a powder for solution for infusion, a concen-
active substance degrades at elevated temperatures. In order trate for solution for infusion, a solution for infusion or these
to keep the risk of non-sterile eye drops as low as possible a dosage forms for injection) has to be adapted into eye drops.
combination of measures must in that case be taken. The The first preparation step involves dissolution of the powder
possible measures are: in the vial, thus resembling the reconstitution for the
• Use of sterile vehicles (sterile stock solutions, sterile designated use. The sterile vehicle used may contain a pre-
purified water or water for injections) servative [123] or may be water for injections [124, 125],
• Addition of preservatives saline or buffer solution [126]. Sometimes dilution to a
• Heating 30 min 100 C over boiling water larger volume is necessary before finally filling the eye
• Filtration through bacterial-retentive membrane with the drops into the container. It depends on the outcome of a
nominal pore size of 0.2 μm risk assessment of each individual case, if filling should
• Use of sterile final container include filtration [123–125] or not (see Table 10.19). Aseptic
• Aseptic preparation in a Class A laminar flow handling, outside a Class A environment, may be achieved by
workbench preparing in a ‘nearly closed system’, by filling the sterile
• Storage in a refrigerator dropper bottle by piercing the package wrapped around it,
• Deep-freeze storage after suitable disinfection of the packaging surface (see
These measures reduce microbial contamination or pre- Fig. 10.4). This technique can include filtration or just mixing
vent an increase in contamination during preparation and of sterile solutions. The conditions for the preparation are
storage. For extemporaneous preparation of eye drops in best described by the term ‘aseptic handling’, see Sect. 31.3.
pharmacies the responsible pharmacist must select the
most adequate sterilisation technique after performing a 10.7.1.5 Handling Containers
risk assessment. During heating at 100 C (over boiling water), the caps of the
Tables 10.18 and 10.19 summarise for preserved and dropper bottles should be closed or open depending on the
non-preserved eye drops respectively the range of obvious kind of container (see Sect. 24.4.2). If the closure is open, the
combinations of methods, procedures, utensils and dropper bottles should be placed immediately after heat
containers for small scale preparation for obtaining a sterile treatment in a Class A laminar flow workbench. After
product. The presence of a preservative in the formulation cooling down the cap has to be closed.
makes heating at 100 C during 30 min (over boiling water) After filling, sealing and sterilisation of single-dose contai-
much more effective (see Sect. 30.7) and is therefore an ners (for example Redipac plastic tubes, see Sect. 24.4.2.6),
important parameter in the risk analysis. the integrity of the container should be confirmed by
10 Eye 181
Table 10.19 Conditions for the preparation of non-preserved aqueous eye drops
Method Filtration Other characteristics (depending on type of container)
Redipac plastic tubes Dropper bottles Syringes
Steam sterilisation 15 min 121 C Membrane filtration 1.2 μm Terminal sterilisation Terminal sterilisation –
Heating 30 min 100 C (over boiling Membrane filtration 0.2 μm Sterile solution of Sterile solution of –
water) + membrane filtration excipients excipients
Class A workbench Class A workbench
Sterile containers Sterile containers
Storage in freezer Storage in freezer
Aseptic handling Membrane filtration 0.2 μm, Sterile solution of Sterile solution of Sterile solution of
if possible excipients excipients excipients
Class A workbench Class A workbench Class A workbench
Sterilised Redipac Sterile dropper bottles Sterile syringes
plastic tubes
Storage in freezer Storage in freezer Storage in freezer
PRODUCT DESIGN
Fig. 10.4 (a and b). Aseptic handling of eye drops preparation (see text under Sect. 10.7.1.3)
squeezing and inspecting for leakage. For prevention of water 10.7.2 Eye Lotions
evaporation during storage, Redipac tubes should be wrapped
individually in foil, already before sterilisation. This makes The preparation of eye lotions is similar to eye drops (see
drying after sterilisation necessary: approximately 10 min at Sect. 10.7.1). As in most cases non-preserved stock vehicles
80 C in an oven has showed to be sufficient. are used, eye lotions should be sterilised by autoclaving for
When heating at 100 C (over boiling water) during 15 min at 121 C in the final container. If not possible,
30 min in combination with membrane filtration sterile several measures may be combined in order to keep the
containers (dropper bottle or Redipac) and sterile solutions risk of contamination as low as possible, analogously to
of excipients are required. The preparation will be Tables 10.18 and 10.19.
performed in a Class A laminar flow workbench. After Low-volume eye lotions with antiseptics (iodinated
sterilisation the containers must be stored in the freezer. povidone, polihexanide or chlorhexidine salts) for use in
When only aseptic preparation is possible Redipac plastic eye surgery must not contain preservatives. They are usually
tubes, dropper bottles and syringes could be used as containers. prepared aseptically in pharmacies using water for injection
The same requirements such as sterile container, sterile solu- and sterile excipients, analogously to Table 10.18. Iodinated
tion of excipients, aseptic preparation in a Class A laminar flow povidone eye lotion is thermally unstable and membrane
workbench and storage in a freezer are valid to ensure sterility. filtration (0.2 μm) has to be applied.
10.7.3 Eye Ointments and Eye Creams Preparation of an eye cream (see Sect. 10.6.3) includes
the preparation and sterilisation of the aqueous phase in a
An ointment base is prepared by melting the ingredients similar manner to eye drops. The aqueous phase is then
together. Sterilisation can be performed by dry heating (see incorporated into the sterile ointment base by aseptic
Sect. 30.5.2) or membrane filtration (see Sect. 30.6.1). Heat processing. Using an oily solution of the active ingredient
sterilisation requires a validated heat steriliser, which may be instead results in an eye ointment.
expensive. In addition, a disadvantage of dry heat sterilisation A semisolid triglyceride (Softisan 378®) that meets the
is the partial decomposition of the fat components. The deg- monograph Hard fat Ph. Eur. may establish the option to
radation products could negatively influence the stability of prepare not only eye creams with water-soluble active
the active substance and probably cause irritation of the eye. substances but also solution-type eye ointments and eye
Some types of tubes can resist 3 h at 140 C (see Sect. creams with active substances soluble in fatty oils
24.4.9). Although this is not exactly the Ph. Eur. requirement (i.e. clotrimazole, ciclosporin). Softisan 378® shows
for dry heat sterilisation, the use of this method has the delayed solidification when molten and drawn into a syringe,
advantage of a much easier and thereby safer aseptic prepa- thus making membrane filtration (0.2 μm pore size)
ration of the medicine. Heat sterilisation of an eye ointment possible at about 30 C. However, specific formulas of
can only be performed if the active substance is dissolved in triglyceride-based eye ointments and creams have not been
the base and is stable to elevated temperatures. fully developed yet. For example the ratio Softisan 378®)/
Sterilisation in the final container obviously is not possi- refined peanut oil or the optimum cholesterol concentration
ble for eye creams. It is practical to distinguish solution-type as an emulsifier still has to be investigated.
preparations from suspension-type preparations. For reading the temperature as an in-process control a
non-contact laser infrared digital thermometer is used. The
10.7.3.1 Solution-Type Preparations consistency could be measured using two glass plates as a
Preparation of a solution-type eye ointment starts with the simple extensometer.
melting and mixing all ingredients as described above.
Mixing Technique with Connected Syringes connectors and a membrane filter (0.2 μm pore size)
For extemporaneous preparation an aseptic procedure aqueous or triglyceride-based solutions and certain
is suitable for the preparation of eye ointments and eye types of molten ointment bases can be filtrated (see
creams in pharmacies. It requires 2 or more Luer- Fig. 10a) and kept into sterile syringes prior to mixing.
Lock-syringes consecutively conjoined by a sterile Molten sterile ointment base can also be drawn into a
Luer-Lock-connector [127]. By pushing liquid and syringe directly. Mixing in the ‘nearly closed system’
semisolid intermediate product from one syringe to reduces the risk of microbial contamination. This
the other and back through the connector, homoge- method has of course to be validated for each formu-
neous ointments or creams can be prepared (see lation, especially with suspension-type ointments if
Fig. 10.5b, c). With the help of additional syringes, agglomerates have to be broken up.
Fig. 10.5 (a–c) Preparation of a solution-type eye ointment or eye cream by the mixing technique with connected syringes.
(continued)
10 Eye 183
10.7.3.2 Suspension-Type Preparations • pH (for eye drops)

Sterilisation in the final container is not possible for • Sterility
suspension-type eye ointments. During heating the ointment • Foreign particles
base melts and the dispersed powder particles will settle. Active • Uniformity of dosage units
substances intended for use in suspension ointments must be Solution-type eye drops must be practically free from
purchased sterile or sterilised by dry heat prior to use if their particles. Eye drops that are suspensions may show a sedi-
thermal stability is sufficient. The container with the raw mate- ment that is readily resuspended on shaking to give a sus-
rial should only be used for the preparation of eye ointments. pension which remains sufficiently stable to enable the
The substance must comply with Ph. Eur. requirements correct dose to be delivered.
concerning particle size (see Sect. 10.8). During incorporation Suspension eye ointments should be prepared with pow-
agglomerates should be broken down. This best may be der as fine as possible, because large particles could mechan-
performed using a stone or porcelain mortar and pestle. The ically injure the eye. Even small needle-shaped crystals
use of plastic mortar and pestle or glass plate and flexible (smaller than 50 μm) could damage the corneal surface.
spatula is usually not sufficient to break down the agglomerates. Suspension-type eye drops and eye ointments must,
The laminar flow is disturbed more by operating with the according to the Ph. Eur. comply with following test: For
PRODUCT DESIGN
open product as happens with the preparation of suspension- each 10 microgram of solid active substance, not more than
type eye ointments, than with eye drop preparation or by the 20 particles have a maximum dimension greater than 25 μm
mixing technique with connected syringes for semisolid eye and not more of two of these particles have a maximum
preparations (see Fig. 10.5). Consequently, a higher risk of dimension greater than 50 μm. None of the particles has a
contamination exists (see Sect. 31.3.2), which has to be maximum dimension greater than 90 μm. The investigation
accounted for in the risk assessment. is carried out using a microscope.
As an in-process control the presence of agglomerates The Ph. Eur. has no test for metal particles originating
and the homogeneity shall be carried out visually after from poor quality metal ointment tubes. The Japanese Phar-
placing a sample of the preparation between two glass slides. macopoeia has a specification for the presence of metal
No particles or agglomerates should be visible. The control particles, number and dimensions. In 10 samples no more
of the particle size is performed using a microscope. For than 50 particles of 50 μm or greater should be present, the
temperature and consistency measurement as in-process shape is not specified. In addition, in 1 sample not more than
controls see Sect. 10.7.3.1. 8 particles should be found.
The preparation of tetracycline eye ointment can be

problematic and it is preferable to use micronised active 10.9 Administration of Ophthalmic
substance to overcome particle size issues, knowing at Preparations
the same time that the raw material must comply with
chemical purity specification. The microcrystalline raw Each type of ophthalmic dosage form has advantages and
material as described in USP meets both requirements. drawbacks. The administration of aqueous eye drops appears
Another way to solve the problem is the preparation of a to be the most practical and comfortable dosage form for an
semi-finished product using tetracycline base, dissolved ocular medication. However, the residence time on the eye is
in semisolid base which significantly reduces the very short. Viscous eye drops and eye ointments adhere
decomposition rate [66, 128, 129]. better to and stay longer on the ocular surface.
The patient, carer or nurse should apply each type of
ophthalmic preparation in the correct and reproducible
way. Table 10.20 describes the best instillation technique
[130, 131] for eye drops.
10.8 Release Control and Quality Many patients, especially the elderly, experience
Requirements difficulties in administrating eye drops. It has been
demonstrated that standardisation of administration
For ophthalmic preparations following quality requirements instructions and the use of mechanical aids can improve
apply (see also Table 32.2): patient compliance. Certain commercial products are sup-
• Identity plied with devices to facilitate instillation such as Xal-Ease
• Appearance (homogeneity, for eye drops: clarity and no and Eyot, and also Autosqueeze developed by the British
precipitation) Royal National Institute for the Blind [133]. An overview of
• Content of active substance(s) and preservative the various mechanical aids can be found in Sect. 24.4.19.
Table 10.20 The instillation of eye drops – how to proceed. Example of a patient instruction for the administration of eye drops [130]
1. Wash your hands using soap and water; dry with a tissue – preferably not with a towel which has been used several times. Your eyes and eye
drops are very sensitive to bacterial contamination
2. Unscrew the cap of the dropper bottle and place the cap on its side on a horizontal surface. This will reduce the risk of the ophthalmic solution
being contaminated
3. Check if the dropper tip is damaged
4. Do not touch the tip, either with the eye, eye lashes or anything else
5. If necessary, remove your contact lenses
6. Hold the bottle like a pencil
7. Tilt your head back and look up to your eyebrows
8. Place your index finger of the other hand under the eye concerned. With your finger pull your lower eyelid gently away from the eye creating an
open conjunctival sac to drop the medication into
9. Invert the bottle and hold the dropper bottle vertically above your eye, but be careful not to touch your eye or eyelashes
10. Use the other fingers of this hand to stabilise your head to avoid unexpected contact with the dropper tip
11. Squeeze the bottle and instil one drop into the open conjunctival sac
12. Sit upright
13. Keep your eyelids closed but without forcibly blinking. Firmly press your free index finger into the inner corner (near the nose) of the closed
eyelids. This will ensure that the eye drop solution remains in the eye and does not drain away immediately into the nose
14. Press for between 1 and 3 min
15. Do not blink or forcefully close your eyelids
16. Wipe away any excess (overflow of eye drop solution) from the cheeks
17. If you have to administer eye drops in both eyes, or two drops in the same eye, repeat procedure from 4 to 16
18. Please wait 5 min before instilling a second drop of medication in the same eye
19. Recap the dropper bottle without touching the dropper tip or wiping the dropper tip
20. Store the bottle according to the instructions on the bottle
21. Finally wash your hands again
For patients on an intensive care ward following Arthritic patients, elderly people and children all experi-
procedures were developed: in principle they should ence difficulties with administering eye drops [43,
be applied conscientiously at each hospital ward and 134–137]. In the group of elderly persons studied less
nursing home [132]: than 33 % were able to instil eye drops or even to
• Avoid ocular contact with dropper(tip) and tip of squeeze the dropper bottle. Only 50 % of the persons,
the ointment tube. who were able to administer their eye drops could apply
• Do not use the same dropper tip or tube for both the eye drops into the conjunctival sac. This illustrates
eyes of the patient. This prevents the possible that clear and practical instructions are required. For
spread of infection from one eye to the other. This children clear instructions were described for an alterna-
implies that a separate preparation for each eye is tive method of administration. The technique was initially
preferable. tested on volunteers (20–33 year old). The patients should
• Do not forget to remove contact lenses prior to lay down and close their eyes. The caregiver instils a drop
administering the ophthalmic preparation. on the inner canthus (near the nose), the patient then
• Do not use an eye covering wound dressing in cases slowly opens their eye lids and the drop runs into the
of secreting ocular wounds. tear film. The pharmacological effect of pilocarpine
• Do not perform pulmonary suction over patient’s nitrate 0.25 % and 0.5 % applied using the above
head without a procedure involving protection of described technique, exhibits an effect between that of
his eyes against infection. pilocarpine nitrate 0.25 % and 0.5 % with nasolachrymal
• Do not use swabs imbibed with ethanol when occlusion. The ‘closed eye’ technique is thus an effective
patient is in coma. and easy to use alternative for reluctant children.
(continued)
10 Eye 185
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Rectal and Vaginal
11
Stineke Haas, Herman Woerdenbag, and Małgorzata Sznitowska
Contents 11.6 Method of Preparation, Fat-Based Solution-

Suppositories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
11.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
11.7 Method of Preparation, Hydrophilic-Based
11.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Suppositories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
11.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 11.7.1 Hydrophilic-Based Suspension-Suppositories . . . . . . . . . . 214
11.3.1 Specific Problems of Rectal Administration . . . . . . . . . . . 192 11.7.2 Hydrophilic-Based Solution-Suppositories . . . . . . . . . . . . . 215
11.3.2 Release and Absorption Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 11.8 Release Control and Quality Requirements . . . . . . . . . 215
11.4 Product Formulation, Suppositories . . . . . . . . . . . . . . . . . 195 11.8.1 In-process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
11.4.1 Particle Size of Active Substance . . . . . . . . . . . . . . . . . . . . . . 195 11.8.2 Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
11.4.2 Solubility of Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . 195 11.8.3 Average Weight and Average Content . . . . . . . . . . . . . . . . . 216
11.4.3 Types of Suppository Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 11.8.4 Uniformity of Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
11.4.4 Hard Fat (Adeps Solidus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 11.8.5 Uniformity of Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
11.4.5 Macrogol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 11.8.6 Distribution of Active Substance in Suppositories . . . . . 217
11.4.6 Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 11.9 Product Formulation, Enemas . . . . . . . . . . . . . . . . . . . . . . . . 217
11.4.7 Shape and Size of Suppository Molds . . . . . . . . . . . . . . . . . . 201 11.9.1 Active Substance: Solubility and Particle Size . . . . . . . . 217
11.4.8 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 11.9.2 Vehicle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
11.4.9 Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 11.9.3 Volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
11.4.10 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 11.9.4 Choice of pH and Buffering . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
11.4.11 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 11.9.5 Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
11.5 Method of Preparation, Fat-Based Suspension 11.9.6 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Suppositories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 11.9.7 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
11.5.1 Calculation of the Required Base . . . . . . . . . . . . . . . . . . . . . . . 204 11.9.8 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
11.5.2 Excess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 11.9.9 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
11.5.3 Dispersing Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 11.10 Preparation, Release Control and Quality
11.5.4 Mixing Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Requirements of Enemas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
11.5.5 Pouring the Melt: Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
11.5.6 Choice of Preparation Method . . . . . . . . . . . . . . . . . . . . . . . . . . 212 11.11 Pessaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
11.5.7 Choice of Pouring Temperature . . . . . . . . . . . . . . . . . . . . . . . . 212 11.11.1 Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
11.5.8 Cooling and Finishing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 11.11.2 Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
11.11.3 Shape and Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
11.11.4 Packaging and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
11.12 Product Formulation, Vaginal Solutions . . . . . . . . . . . . 223
11.12.1 Vehicle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
11.12.2 Volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Based upon the chapter ‘Rectaal en Vaginaal’ by Stineke Haas and
11.12.3 Choice of pH and Buffer Capacity . . . . . . . . . . . . . . . . . . . . . 223
Christien Oussoren in the 2009 edition of Recepteerkunde.
11.12.4 Sterility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
S. Haas (*) H.J. Woerdenbag 11.12.5 Excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Department of Pharmaceutical Technology and Biopharmacy, 11.12.6 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
University of Groningen, Antonius Deusinglaan 1, 11.12.7 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
9713 AV Groningen, The Netherlands 11.12.8 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
e-mail: [email protected]; [email protected] 11.12.9 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
M. Sznitowska 11.13 Preparation, Release Control and Quality

Department of Pharmaceutical Technology, Medical University of Requirements of Vaginal Solutions . . . . . . . . . . . . . . . . . . 224
Gdansk, Hallera 107, 80-416 Gdansk, Poland

190 S. Haas et al.
alternative to oral administration, especially in the following

11.14 Semisolid Dosage Forms, Rectal or Vaginal . . . . . . . . . 225
11.14.1 Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 situations:
11.14.2 Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 • Swallowing problems
11.14.3 Additives with a Spermicidal Effect . . . . . . . . . . . . . . . . . . . . 225 • Nausea and vomiting
11.14.4 Dosage Delivery Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
• Impaired consciousness
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 • Severe gastro-intestinal complaints after oral
administration
• An unpleasant taste, especially in children
• A non-cooperative patient, e.g. a small child and the
mentally disabled
Abstract
• When abuse of the medication is suspected or may be life
This chapter is on dosage forms for rectal and vaginal use,
threatening (to take a rectal overdose is difficult)
with the main focus on suppositories and small-scale For rectal administration an active substance can be
preparation methods. The position of rectal and vaginal
formulated into a suppository (solid dosage form) or in an
administration in therapy and research is discussed as
enema (liquid dosage form). The desired onset of action is
well as the main biopharmaceutical issues followed by important for the choice. For a rapid onset an enema is
the design of the formulation and preparation method.
preferable, because a suppository base has to melt or to
The suspension suppository is the most used form and
dissolve first. A suppository may be preferred because its
the qualities of the active substance as well as of the use is easier and more patient-friendly. An enema is the best
excipients largely influence the therapeutic action. There-
choice when a local effect over a large surface is desired, for
fore the chemical form of the active substance, its particle
instance in the treatment of ulcerative colitis. From a practi-
size and the suppository base get the most attention. cal viewpoint an enema can be prepared faster, but is more
The method of preparation is presented in detail,
sensitive to chemical degradation, due to the presence of
i.e. dispersing, mixing and pouring.
water.
The onset of action with enemas is often faster than Examples of rectal administration of active substances for
with suppositories and a larger part of the rectum and
systemic effect are:
colon can be used for absorption. The latter is relevant for
• Treatment of epileptic seizures in children where a rapid
a local action. The chemical form of the active substance, onset of action is very important , e.g. by rectal adminis-
the choice of the solvent and the pH of the preparation are
tration of a diazepam enema (diazepam solution) at
important criteria.
home.
Vaginal pessaries resemble rectal suppositories in • Many active substances for pain control, such as paracet-
many aspects. Differences from rectal suppositories are
amol, diclofenac and opioids such as tramadol and mor-
discussed. Vaginal solutions are mentioned briefly. They
phine, administered as suppositories.
are not frequently used and largely resemble irrigation • Migraine headaches accompanied with nausea and
solutions and solutions for cutaneous use.
vomiting can be controlled by starting with a prokinetic
Finally, semisolid preparations for rectal and vaginal
such as metoclopramide or domperidone in a suppository,
administration are focused on. Little difference exists followed by an analgesic in a second suppository.
from the corresponding cutaneous preparations and they
• Morphine and oxycodone suppositories might be
are only discussed as far as there are specific
useful in terminal patients when oral therapy is
requirements. difficult, but this therapy is often replaced by transdermal
fentanyl.
Keywords
• When nausea and vomiting occur in patients with
Suppositories Enemas Pessaries Vaginal solutions any illness, a chronic oral medication may be temporarily
Biopharmaceutics Formulation Preparation Hard fat
replaced by the same active substance in a rectal
Content uniformity
dosage form: so a hydrocortisone suppository may
replace hydrocortisone in tablet or capsule; a carbamaze-
pine suppository may replace carbamazepine and a
11.1 Orientation valproic acid suppository sodium valproate in syrup, tab-
let or capsule.
Rectal dosage forms may be applied for systemic as well as Even so many active substances may be given rectally to
for local action. Vaginal dosage forms are almost exclu- obtain local action. Some examples are:
sively used for local action. Rectal administration of an • Laxatives such as bisacodyl in a suppository; docusate
active substance for systemic action is sometimes a good sodium and sodium phosphate in an enema.
11 Rectal and Vaginal 191
• Anti-hemorrhoid medication as hydrocortisone acetate, The Ph. Eur. lists under Rectal preparations or Rectalia
lidocaine and zinc sulphate in a fatty cream or ointment the following dosage forms:
and zinc oxide in suppositories. • Suppositories
• Chronic inflammatory bowel conditions (ulcerative • Rectal capsules
colitis, Crohn’s disease) treated by mesalazine, • Rectal solutions, emulsions and suspensions (enema)
beclometasone and budesonide given as a suppository • Powders and tablets for rectal solutions and suspensions
or enema for a local action, but only if the disease is • Semisolid rectal preparations (ointments, creams and
limited to the rectum (suppository) and the distal part of gels)
the colon (enema). • Rectal foams
• A contrast medium like barium sulphate may be given • Rectal tampons
as a suspension by a large volume enema for colon Vaginal preparations are liquid, semisolid or solid
diagnostics. preparations intended for administration to the vagina usu-
Vaginal preparations may especially be used for a local ally in order to obtain a local effect. They contain one or
antifungal or antimicrobial therapy, or for a local treatment more active substances in a suitable basis.
with sex hormones. Butoconazole is used in vaginal Under Vaginal preparations or Vaginalia the Ph. Eur.
PRODUCT DESIGN
suppositories (pessaries or ovules) or in a vaginal cream, lists:
clindamycin in a cream, clotrimazole in a vaginal tablet or • Pessaries
pessary and in a cream, miconazole in a vaginal capsule and • Vaginal tablets
in a cream, nystatin in a cream and metronidazole in a • Vaginal capsules
vaginal tablet or pessary and in a cream or gel. Iodinated • Vaginal solutions, emulsions and suspensions
povidone (povidone iodine) may be applied in the form of a • Tablets for vaginal solutions and suspensions
vaginal solution. • Semisolid vaginal preparations (ointments, creams,
A new development is the incorporation of antiretroviral gels)
substances, such as dapivirine and tenofovir, into an • Vaginal foams
intravaginal ring for HIV prophylaxis. A ring can stay in • Medicated vaginal tampons
situ for 1 (to 3) month(s) and delivers controlled doses of the From the rectal dosage forms the suppositories, enemas,
active substance(s). The antiretroviral substance may be ointments and creams are important as extemporaneous phar-
combined with a contraceptive such as levonorgestrel macy preparations; from the vaginal dosage forms these are the
[1]. These vaginal rings are in various phases of clinical vaginal suppositories (pessaries), solutions, creams and gels.
trial. A similar vaginal ring with only contraceptive action Suppositories are solid, single-dose preparations. Their
has been available for 10 years as NuvaRing® with shape, volume and consistency make them suitable for rectal
etonogestrel and ethinylestradiol. Traditional examples of administration. They contain one or more active substances
sex hormones for vaginal application are estradiol in a vagi- dispersed or dissolved in a suitable basis that may be soluble
nal tablet and estriol in vaginal cream and pessaries. Finally, or dispersible in water or may melt at body temperature.
lubricants and spermicidals are applied vaginally. Excipients such as diluents, adsorbents, surface-active
In clinical practice various oral dosage forms are also agents, lubricants, antimicrobial preservatives and colouring
used for rectal administration. There is often little scientific matter, authorised by the competent authority, may be added
support for such use, nevertheless it may be effective. Evi- if necessary (Ph. Eur.).
dence exists for rectal administration of an oral controlled Rectal solutions, emulsions and suspensions are liquid
release morphine tablet (MS-Contin®) [2, 3]. Rectal use of preparations intended for rectal use in order to obtain a
temazepam oral capsules is not effective. There is a broad systemic or local effect, or they may be intended for diag-
variation in time to reach the maximum plasma concentra- nostic purposes. Rectal solutions, emulsions and suspensions
tion and in the biological availability. Better outcomes are are supplied in single-dose containers and contain one or
obtained with temazepam dissolved in glycofurol:ethanol: more active substances dissolved or dispersed in water, glyc-
water ¼ 5:1:4 and given rectally as an enema [4]. erol or macrogols or other suitable solvents. Rectal solutions,
emulsions and suspensions may contain excipients, for
example to adjust the viscosity of the preparation, to adjust
or stabilise the pH, to increase the solubility of the active
11.2 Definitions substance(s) or to stabilise the preparation. These substances
do not adversely affect the intended medical action or, at the
Rectal preparations are intended for rectal use in order to concentrations used, cause undue local irritation (Ph. Eur.).
obtain a systemic or local effect, or they may be intended for Pessaries are solid, single-dose preparations. They have
diagnostic purposes. various shapes, usually ovoid, with a volume and
192 S. Haas et al.
consistency suitable for insertion into the vagina. They con- bypassing of the hepatic portal circulation and thereby the
tain one or more active substances dispersed or dissolved in first-pass effect. However, clinical studies in men do not
a suitable basis that may be soluble or dispersible in water or support this argument, see also Sect. 16.2.4.
may melt at body temperature. Excipients such as diluents, Rectal absorption of an active substance proceeds, usu-
adsorbents, surface-active agents, lubricants, antimicrobial ally, more slowly and less completely than oral absorption.
preservatives and colouring matter, authorised by the com- The active substance can only be absorbed after melting or
petent authority, may be added if necessary (Ph. Eur.). dissolution of the base and dissolution of the active sub-
stance in the rectum fluid. These processes take time. Addi-
tionally, the surface for rectal absorption is much smaller
11.3 Biopharmaceutics than for oral absorption. Literature often advises higher
standard dosages for rectal administration. The rectal dose
An active substance is rectally administered for either a of carbamazepine, for example, is for children 125 % of the
systemic or a local effect. The biopharmaceutics of the oral dose [6]. No universal guidance could be found for the
systemic effects have been studied quite well. The outcomes dose correction for rectal administration. When a rectal
of these studies support recommendations for the formula- dosage cannot be found in literature the safest approach is
tion of rectal dosage forms, see Fig. 11.1. See also Sect. to use the oral dosage.
16.2.4.
In contrast, very little is known about the
biopharmaceutics of vaginal dosage forms. The vagina has
11.3.2 Release and Absorption Rate
good absorbing properties, but this is seldom used for a
systemic effect. Vaginal dosage forms are administered for
Contemporary research focuses on the development of dos-
a local effect only.
age forms with a better and faster release of the active
Rectal and vaginal dosage forms aimed to obtain a local
substance and on dosage forms with a delayed or controlled
effect are, from a biopharmaceutical viewpoint, comparable
release. The addition of surfactants to the suppository often
with dermal preparations. However it should be known that
enhances the rate and extent of release and even the absorp-
after rectal and vaginal application a greater part of the
tion of an active substance, but there are many exceptions.
active substance may reach the general circulation than
For a delayed or controlled release an increased viscosity of
after cutaneous application. This may result in significant
the suppository mass appears to be relevant. Most research
blood levels and unwanted systemic effects.
has not yet yielded a licensed medicine.
Rectal administration of an active substance can be
justified only if adequate data are available about the release
from the dosage form and the absorption from the rectum. Absorption Enhancers
Without such a support rectal administration of an active Many studies have been published on the use of vari-
substance should be discouraged. Tables with data from ous enhancers for the rectal absorption. They increase
biopharmaceutical and pharmacokinetic research on rectally the absorption of an active substance by enhancing the
administered active substances are available from literature membrane permeation, rather than increasing the sol-
[5a]. ubility. Published examples of absorption enhancers
are capric acid and sodium caprate, lauric acid and
sodium laurate, sodium salicylate and sodium cholate.
11.3.1 Specific Problems of Rectal These enhancers however give an unpredictable and
Administration strongly variable improvement of the biological avail-
ability [5b]. Nevertheless they sometimes lead to a
Compared to oral administration, rectal administration licensed medicine: sodium caprate is already in use
encounters some specific problems. Degree and rate of in a suppository product available in Japan [7].
absorption of the active substance are more difficult to
predict and depend largely on the never predictable resi-
dence time in the rectum. Both irritation of the rectal mucosa Non-ionic surfactants can be added to a fatty suppository
by the active substance or the excipients and a large (liquid) base to enhance the release of poor water-soluble active
volume in the rectum may cause a defecation reflex substances [5b]. The results of studies on this subject, how-
terminating the absorption process of the active substance. ever, vary considerably. Often the in vitro release is
Also the degree of filling of the colon and sometimes the improved, whereas the in vivo results are disappointing
rectum influences the release and the absorption of the active [8a]. This is partly caused by the formation of micelles in
substance. In favour of rectal administration would be the rectal fluid and partly by the influence of the surfactant
positive negative
choice of dosage form
suppository • easy administration • melting takes time

• mostly suspension
enema • no melting process • packaging more complex

• mostly solution • demanding administration
• larger volume may give
faster absorption
choice of base
fatty • hardly any incompatibility • 2 compartments -> takes
PRODUCT DESIGN
more time
water(soluble) • 1 compartment -> faster • dissolution of suppository

takes more time than the
melting of a fatty one
choice of form active substance
salt/ free base/ free acid • form not soluble in base • active substance, very
is (often) positive for a fast badly soluble in rectum
release fluid, is hardly absorbed
• best form in combination • active substance,
with type of base has to be completely ionized, is
chosen based on literature hardly absorbed
data
choice of particle size
(for suspensions)
fatty base, active • rate of particle transport • particles maximal 180 μm,
substance good water to interface determines rate otherwise the preparation
soluble of active substance release will be difficult
• larger particles have • particles >240 μm not
faster transport and optimally spread with the
therefore a faster release base -> slower release
fatty base, active • extent of interface • very small particles may

substance poorly water determines rate of release irritate the rectal mucosa if
soluble • small particles do better the solubility is a little better
spread with the base • e.g. acetylsalicylic acid
• best choice is a large does, paracetamol does
volume of the dosage form not
and a small particle size
water(soluble) base, • small particles dissolve • particles maximal 180 μm,

active substance poorly faster otherwise the preparation
water soluble • larger volume of dosage will be difficult
form -> faster absorption
Fig. 11.1 Rectal dosage forms for systemic action: biopharmaceutical considerations
194 S. Haas et al.
on the rectum wall. In fat-based suspension-type

suppositories the release rate is determined by the particle H15 alone. In vivo the morphine level initially
transport to the surface of the fatty phase and by the dissolu- increases slowly and remains on a relatively high
tion rate in the aqueous rectum fluid. For active substances level for a longer time.
with a moderate to poor solubility in water the rate- Morphine sulphate in a matrix of a fatty base
determining step is the dissolution of the active substance (Witepsol® W25) with colloidal anhydrous silica
in the rectal fluid, see also Sect. 16.2.4. This dissolution may (Aerosil® R 972 ) and hydroxypropylmethylcellulose
be accelerated by a better wetting of the active substance (HPMC 4000) [10] showed an absorption rate and a
particles. This can be achieved by adding a surfactant [8b]. biological availability equivalent to orally given mor-
In general, the rate of release in vitro increases with an phine sulphate retard tablets (MS Contin®). Such
increasing amount of surfactant [8a]. However, in vivo suppositories can be made as a regular pharmacy
there is a critical concentration. It appears that at higher preparation [11] but in our opinion this requires more
concentrations of surfactant the absorption of active sub- convincing evidence that morphine release is suffi-
stance decreases again. The critical concentration of sur- ciently reproducible. MS-Contin® suppositories (not
factant seems to be 1–3 % of the suppository weight. available in all countries) have a fatty base with
Probably the active substance gets enclosed in micelles sodium alginate and calcium phosphate [12].
in the rectal fluid. This may reduce or even impair the Metoclopramide hydrochloride controlled release
absorption [8a]. Surfactants may also change the mem- suppositories were prepared by mixing Witepsol®
brane permeability. These changes depend on surfactant W35 with 30 % lecithin [13]. The metoclopramide is
concentration and will alter the absorption. Because of incorporated in this base in a (solid) reversed micellar
such large and varying influences on the absorption of solution. The diffusion rate of the active substance
active substance, surfactants may only be added based on from the melted suppository in contact with the aque-
in vivo research, such as has been done with the influence of ous rectum fluid was very low. Compared to licensed
lecithin on absorption from indometacin suppositories. The normal metoclopramide suppositories a five times lon-
influence of different concentrations of surfactant on ger mean residence time was found in vivo for the
release and absorption is illustrated with indometacin lecithin suppositories.
suppositories. Witepsol® H15 was used as suppository A survey of research on special formulations of
base and increasing amounts of lecithin were added. The suppositories, such as hollow type suppositories, can
addition of 1 % lecithin (about 25 mg per suppository) gave be found in [5d].
a distinctly higher blood concentration. The dissolution
rate of indometacin was increased and, as a result of the
decreased viscosity of the suppository mass by the surfac-
tant, the suppository spread better in vivo, giving a larger
area for indometacin release. In this way the surfactant
increased dissolution over a larger area and hence increased
the blood concentration [8a]. However, increasing the Unconventional (Suppository) Bases and (Vaginal)
quantity of lecithin to over 300 mg per suppository pro- Delivery Systems
duced slow release profiles and sustained plasma levels of Other rectal dosage forms may be used other than
indometacin when administered to rabbits. Consequently, a fat-based suppositories. One study describes a liquid
sustained release (controlled release) indometacin supposi- ‘suppository’ that immediately after administration
tory was created [5c]. forms a gel with strong adhesion to the rectal mucosa
[14]. The gelling at body temperature is caused by a
poloxamer. Adhesion to the rectal mucosa is provided
Controlled Release by carbomers and cellulose derivates. Compared to a
Controlled release by increasing the viscosity of the fatty suppository, this delivery system is expected to
suppository base has been studied with morphine. spread less far into rectum and colon, thereby avoiding
A fatty base such as Witepsol® H15 is miscible the hepatic portal system (see also Sect. 11.3).
with polyglycerol esters of fatty acids with a relatively The vaginal delivery system for dinoprostone
high melting point, such as decaglycerol (Propess® 10 mg) is even more different from the
heptabehenate (HB750®) [9]. The increased viscosity classical dosage forms for rectal or vaginal use. It is
of the melted mixture, results in a slower in vitro a thin, flat polymeric matrix of crosslinked macrogols
release of morphine sulphate compared to Witepsol forming a hydrogel in the vagina. Dinoprostone is
• The irritation of the rectal mucosa

released from the matrix in a controlled way: about • The chemical stability of the active substance
0.3 mg per hour during 24 h. A knitted polyester The particle size is preferably chosen based on published
retrieval system envelopes the matrix and facilitates data. If these are not available it has to be chosen in accor-
removal from the vagina at the time the cervical dance with the physico-chemical properties of the active
ripening has completed as decided by the substance. Section 16.2.4 gives guidance for such a choice,
gynaecologist [15]. summarised as follows:
Another intravaginal device is the vaginal ring see • For a fatty base with a good water soluble active sub-
also Sect. 11.1. Already available is the NuvaRing®, stance, a particle size as large as possible should be taken,
used as contraceptive. It is a polymeric vaginal ring but not above 180 μm.
containing etonogestrel and ethinylestradiol. The ring • For a fatty base with a slightly water soluble active
has to be placed high in the vagina and should stay substance that is very slightly or practically insoluble in
there for 3 weeks. After a 1-week break the next ring is the fatty phase as well, a particle size as small as possible
inserted. Vaginal rings containing antiretroviral should be taken, for instance 45 μm for paracetamol.
medicines for HIV prevention have been developed, • For a fatty base with a slightly water soluble active
PRODUCT DESIGN
but are not yet available for use. They show a sustained substance that is sparingly to freely soluble in the fatty
and controlled active substance release over 28 days, phase, the particle size of the active substance has hardly
sometimes over 90 days. Polymers used for the rings any influence.
are, for example, polysiloxanes and polyurethanes. For • For a water soluble base with a slightly water soluble
the NuvaRing® 2 different ethylene vinyl acetates active substance, small particles are chosen because they
are used. dissolve more readily; usually a particle size not exceed-
ing 180 μm satisfies.
A stable suspension of active substance in the base is
important during the preparation process, especially when
11.4 Product Formulation, Suppositories
the melted mass is poured into the molds and during
subsequent cooling and solidification. The smaller the
This section discusses the active substance (particle size and
particles, the more stable the suspension (see also Sect.
solubility), the bases and the excipients to obtain optimal
18.4.2). In practice, a particle size not exceeding 180 μm
release and absorption. Obviously these three components
meets all demands. Any agglomerates should be carefully
are closely interrelated. The active substance must be used in
fragmented.
a chemical form, ionised or not, and with a particle size that
Irritation of the rectal mucosa occurs when large particles
are optimal for release and rectal absorption. In addition a
are used. A particle size of 180 μm should therefore be the
base has to be chosen that optimises release, see also
maximum. Irritation of the mucosa may also occur when
Fig. 11.1. Excipients can be added to improve dissolution
small particles of an irritating active substance dissolve (too)
and absorption or for technological reasons. However,
quickly. This happens for instance when acetylsalicylic acid
excipients aimed at technological improvement may also
with a particle size of 45 μm is used in suppositories. It has a
influence the release of active substance. Whatever choice
fast release of the active substance from the suppository and
is made for active substance, base and excipients, their
it dissolves rapidly, but as a result it irritates the mucosa.
impact on the preparation process, the stability of the prod-
Therefore acetylsalicylic acid should be used with a particle
uct and the shelf life must also be considered.
size of 180 μm.
Chemical degradation occurs faster when the total surface
of the particles is larger. Therefore a larger particle size
11.4.1 Particle Size of Active Substance enhances chemical stability, for instance particles of
90–180 μm.
Usually the active substance does not dissolve in the
base. Even lipophilic substances are often poorly soluble
in fatty bases, so most suppositories are suspensions of
the active substance in a (solid) vehicle, the suppository 11.4.2 Solubility of Active Substance
base. For these suspension suppositories the particle size
of a dispersed active substance is important because it If an active substance is practically insoluble in water (and
influences: therefore in the rectal fluid), the suppository will be ineffec-
• The pharmaceutical availability of the active substance tive. Certain excipients may increase the water solubility
• The physical stability of the suspension and, as a result, the absorption. A surfactant can be added
196 S. Haas et al.
for a better wetting of the particles and thereby increasing

dissolution rate. A macrogol (polyethylene glycol) supposi- Methadone is best incorporated in a macrogol base
tory base may increase the solubility of the active substance in the form of its hydrochloride salt, to obtain a good
by acting as a co-solvent. As the suppository dissolves in the efficacy. Methadone hydrochloride (pKa 8.25) will be
rectal fluid, a mixture of macrogol and rectal fluid develops, released from a fatty base, but at the rectal membrane
in which the active substance may dissolve better. methadone is converted to its unionised form. This
The active substance should have certain lipophilicity as lipophilic substance is so poorly soluble in the aqueous
well. If not, it will not pass the rectal lipoid membranes. On rectal fluid that it is not absorbed. By using a macrogol
the other hand, a too high lipophilicity causes the active base (macrogol 1500 or PEG 1500), the solubility of
substance to be hardly released from a fatty base. For a the unionised methadone in the rectal fluid (now
systemic effect a good water-soluble active substance is containing the macrogol as co-solvent) is improved
preferred with sufficient lipophilicity at the pH of the rectal [19, 20].
fluid to allow passage of the rectal membranes for absorption
[8c].
Which form of the active substance should be chosen,
more hydrophilic or more lipophilic, is related to the choice 11.4.3 Types of Suppository Base
of the suppository base, fatty or water soluble. These choices
can only be based on published data about release and The common suppository bases can be classified into two
absorption. main categories: the lipophilic and the hydrophilic bases.
See Sect. 11.3 and Fig. 11.1 for the choice between these
types from a bioavailability viewpoint. Usually a fatty base
Form of Active Substance and Type of Base will comply but a lipophilic active substance may not be
in Relation to Efficacy released well enough, because the partition coefficient lipid/
Glafenine has a solubility in water of 1 in 60,000 at water is unfavourably high. The consultation of published
pH 7. The rectal absorption of glafenine from an data about active substance release and absorption is
aqueous micro-enema, and of glafenine hydrochloride recommended. When published data are not available, the
from a fatty suppository is extremely slow and incom- solubility of the active substance (Sect. 11.4.2) should be
plete, due to the low solubility of glafenine at the pH in considered, but without in vivo test the therapeutic action is
the rectum [16]. Therefore this active substance is not not assured. This section considers some general character-
effective after rectal administration, although istic points of the bases and gives some information on the
glafenine suppositories were commercially available less usual bases cocoa butter and glycerinated gelatin. The
in the past century. On the contrary, for example, the most used bases, hard fat and macrogol, are dealt with in
solubility of phenobarbital in water of 1 in 1,000 is Sects. 11.4.4 and 11.4.5.
sufficient for rectal administration. A suppository base should not irritate the rectum and be
Hydrocortisone (soluble in water 1 in 3,500) is harmless in case of absorption. Chemically and physically,
better soluble than hydrocortisone acetate (practically the base should have a good shelf life and not decrease the
insoluble in water). Therefore, in a suppository given stability of the active substance.
for a systemic effect, hydrocortisone is used, but in a With regard to the preparation process the following
suppository given for local problems such as requirements are set:
haemorrhoids, hydrocortisone acetate is preferred, in • Upon solidification, the base must not form unstable
order to avoid unwanted systemic effects. modifications with a solidification point below room
Phenobarbital sodium can be processed in a fatty temperature, as is seen for cocoa butter.
base and the release of this salt is faster than that of the • Upon solidification, the suppository mass (base + active
corresponding acid, phenobarbital. The bioavailability substance(s) + excipient(s)) preferably contracts slightly,
of both substances is almost equal, but for the rapid facilitating removal from the mold.
increase of plasma concentrations the salt is the better • At the pouring temperature, the suppository mass should
choice [17, 18]. be sufficiently viscous to prevent the settling of dispersed
Sodium valproate is released well from a fatty base, particles during the filling process.
but absorption is better with the free acid in a fatty • At room temperature, the suppository mass must be solid
base [17]. Moreover, the processing of valproic acid is and must keep its shape.
much easier than that of the strongly hygroscopic Seldom will a suppository base meet all these qualities.
sodium salt. For both reasons the acid is preferred. The properties of a base may be improved by the addition
of a substance that influences the melting point. For instance,
(continued)
Table 11.1 Chloral Hydrate Suppositories 500 mg [21] 34–35 C, 28 C, and 18 C respectively. The beta-form is
For a suppository mold 2.3 mLa: the most stable one.
Chloral hydrate 0.5 g Cocoa butter suppositories can be extemporaneously
Macrogol 1500 2g prepared by hand rolling (the oldest, historical method),
Macrogol 6000 0.17 g compression molding (compressing cold mass into the
a
In case of a different volume of the mold, the ratio between chloral molds) and fusion molding (filling the molds from a melt).
hydrate, macrogol 1500 and macrogol 6000 has to be reinvestigated The first and the second method have the advantage of
avoiding heating and melting of the cocoa butter. Problems
on solidification of the mass, caused by the polymorphism,
Table 11.2 Zinc Oxide Suppositories 10 % [23]
are bypassed in this way. In both methods grated cocoa
butter is mixed with the active substance in a mortar, using
For a suppository mold of any volume:
a plastic card. In hand rolling the mass from the mortar is
Zinc oxide (90) 10 g
pressed in the palm of a hand into an elastic mass that is cut
Triglycerides, medium-chain 20 g
into an appropriate number of portions and subsequently
Hard fat 70 g
rolled by hand on a flat surface to obtain a cylindrical
Total 100 g
PRODUCT DESIGN
shape, conical at one end. Plastic gloves should be worn
when forming the suppositories. Hand-operated compres-
sion molds facilitate different shapes and sizes of the
the use of a macrogol (polyethylene glycol or PEG) combi- suppositories, so there is little need for shaping by hand
nation with a higher melting point than the usual macrogol anymore [5e].
base gives chloral hydrate suppositories a sufficient consis- In compression molding, the mixture in the mortar is
tency (Table 11.1). transferred to special pressing equipment, holding the proper
A low melting point may be necessary when the body compression mold (see Fig. 11.2). The method requires a
temperature of the patient is below normal. A low body replacement factor (see Sect. 11.5.1) specifically valid for
temperature may occur at terminal illness. From a standard this compression method. In both ‘cold’ methods the quality
suppository base, the release of the active substance will be of mixing active substance and grated base is very critical for
insufficient. For a low melting point, 20 % of the fatty base sufficient content uniformity of the suppositories. Although
is replaced by a liquid triglyceride such as Miglyol®, such as no investigations are available, it is obvious that this process
is done for morphine suppositories in clinical practice [22]. is most critical with low-dosed active substances and defi-
A low melting point may also be needed to obtain a better nitely has to be validated.
local effect, for example in 10 % zinc oxide suppositories Fusion molding involves mixing the active substance
(Table 11.2) that are used to soothe haemorrhoidal pain. In with molten cocoa butter and pouring the mixture into the
this formulation 20 % of the total weight consists of mold. Because of the polymorphism, great care is needed to
Miglyol® 812. As a result of the low melting point, the melt the base properly. When cocoa butter is melted too fast
suppository melts superficially at insertion, creating a pro- and too far above 36 C is kept too long too warm or is
tective layer in the anal canal. cooled down too quickly, the result is the metastable alfa-
Increasing the melting point of a fatty suppository modification. This modification has a substantially lower
above a normal body temperature is not an option. Not melting point giving rise to difficulties in solidification. In
even in suppositories for tropical use if melting during fact, the melting point may become so low that the cocoa
storage and transport has to be prevented. With a higher butter will not solidify at room temperature any more. How-
melting point the in-patient melting time and therefore the ever there is a slow transition from the alfa-form to the more
time to the release of the active substance will be stable beta-form (with higher melting point), which may
unacceptably long. take several days [5f]. An ongoing transition of unstable to
stable modifications during storage may affect the melting
11.4.3.1 Cocoa Butter properties of the suppository and therefore the release of the
Cocoa butter (Cacao oleum) is a solid fat, pressed from the active substance.
roasted seeds of Theobroma cacao. Since the middle of the As opposed to these disadvantages of cocoa butter in
eighteenth century it is used as a suppository base. Cocoa fusion molding, there is the advantage that in compression
butter melts at body temperature. At room temperature it is a molding (cold preparation) no settling of particles will
solid mass. But cocoa butter has a number of undesirable occur, thus eliminating a main cause for content uniformity
properties: it soon becomes rancid on storage and it exhibits problems.
marked polymorphism. It has four polymorphic forms: alfa, Hard fat, the alternative for cocoa butter, is less sensitive
beta, beta-accent and gamma. The melting points are 22 C, to rancidity and shows substantially less modifications.
198 S. Haas et al.
Fig. 11.2 Hand press (a) and molds (b), used in compression molding. Source: Department of Pharmaceutical Technology GUMed Gdansk,
with permission
Therefore it has replaced the cocoa butter as a suppository 11.4.4 Hard Fat (Adeps Solidus)
base in Dutch pharmacies, although the disadvantage of
particle settling during pouring has to be overcome instead. Hard fat is a collective name for (semi-)synthetic mixtures of
Hard fat is the main suppository base in many countries. mono-, di- and triglycerides of the fatty acids C10 - C18 with
Cocoa butter has until now a place in suppository prepara- a melting range between 33 and 36 C. It is marketed in
tion in some other countries. many varieties and under various brand names. An elaborate
survey with the composition, melting and solidification
range, hydroxyl value, acid value, saponification value, per-
11.4.3.2 Glycerinated Gelatin oxide value and iodine value can be found in [5g]. Table 11.3
The oldest water-soluble suppository base is a mixture of shows the characterisation parameters of common fats used
gelatin, glycerol and water. The ratio differs from country as suppository bases. Some of these properties will be
to country. The Dutch pharmacopoeia (Ph. Ned. VI) described.
specified Suppositoria Gelatinosa as containing 2 parts of
gelatin, 5 parts of glycerol 85 % and 4 parts of water. BP
11.4.4.1 Hydroxyl Value
and USP describe this type of base as well. The
By varying the ratio of mono-, di- and triglycerides, different
glycerinated gelatin base has long been used in pessaries
hydroxyl values are obtained. A higher hydroxyl value is,
(vaginal suppositories) for its good adhesion properties to
among others, associated with more tendency to further
the vaginal mucosa and its patient friendly softness. How-
hardening after preparation and a higher elasticity and vis-
ever, a glycerinated gelatin base may give microbiological
cosity of the (molten) base [8d]. Higher elasticity diminishes
problems on storage. Using a natural starting material (gel-
the risk of fracturing at rapid cooling. A higher viscosity is
atin) enhances the chance of microbiological contamina-
advantageous for the suspension stability of the active sub-
tion. Water can condense at the package and micro-
stance in the molten base, but may also reduce the availabil-
organisms may then grow. Physical problems related to
ity of the active substance [24]. Otherwise, a very low
storage are loss of water in dry circumstances and a ten-
hydroxyl value may have an unexpected influence on the
dency to absorb moisture under damp conditions. For these
active substance release. Therefore bases with very different
reasons and from the authors’ viewpoint, the use of
hydroxyl values should not be exchanged without further
glycerinated gelatin base for rectal and vaginal dosage
investigation.
forms is obsolete. Nevertheless, in many countries this
base is used for pessaries. Such pessaries must be kept in
well-closed containers and in a cool place. For an extended 11.4.4.2 Acid Value
shelf life a preservative should be added, such as methyl A low acid value is desirable because irritation of the
parahydroxybenzoate or propyl parahydroxybenzoate or mucous membrane and chemical reactivity increase with a
both (see Sect. 23.8.5). Otherwise the shelf life should be higher content of free fatty acids. According to the Ph. Eur.,
limited to 1 or 2 weeks. the maximum acid value is 0.5.
Table 11.3 Characterisation parameters of commonly used lipophilic suppository bases

Suppository base Melting range ( C) Solidification range ( C) Hydroxyl valuea Iodine valueb Acid valuec
Adeps solidus (hard fat)d 30-45 – 50 3 0,5
Novata B 33.5–35.5 31–33 20–30 3 0.3
Suppocire AM 35.0–36.5 – 5 – –
Witepsol H15 33.5–35.5 32.5–34.5 5–15 3 0.2
Witepsol W25 33.5–35.5 29–33 20–30 3 0.3
Witepsol W35 33.5–35.5 – 40–50 3 0.3
Witepsol E75 approx. 38 – 15 3 0.3
Cocoa butter 31–34 – approx. 0 31–38 <5
a
Milligrams of potassium hydroxide required to neutralise the acid that is bound by acylation of 1 g of the substance
b
Grams of halogen, calculated as iodine, that can be bound by 100 g of the substance
c
Milligrams of potassium hydroxide required to neutralise the free acids in 1 g of the substance
d
According to the Ph. Eur.
11.4.4.3 Iodine Value requirements of Ph. Eur. and have the same melting range,
PRODUCT DESIGN
The iodine value is a measure of the number of double bonds may still have different solidification ranges due to a differ-
in an oil or a fat. A low iodine value in the base is achieved ent composition.
by using esters from saturated fatty acids. A large number of A short interval between melting point and solidification
double bonds increases the tendency to oxidation and point seems to be advantageous as it shortens the time that
rancidity. particles can settle after the suppository mass has been
poured into the molds. This settling may lead to a brittle
11.4.4.4 Peroxide Value tip. This is however not necessarily true, because often
The peroxide value is a measure of the amount of reactive supercooling occurs before the mass starts to solidify [8e].
oxygen in the fat. A low peroxide value decreases oxidation Forced cooling will shorten the solidification time but it
of the active substance by the base which enables processing cannot be applied to each type of hard fat; fractures easily
of easily oxidisable active substances, such as ergotamine occur in the suppository.
and chlorpromazine. A different composition of hard fat also influences the
solidification behaviour and may cause a (welcome) increase
of viscosity before the mass solidifies completely. The vis-
11.4.4.5 Saponification Value
cosity increase may decrease settling during the filling pro-
The saponification value is directly related to the molecular
cess and thereby improve content uniformity. Often
weight of the fats, and thus to the chain length of their fatty
however, during cooling, no increase of viscosity is seen
acids and to the melting point. Hard fat with a melting point
but suddenly a fast solidification occurs. This solidification
(actually a melting range) between 33 and 36 C meets the
behaviour complicates manual preparation of suppositories.
requirements of the Ph. Eur. regarding the saponification
The lack of gradually increasing viscosity is a quality aspect
value of 210–260.
of hard fat that usually gets too little attention.
The requirements set by the Ph. Eur. to hard fat are rela-
As for cocoa butter various modifications exist for hard
tively broad; all mentioned brands meet them. To limit for-
fat, but their consequences are much less pronounced [8f].
mulation variation, it is recommended to use only one or two
Therefore, control of temperature during melting and
types of fatty suppository bases. Commonly used are
cooling comes far less precise than in cocoa butter. Never-
Witepsol ® H15, Suppocire ® AM, Novata ® B and Witepsol
theless, the polymorphism of hard fat is responsible for some
W25. Witepsol H15 is the most commonly used suppository
physical processes including the process of secondary hard-
base in the Netherlands and many other countries. Suppocire
ening (ageing) as described in Sect. 11.4.8. It is hardly
AM is useful for acidic ingredients. Its low hydroxyl value
possible yet to trace back this process to certain phase
may diminish interaction between free hydroxyl groups and
transitions.
acidic active substances. The last two bases may withstand
forced cooling, as they have a higher hydroxyl value and
consequently a larger elasticity [25]. 11.4.4.7 Compatibility
Hard fat is compatible with the majority of active
11.4.4.6 Solidification Point or Solidification substances. However, active substances with free acid
Range groups can react with the free hydroxyl groups of the
The Ph. Eur. sets no requirements for the solidification point mono- and diglycerides. For such active substances a base
or range of hard fat. Hard fat types which meet the with a low hydroxyl value should be used.
200 S. Haas et al.
Active substances can also react with the free fatty acids circumstances. Its usability is however restricted by the
in the base. To avoid this, a base with a low acid value can be chemical incompatibilities and the hygroscopic character.
chosen, so with few free fatty acids.
Reactions of an active substance with free hydroxyl 11.4.5.3 Irritation
groups or free fatty acids of the base changes the melting From a macrogol base the active substance is released not
behaviour and thereby may affect the release of the active only by melting of the base, but primarily by dissolving of
substance. the base in the rectal fluid. Due to the high osmotic value of
Reactions of an active substance with peroxides in the the dissolved macrogol, water is withdrawn from the
base can be prevented by choosing a base with a low perox- surrounding tissue. This may cause irritation [8g]. Moisten-
ide value. When formulating ergotamine or chlorpromazine, ing the suppository with water before insertion is suggested
the peroxide value of the base must not exceed 0.5. to avoid irritation [5h]. It will help insertion but the effect on
irritation is questionable because much more water will be
attracted when the suppository dissolves.
11.4.5 Macrogol
Macrogols are polymers of ethylene oxide, see Sect. 23.3.4. 11.4.6 Excipients
Usually mixtures of macrogols are used as suppository base.
The desired hardness can be adjusted by choosing the molec- In suppositories all excipients should be used with care. The
ular weight and suitable ratios. Even macrogol 1500 is too addition of excipients often negatively influences active
soft if used as such [8g]. The most commonly used base in substance release. This applies for instance when tablets
Dutch pharmacies is 1 part of macrogol 1500 plus 2 parts of are used as starting material because of costliness or unavail-
macrogol 4000. If suppositories with this base become too ability of the active substance as such or when the quantity
soft, a macrogol with a higher molecular weight should be needed is too small to be weighed with sufficient accuracy
used, see the example in Table 11.1. (see Sect. 29.1.8). The very nature and the amount of
excipients in tablets is usually unknown and may have
unexpected effects on active substance release. Especially
11.4.5.1 Advantages and Disadvantages talc and magnesium stearate, common excipients in tablets
A macrogol base will mostly be chosen based on published and insoluble both in fat and in water, may strongly impair
data showing better release or absorption, or both. The the release by accumulating in the interface between fat and
advantage of water solubility and thus avoidance of the water [24].
melting time is somewhat overestimated because the disso-
lution of macrogol in the rectal fluid takes time as well. Once 11.4.6.1 Lactose
the macrogol has been dissolved the active substance release In suspension suppositories, the active substance is
is faster than from a fatty base because in the latter transport processed as small particles that are prone to form
of the active substance from the fatty to the aqueous phase agglomerates. The effective dispersion of the agglomerates
still has to take place. Moreover the active substance can (see Sect. 29.3) is a prerequisite for a sufficient content
dissolve in the rectal fluid simultaneously with the base. The uniformity. Lactose may be used in pharmacy preparations
base has considerable disadvantages however: chemical to disperse the agglomerates and to maintain separation of
incompatibilities and irritation. the primary particles. This is most important with low dosed
active substances, which do not easily lead to a good content
uniformity. If 50 mg or less of active substance(s) is used
11.4.5.2 Incompatibilities
per suppository, as a standard 100 mg lactose may be
Macrogols are incompatible with many more active
added to each suppository, as illustrated by chlorpromazine
substances, compared to hard fat. Upon storage, macrogols
suppositories in Table 11.4. The added lactose should not
can form peroxides and therefore they are not suitable for the
be considered as a filler only as it is in tablets or capsules, but
processing of easily oxidisable substances such as ergota-
its main function in suppositories is the dispersing of the
mine and chlorpromazine (Sect. 22.2.2). Incompatibilities
active substance.
may also be caused by complex formation and trans-
esterification. Acetylsalicylic acid decomposes rapidly in a
Table 11.4 Chlorpromazine Hydrochloride Suppositories 25 mg [27]
macrogol base, yielding salicylic acid while macrogol is
acetylated. A list of incompatibilities with macrogols can Chlorpromazine hydrochloride 0.025 g
Lactose monohydrate (180) 0.1 g
be found in [26]. Because of its high melting point, a
Hard fat with peroxide value 0.5 q.s.
macrogol base is often recommended for use in tropical
Table 11.5 Paracetamol and Codeine Suppositories 1000 mg/60 mg [29] Table 11.6 Suppository Molds
For a suppository mold of at least 2.8 mL: Volume Application
Paracetamol (45) 1g 1.15 mL Children up to about 4 years
Codeine phosphate hemihydrate (90) 0.06 g 2.3 mL Standard
Silica, colloidal anhydrous (compressed) 0.005 g 2.8 mL Larger quantities of active substance
Lecithin (NF) 0.06 g
Hard fat At least 1.8 g
11.4.6.3 Lecithin
When large amounts of active substance are incorporated in
a suppository, especially when the active substance particles
In large-scale preparations of suppositories lactose are very small, the viscosity of the melted mass may become
may be added for another purpose. Sometimes a high so high that it cannot be poured out into the mold. This
dose analgesic suppository has a good structure, while happens in the preparation of suppositories containing
a low dose suppository is brittle. In such case another 1,000 mg paracetamol with a particle size of 45 μm and
suppository base may be used. More easily, the vol- Witepsol H15 as the base (Table 11.5). Adding a small
PRODUCT DESIGN
ume of the suspended active substance may be quantity of soya lecithin renders the mass more fluid. In
increased by adding lactose. This provides a good general, 1–2 % of soya lecithin, calculated on the supposi-
suppository too. In this case the lactose only acts as tory weight, is sufficient [8h], see Table 11.5. A disadvan-
filler. Other fillers used in suppositories are sucrose tage of adding soya lecithin is that air gets beaten into the
and microcrystalline cellulose [8h]. suppository mass more easily [28]. Larger amounts of leci-
thin may delay the absorption of the active substance (see
Sect. 11.3.2).
11.4.6.2 Colloidal Anhydrous Silica 11.4.6.4 Antioxidants

Dispersing of agglomerates may also be achieved by using In pharmacy preparations of suppositories antioxidants are
colloidal anhydrous silica (colloidal silicon dioxide use seldom used. If needed, butylhydroxytoluene (BHT) and
Aerosil® 200V, the compressed quality). For example, butylhydroxyanisole (BHA) may be the right choice in
colloidal anhydrous silica facilitates the dispersing of fatty suppositories, but see Sect. 22.2.2. These antioxidants
agglomerates in a mixture of paracetamol and codeine phos- are lipophilic and dissolve easily in a fatty base. The usual
phate. It should be added in an amount of 0.5 % of the concentration in fats is 0.02 % [30], see also Sect. 23.9.
amount of paracetamol, as in suppositories with high doses
of paracetamol and codeine (Table 11.5). In general, colloi-
dal anhydrous silica can be added up to a maximum of 1 %
11.4.7 Shape and Size of Suppository Molds
of the weight of the active substance.
Suppositories may appear in various shapes, including a
When silica is used, it should be considered that the cylindrical, a conical and a torpedo form. The torpedo
release of aqueous soluble to very soluble active shape is generally used in pharmacy preparations, see
substances may be reduced. Silica increases the vis- Fig. 11.6. Suppository size varies from 1 to 4 mL. Com-
cosity of the base which may impair the transport of monly a size of 2–3 mL is used, for young children usually a
the active substance to the interface between water and size of 1 mL is taken, see Table 11.6.
fat, thereby impairing active substance release. For From a biopharmaceutical viewpoint, a large sized sup-
water-soluble active substances, crossing the interface pository may be advantageous. In principal, a larger volume
is rate determining (Sect. 16.2.4). For this reason the spreads over a larger intestinal surface. As a result more
amount of silica has to be limited to 1 % of the weight active substance is released from the base, more active
of the active substance. A negative influence of anhy- substance dissolves in the rectal fluid and the absorption is
drous colloidal silica on active substance release is faster. This is especially important for substances that are
evident for amounts above 1.5–2 % of the suppository poorly soluble in both fat and water, such as paracetamol.
base [8i]. Concentrations above 1.5–2 % are used only The release of active substance from the base in this case
for suppositories with an intentionally delayed release strongly depends on the extent of the interface between fat
profile. and rectal fluid available for active substance release. From a
technological point of view a large size suppository must be
202 S. Haas et al.
Table 11.7 Ergotamine and Caffeine Suppositories 1 mg/100 mg [31] Table 11.8 Valproic Acid Suppositories 500 mg [32]
Caffeine 0.1 g For a suppository mold of at least 2.8 mL:
Ergotamine tartrate 0.00105 g Valproic acid 0.5 g
Tartaric acid 0.002 g Hard fat q.s.
Hard fat with peroxide value 0.5 q.s.
11.4.8.2 Physical Stability: Crystallisation

of the Active substance
chosen if a large amount of active substance, such as
Active substances, and especially those that are partially
1,000 mg paracetamol, has to be incorporated. Even using
soluble in the fatty suppository base, may crystallise during
a 2.8 mL mold, the viscosity of the suppository melt is so
storage. Heating the suppository mass before or in the filling
high that the addition of lecithin is necessary to allow
process may lead to a partial dissolution of the active sub-
pouring of the melt into the molds (see Table 11.5).
stance in the base. A supersaturated solution will be formed
on cooling down, with, as a consequence, re-crystallisation
and crystal growth during storage (see Sect. 18.4.2.3). This
11.4.8 Stability makes particle size uncontrollable. In a macrogol supposi-
tory base partially dissolved indometacin may recrystallise
Chemical and physical processes may limit the stability of at storage, which becomes visible as a spotted appearance. In
active substance, base and excipients in suppositories. Also a fatty base an active substance such as valproic acid
the packaging and the conditions and times of storage need dissolves into a higher amount at the preparation process
attention. Suppositories with a fatty or a macrogol base do than at storage at room temperature. It is recommended to
not contain water. Therefore bacterial growth is unlikely and add this kind of substances to the molten base immediately
preservation is not needed. before the filling process, meaning at the lowest temperature
of the melt. The rate of solidification also may influence the
physical stability. The longer the solidification process of
11.4.8.1 Chemical Stability fatty valproic acid suppositories, the more the valproic acid
Modern suppository bases usually do not contain water. separates from the solution in visible structures. This may
Hydrolysis of an active substance will therefore seldom be even lead to a ‘wet’ and grainy suppository tip. Therefore the
an issue. Oxidation, in contrast, occurs. Oxidative valproic acid suppositories (Table 11.8) are placed in the
reactions occur in the presence of oxygen and peroxides, refrigerator immediately after the filling process.
under the influence of light and heat and are catalysed by In most other suppositories rapid solidification, due to
traces of heavy metals, see Sect. 22.2.2. Macrogols (see placement of the suppositories into the refrigerator, leads
Sect. 11.4.4) and some types of hard fat may form to faults and fractures in the suppositories and should there-
peroxides under influence of light, air and heat. These fore be avoided.
peroxides may readily oxidise oxidisable substances such
as ergotamine and chlorpromazine which should, there-
fore, be incorporated in a hard fat (with a low peroxide Control of Chemical and Physical Stability,
value). Storage in the refrigerator (2–8 C) will increase an Example
storage times, for example of suppositories with ergota- Indometacin is often formulated in a macrogol base to
mine and chlorpromazine hydrochloride (see Tables 11.7 get a good biological availability [33]. In that base
and 11.4). Both active substances have to be protected discoloration and esterification may easily occur. Fur-
from light as well by choosing an appropriate packaging. thermore, the indometacin slowly crystallises giving
Chemical degradation by oxidation increases proportion- the suppository a spotted appearance. The antioxidants
ally with the particle surface area in contact with the base. butyl hydroxytoluene (BHT), butyl hydroxyanisole
Smaller particles of an active substance will therefore (BHA) and disodium edetate are added to improve
oxidise more rapidly. the stability as well as glycerol to limit crystallisation,
Isomerisation and esterification may be other causes of for instance in Indocid® suppositories (Aspen, UK)
degradation of an active substance. Ergotamine tartrate, [34]. Nevertheless, a fatty base must be preferred.
for instance, is very sensitive to isomerisation which in a Indometacin is released almost equally from a fatty
fatty suppository base, can be limited by adding tartaric base as from a macrogol base [8a, 35, 36] and the
acid (see Table 11.7). For esterification effects see
Sect. 11.4.4. (continued)
11.4.10 Storage
chemical and physical stability is better in fat. For
instance indometacin suppositories (Centrafarm, Shelf life of pharmacy preparations depends on the character
Netherlands) [37] and indometacin suppositories BP and stability of the preparation and has a maximum of
(Actavis, UK) are manufactured with hard fat without 3 years as is explained in Sect. 22.7.1. Generally, physically
additives [34]. and chemically stable suppositories have an expiry date of
3 years after preparation, both in strips in a carton or without
strip in a jar. It may be convenient to split up this period in
24 months in the pharmacy and 12 months for use by the
11.4.8.3 Physical Stability: Hardening
patient.
Further hardening of suppositories on storage (secondary
Suppositories prepared as extemporaneous preparations
hardening or ageing) may change the crush strength (resis-
following a non-standardised formula, having an unknown
tance to crushing) and the melting behaviour. This may be
chemical or physical stability, should immediately be dis-
relevant for the therapeutic effect [38, 39]. The secondary
pensed to the patient who gets a maximal usage period of
hardening process of the suppository base is caused by a
1 month only (see Sect. 22.7.2) if classified as semisolid
further conversion from the liquid phase to the solid phase
preparation. If the patient only takes a suppository ‘on
PRODUCT DESIGN
and by a slow transition into modifications with a higher
demand’ a usage period of 1 month is very short and it
melting point. These changes usually cause crush strength to
may be justified to consider them to be comparable to a
increase. They also lengthen the melting time, resulting in a
dry dosage form with an arbitrarily chosen maximum
slower release of the active substance. Secondary hardening
usage period of 6 months.
of suppositories may be limited by cool storage, after suffi-
For standard preparations the storage conditions and the
cient initial hardening. Therefore, suppositories should gen-
maximum shelf life are determined in the design phase and
erally be stored in a cool place.
stated in the formulary.
11.4.9 Packaging 11.4.11 Labelling
For the packaging of suppositories the chemical and physical Section 37.3 gives the general requirements for labelling.
properties of the active substance and the base have to be There should be a clear indication how to use the dosage
considered. This should be done with respect to sensitivity to form, for instance ‘for rectal use’ or ‘(rectal) suppositories’
oxygen and light, compatibility with the (plastic) package, as well as how to take a suppository out of the plastic strip.
material evaporation (chloral hydrate) and hygroscopicity This requires some expertise and strong hands as well.
(macrogol and different active substances). The correct way to use and insert the suppository should be
Suppositories are preferably dispensed in the plastic dis- explained in a patient information leaflet. A Dutch leaflet
posable molds in which they have been filled (see Sect. advises the patient to insert the suppository while lying in a
24.4.10). The molds are placed in a carton. An alternative lateral position with the upper knee flexed. After the supposi-
is a well-closed container, a glass or plastic jar, protecting tory has been inserted the patient should stay in the horizontal
the content against the influence of light and air (see Sect. position for 5–10 min, if possible. Another position is bending
24.4.7). Such a jar is needed for instance for suppositories forward or squatting (sitting on the heels) while inserting
with a macrogol base, such as those with chloral hydrate the suppository. The patient should insert the suppository
(Table 11.1). These hygroscopic suppositories remain dry in (torpedo) tip into the anus and then push the suppository
the plastic strip (mold) placed in a glass jar, while in the with his finger until that finger is about 2 cm in the anus
plastic strip placed in a carton they become wet. Even with (for children 1 cm). However, insertion of the suppository
no plastic strip and placed in a glass jar these suppositories with the blunt side forward is reported to have real advantages
become wet and stick together. The upper surface of the [40]. There is no need to introduce a finger into the anal canal.
plastic strip with macrogol suppositories may be taped The external anal sphincter constricts physiologically better
before they are placed in a carton, but this is not always around the tip of the suppository and following this method
sufficient to prevent the suppositories getting wet. the patient will better retain the suppository. It is also not
Suppositories that are not molded in a plastic strip should necessary to stay horizontal after insertion.
always be packed in a light and air resistant jar. For arthritic Whatever the method of insertion, the instruction should
patients it is impossible to open plastic strips, which makes mention that the rectum is better empty before insertion and
dispensing the suppositories out of the strip in a glass or thus free from stool. The patient should go to the toilet first if
plastic jar necessary. necessary.
204 S. Haas et al.
Fig. 11.3 Patient information should be bright and clear. Copyright Gerrit de Jager [41]
To minimise the burning sensation of macrogol 11.5.1 Calculation of the Required Base
suppositories it is often suggested to moisten the suppository
prior to insertion. The authors do not expect this will prevent Most active substances possess a higher density than the
irritation of the mucosa, because the macrogol attracts much suppository base. As a result, if dispersed in the base a
more water after being inserted than supplied by moistening. weight quantity of active substance occupies less volume
But it might facilitate insertion of the suppository (Sect. 11.4.5). than the same weight quantity of base. The ratio between
When dispensing suppositories to the patient he or she both densities is designated as the dosage replacement
should be fully informed about the use. Frequently, patients factor f:
are insufficiently aware of how to handle a suppository
density of suppository base
(Fig. 11.3). f¼ ð11:1Þ
density of active substance
The density of Witepsol H15, as determined after processing

11.5 Method of Preparation, Fat-Based the base as in the preparation process of suppositories, is
Suspension Suppositories 0.92 and differs from the density of 0.96 as specified by the
manufacturer [8k]. In many cases the density of active
The method of preparation particularly depends on the substances is unknown. When a dosage replacement factor
physico-chemical form of the suppository: a solution or a is calculated, it is important that the active substance is
suspension of the active substance in the base. The nature of insoluble in the base and perfectly wetted by the base. In
the base is of less importance for the preparation method. practice the base is not only replaced by the active substance
The most frequently occurring suppository is the fat-based but also by the air stuck to the active substance. Therefore a
suspension-suppository. The preparation of a suspension dosage replacement factor should be determined experimen-
suppository is more critical than a solution suppository and tally. Generally however, for low concentrations of active
therefore requires special attention. substances in hard fat suppositories, a replacement factor of
First the calculation of the required quantity of base and 0.65 can be taken for most organic active substances. Simi-
the necessary excess is dealt with. Next the preparation larly a factor of 0.85 is valid for a macrogol base. The
steps, dispersing, mixing and pouring, are discussed. These estimated replacement factors cannot be used with high
steps are important for a homogeneous distribution of the concentrations: in the case where the quantity of active
active substance over the suppositories, its content unifor- substance exceeds 125 mg in a 1.15 mL suppository,
mity (see Sect. 32.7.2). For a homogeneous distribution the 240 mg in a 2.3 mL suppository and 300 mg in a 2.8 mL
so-called squeeze bottle method, has proven to be more suppository. These amounts are based on calculation of the
effective than more well-known methods. In this method a possible deviation in active substance content. For those
plastic bottle with a straight nozzle is used, called squeeze high concentrations the actual replacement factor has to be
bottle. Figure 11.4 surveys suitable combinations of dispers- determined experimentally [28]. Inorganic active substances
ing and pouring methods for small batches of suppositories have strongly deviating replacement factors that should be
[42]. The last processing step includes cooling and finishing determined as well for each individual substance. The deter-
the suppositories. mination of replacement factors shows much variation if
PRODUCT DESIGN
Fig. 11.4 Combinations of dispersing, mixing and pouring methods in the preparation of small batches of suppositories. The bottle used for
pouring is a plastic bottle with a straight nozzle (Sect. 11.5.5), called squeeze bottle. Source: Recepteerkunde 2009, #KNMP
Table 11.9 Replacement factors in Hard Fat there is little experience with this method. In that case a
Active substance Replacement factor replacement factor taken from literature is preferred.
Acetylsalicylic acid (180) 0.65 Replacement factors of some organic and inorganic
Atropine sulphate 0.65 substances in hard fat are given in Table 11.9.
Bisacodyl 0.65 If a dosage replacement factor cannot be found in litera-
Bismuth compounds 0.3 ture it has to be determined. This may be done as follows:
Caffeine 0.60 • Prepare a suppository mass using a large proportion of
Chlorpromazine hydrochloride 0.65 active substance, for instance 1 (mass) part of active
Codeine phosphate hemihydrate (90) 0.65 substance and 2 parts of base. The amount of mass must
Cyclizine hydrochloride 0.70 be sufficient to fill 10 mold cavities of 2.3 mL for about
Ergotamine tartrate 0.65 three-quarters. Beforehand, the weight of the used (stain-
Lactose monohydrate (180) 0.60 less steel) mortar, pestle and ointment cards (scrapers) is
Lidocaine 1.0 recorded.
Mesalazine 0.55 • Fill every mold three-quarters full, the tenth one for as far
Morphine hydrochloride 0.65 as there is suppository mass left. Then weigh again mor-
Paracetamol (45) 0.65
tar, pestle and scrapers.
Pethidine hydrochloride 0.65
Prepared mass – loss of mass on utensils ¼ mass in
Progesterone 0.85
10 molds.
Silica, colloidal anhydrous, compressed 0.65
• Amount of active substance present in 10 molds ¼ mass
Soya lecithin (NF XVII) 0.9
Tartaric acid 0.65
in 10 molds 1/3 (¼ A).
Valproic acid 1.0 Average amount of active substance per suppository ¼
Zinc oxide 0.25 A/10 (¼ a).
206 S. Haas et al.
• Next, just before the mass solidifies, top up the 10 par- In this equation the weight of active substances (AS) and
tially filled molds to completion with pure base (melted in excipients (E) is given per suppository and n is the number of
a clean stainless steel mortar) with a slight excess. After suppositories to be prepared.
solidification scrape off the excess of mass. For this calculation the blank weight for the suppository
• Weigh the 10 suppositories together (¼ B). mold used should be known. This is the weight of a supposi-
Amount of suppository base in 10 molds ¼ B – A; per tory processed in the given mold consisting of the designated
suppository ¼ (B – A) /10 (¼ c). base only and given in terms of gram of base. It is obtained
• Compare c with the average blank weight of this base in by filling the mold with the particular suppository base,
this mold (¼ d). cooling down, scraping off the excess of base, and then
• The amount of base displaced by the active substance (per weighing the suppositories and calculating the average
suppository) ¼ d – c (replacement value). weight. The blank weight obtained with one type of hard
• The dosage replacement factor f is the displaced amount fat may be used for all types of hard fat. The blank weights of
of base per gram of the active substance, so f ¼ (d – c)/a. standard suppository molds (FNA) in the Netherlands are
The amount of base required for suppositories with active given in Table 11.10 for hard fat and for macrogol.
substances and excipients can be calculated as follows:
required base ¼ n x ½ðblank weight moldÞ ð f 1 x AS1 Þ 11.5.2 Excess

ð f 2 x AS2 Þ ð f e1 x E1 Þ ð f e2 x E2 Þ
ð11:2Þ For extemporaneous preparation of a fixed number of
suppositories, each containing the right amount of active
substance, a sufficient excess of the suppository mass has
About Dosage Replacement Factor, Density Dis- to be prepared. An excess of mass is not required if the
placement Factor and Displacement Value suppositories are filled serially for stock preparation,
In textbooks about suppository preparation not only because there is no need to deliver a precise number of
dosage replacement factors are used but there are also suppositories. In that case it is only necessary to know how
tables with density factors and displacement values. many of the first or finally filled suppositories are to be
The relation between these terms needs to be clarified. rejected because of unreliability of the content of these
The dosage replacement factor (f) of an active suppositories.
substance is the number of parts by weight of hard The excess of mass is needed for the following reasons:
fat displaced by one part of the active substance. • There is a loss off mass during the preparation. This is due
The density displacement factor (DDF) of an active to the fact that the mass can never be transferred quanti-
substance is the number of parts by weight of the tatively, because it sticks to the utensils and because the
active substance that displaces one part of hard fat molds are filled with a slight excess.
[43] and is therefore equal to 1/f. • During the serial filling procedure the suspended active
Regularly, for the dosage replacement factor substance will easily settle. Optimal stirring or mixing is
(f) other terms are used, for example replacement difficult, because appropriate utensils and a sufficient
factor, dose-replacement factor and even displacement mass is necessary for effective stirring. Therefore, despite
factor. The density displacement factor (DDF) is fre- frequent stirring or mixing, a content gradient will easily
quently called displacement value; the terms displace- occur within a single batch. Extent and character of the
ment factor and density factor are used too. To gradient are determined by the pouring method (from a
recognise what authors mean, it is good to realise mortar, squeeze bottle (Sect. 11.5.5), or suppository
that mostly f 1 and DDF ¼ 1/f 1. molding machine), by the particle size of the active sub-
Sometimes the replacement value is used. This is stance, the effectiveness of dispersion, the size of the
the weight of base displaced by the active substance batch, the mixing method before and especially during
(per suppository). Used is also the term displacement
value. The replacement value is calculated by
multiplying the weight of active substance per suppos- Table 11.10 Volume and Blank Weight of FNA Suppository Molds
itory by the dosage replacement factor or by dividing Volume Blank weight (g) hard Blank weight
the weight of active substance per suppository by the (mL) fat [28] (g) macrogola
density displacement factor [44]. 1.15 1.07 1.32
This seems a real labyrinth of terms, but frequently 2.3 2.07 2.54
the right term may be distilled from the context. 2.8 2.61 3.16
a
1 part macrogol 1500 and 2 parts macrogol 4000
Fig. 11.5 Course of content a

during filling processes. content (%)
(a) Course of content in
150
suppositories with Acetylsalicylic
acid (180) 200 mg, when pouring
from a mortar under frequent 140
stirring, following on dispersing
with mortar and pestle
(suppository mass for 26, 28, 130
52 and once more
52 suppositories, volume 2.3 mL, 120
no excess of mass) [45].
(b) Course of content in
suppositories with (■) 110
Acetylsalicylic acid (180) 100 mg
or (+) Paracetamol (45) 100 mg, 100
when pouring from a squeeze
bottle under frequent
homogenising, following on 90
PRODUCT DESIGN
dispersing with mortar and pestle
(suppository mass for 10 and 0 10 20 30 40 50
14 suppositories with
acetylsalicylic acid and for 10 and sequence number of the suppositories, (• = the last filled suppository of each series)
15 suppositories with
paracetamol, volume of both b
suppositories 1.15 mL, no excess content (%)
of mass) [45]. 115
X-axis: number of the
suppositories, (●) is the last filled
suppository of each series; 110
Y-axis: content as %.
Source: Recepteerkunde 2009,
#KNMP 105
100
95
90
0 5 10 15
sequence number of the suppositories, (• = the last filled suppository of each series)
the filling process, and by the filling ratio1 of the squeeze • When suspension suppositories are molded in a compos-
bottle. Some examples of the content variation in the ite metal mold with cadre, the entire mass is poured out
filling process are given in Fig. 11.5. When pouring over the mold at once. An excess of mass is needed to be
from a mortar or, less obviously, from a squeeze bottle, able to divide the mass quickly enough over all cavities
a sudden, large deviation is observed in the content of the before the active substance settles.
last-filled one or two suppositories. This in spite of • With all methods of preparation some suppositories may
pouring the mass only as long as it flows freely, so have to be rejected because of insufficient appearance or
without scraping the mass out of the mortar. Therefore a breaking.
number of suppositories has to be rejected, which has to Taking into account the mentioned loss of mass and
be fixed when validating the preparation method [45]. possible content variation, Table 11.11 presents the required
excess of suppositories for increasing batch sizes. This table
is based on relatively fast settling substances such as
1
Filling ratio means the ratio between the used volume of suppository acetylsalicylic acid (180) and cyclizine hydrochloride
mass and the nominal volume of the bottle. (180). For instance in paracetamol (45) the content variation
208 S. Haas et al.
Table 11.11 Excess for small batches of Suppositories commonly contain agglomerates. Usually the agglomerates
Batch size Advised methods are pulverised by rubbing the active substance with an
(number to be almost equal volume of some other substance. This might
Number to dispensed plus be a solid, such as another active substance, colloidal anhy-
Volume be dispensed excess) DispersingPouring drous silica or lactose monohydrate (see Sect. 11.4.6). This
1.15 mL 6 11 (6 + 5)a Hand Mortar ‘dry’ technique is called trituration. More often a semisolid
10 16 (10 + 6)a Hand Mortar and
substance or a liquid is used, generally a small quantity of
squeeze bottle
20 28 (20 + 8) Hand Squeeze
the molten base. Only when rubbed into the smallest possi-
bottle ble quantity of molten base the lateral shearing forces are
30 41 (30 + 11) Hand and Squeeze sufficient to break up the agglomerates effectively. This
rotor-stator bottle ‘wet’ technique is frequently called levigation, but the term
2.3 mL 6 10 (6 + 4) Hand Mortar trituration is more common. In these techniques, with
2.8 mL 10 15 (10 + 5) Hand Mortar and another solid or with some molten base, the primary particles
squeeze bottle
remain separated, dispersed in the mixture. The
20 26 (20 + 6) Hand Squeeze
bottle
agglomerates should not be reduced by rubbing the active
30 40 (30 + 10) Hand and Squeeze substance on its own. This enhances static charging, giving
rotor-stator bottle even more agglomerates [42]. Which method should be
40 49 (40 + 9) Hand and Squeeze chosen for particle size reduction and dispersion depends
rotor-stator bottle particularly on the batch size.
a
These batches are too small for suppository molds of 1.15 mL. Without
adjustment of the preparation method, a minimum batch size of 20 must 11.5.3.1 Dispersing with Mortar and Pestle
be taken
For small batches it is a good choice to break up the
agglomerates in a plastic or stainless steel mortar with a
as a result of sedimentation could hardly be observed plastic pestle. The agglomerated active substance may be
(Fig. 11.5). For non-standardised preparations this ‘worst triturated with some other solid substance or with no more
case’ table is a good guideline. For standard preparations it than an equal volume of molten base. After trituration with a
might be worthwhile to investigate, for each preparation, solid, the mixture is incorporated in the molten base, at first
whether a smaller excess will do just as well. If less than in an equal volume, thereafter the remaining base is added
20 suppositories of 1.15 mL are prepared the loss of melted part by part (geometric dilution, see Sect. 29.4.4).
base is relatively high, caused by transference of the melted Two or more agglomerated solid substances, not suited
base to the active substance in the mortar. As a result, the for ‘dry’ trituration, are roughly mixed before trituration
suppositories obtained do have a too high content of active with some molten base. Once more a plastic or stainless
substance. Therefore it is necessary either to maintain a steel mortar is used, but with a scraper instead of a plastic
minimal batch size of 20 or to adjust the preparation method. pestle. Thereafter the mixture is rubbed, with no more than a
In the latter case an excess of suppository base should be half to an equal volume of molten base, in the same mortar,
melted and transferred to the active substance in the mortar but now again with a plastic pestle.
until the right weight of mass in the mortar is obtained. The mass is visually checked for homogeneity. The mor-
tar and pestle method to break up the agglomerates is usually
very effective. However, if agglomerates remain once the
11.5.3 Dispersing Methods rest of the suppository base has been added, they cannot be
broken up anymore. In that case one has to start again with
In the preparation of suspension suppositories it is important new amounts of substances. Usually such inadequate break
that the used particles of the active substance are small and up is caused by using too much molten base or by improper
remain small (don’t reagglomerate). Small particles being rubbing.
essential for a correct content and a sufficient content uni- Certain fat based suppositories formulations contain a
formity of the suppositories, dispersion of the active sub- lipophilic liquid, such as Miglyol 812 in zinc oxide
stance in the suppository base will usually be preceded by or suppositories (see Table 11.2). Such a liquid is very useful
combined with particle size reduction, see Sects. 29.2 and for trituration and cannot solidify in the meantime, as a
29.3). Large primary particles should be ground and molten suppository base often does.
agglomerates should be broken up. If an active substance is The suppository base should be warmed on a water bath
not available in the required particle size, the coarse powder or heating plate to a maximum temperature of 40–45 C.
must be ground in a rough stone or porcelain mortar. Active Solidifying (and remelting) during dispersion and mixing
substances kept in stock in the required primary particle size should be avoided as much as possible by working
sufficiently fast. Choosing a higher temperature for the melt 11.5.4.1 Mixing with Mortar and Pestle
is not a good alternative, regarding the stability of base and A stainless steel or plastic mortar is used, the same in which
active substance. active substance and excipients, if any, were dispersed. After
disintegration of agglomerates with a minimum quantity of
molten base, the remaining base should be admixed using
11.5.3.2 Dispersing with a Rotor-Stator Disperser the geometric or doubling-up technique (see Sect. 29.4.4).
For larger batches the agglomerates are more effectively Mixing should be done gently and without entrapping too
disintegrated with a rotor-stator disperser (see Sect. much air. Entrapment of too much air results in a too low
28.6.2). A high and narrow vessel must be used, because suppository weight thus containing an insufficient quantity
the distance between liquid surface and dispersing element of active substance. Mixing with mortar and pestle is not
should be enough to limit air impact. Usually a graduated very effective because in a mortar the mixing in a vertical
cylinder will be appropriate. A glass cylinder breaks easily; direction is difficult (see Sect. 28.6.4). If the mass, after the
especially contact with the heating element of the water bath mixing, is put into a squeeze bottle for filling the molds, the
should be prevented. Plastic cylinders are unbreakable, but insufficient mixing does not matter, because the mass can be
in plastic the melting and cooling of the fatty base takes perfectly mixed by turning the squeeze bottle several times
PRODUCT DESIGN
more time than in a glass vessel. The effectiveness of the upside down and back again. However, when the mold is
dispersion process is also more difficult to monitor in a filled directly from the mixing mortar, there is a risk of
plastic vessel. Because melting and dispersing may be insufficient content uniformity (see Fig. 11.5).
done in the same vessel, the rotor-stator method results in a
smaller loss of pure suppository base. For small batches the 11.5.4.2 Mixing in a Squeeze Bottle
loss of suppository mass is larger with the rotor-stator In a squeeze bottle mixing occurs by gently turning the bottle
method. However, unlike loss of pure base, loss of mass upside down and back again. At the filling of the molds the
does not influence the content of active substance in the mass should be mixed at every 2–3 suppositories. Do not
suppositories [45]. When dispersing with the rotor-stator shake the bottle because too much air may be entrapped.
method the active substance or the mixture of active sub-
stance and excipients is usually added all at once to the entire 11.5.4.3 Mixing in a Suppository Filling Apparatus
amount of base. This is followed by pre-blending, by stirring In a suppository filling machine the effectiveness of the
the mass with a spoon. If a squeeze bottle is used, mixing process depends on the construction of the stirring
pre-blending may be done by swinging the bottle around device (see Sect. 28.7.2).
gently, to minimise air enclosure. Thereafter the dispersion
will be achieved using the rotor-stator disperser. To monitor
the effectiveness of the dispersion process (in-process con- 11.5.5 Pouring the Melt: Methods
trol) the dispersing element is raised from the mass and
checked for agglomerates. Alternatively a sample may be After the active substance and excipients have been dispersed
taken from the bottom of the dispersion vessel (with a spoon) in and completely mixed with the suppository base the mass
and checked for agglomerates. Using a squeeze bottle as should be poured into the molds. The molds can be filled
dispersion vessel the presence or absence of agglomerates serially (one by one) or simultaneously (all cavities at once).
is checked by holding the bottle against the light and turning For serial filling usually plastic strips are used (Fig. 11.3).
it slowly upside down. The real advantage of the rotor-stator When using a composite metal mold with cadre or a bearer
method is that insufficient dispersion can be corrected, with a number of strips, 100 cavities can be filled simulta-
at any moment, by continuing the dispersing process. neously. Such metal molds are composed of 10 elements of
Disadvantages of the rotor-stator method are a greater risk 10 cavities. Once fixed together a cadre is placed over the
of air enclosure and a disappointing mixing. mold (Fig. 11.6) and all the mass is poured out at once.
While filling the molds, the suppository mass should be
kept homogeneous and at a nearly constant temperature,
which requires agility. This is especially important for serial
11.5.4 Mixing Methods filling and a key issue in the product quality assurance of
suspension suppositories. The squeeze bottle is a good help
After dispersing the active substance with mortar and pestle, for a fast and homogeneous serial filling. Figure 11.7
the remaining suppository base should be added and thor- pictures the squeeze bottle and other pouring methods that
oughly mixed. After dispersing with the rotor-stator dis- will be dealt with in this section and Table 11.12 compares
perser all base has already been added, but the mass still the suitability of the different pouring methods for different
needs to be mixed well. batch sizes.
210 S. Haas et al.
Fig. 11.6 Suppository molds: composite metal mold with cadre for 50 suppositories (a and b); disposable plastic strip for 12 suppositories of ca
3 g (c); single metal mold for 6 suppositories of 3 g (d). Copyright Rijksuniversiteit Groningen
Table 11.12 Comparison of Different Pouring methods 11.5.5.1 Pouring from a Mortar
Optimal Ease of A stainless steel mortar with a good pouring spout permits
Pouring method batch size Reliability preparation Yield convenient pouring of the melt into the cavities of the mold.
Mortar series <24 Using a mortar, frequent stirring is essential but cannot
Squeeze bottle series 12–200 + + entirely prevent sedimentation of active substance during
Composite mold 20–100 +
the filling process. To avoid large deviations in the content,
Strips in frame 36–120 +
this method must be limited to small batches (up to
Machine, hand >250 +
24 suppositories) and, as already stated, much attention
Machine, semi-automatic >250 + + +
must be paid to monitoring. If the mass is kept insufficiently
homogeneous during filling, the content of active substance
When a filling method is used that is not or less adequate will show an increase from the first filled suppository to
for the batch size, extra attention has to be paid to a proper the last.
implementation. Each filling method must be validated. For Pouring from a mortar usually follows on dispersing and
serially filled suppositories a determination of the active mixing with mortar and pestle. The recommended pouring
substance content in the first and the last filled suppositories (filling) temperature is 33–34 C. The pouring temperature
is required, see also Fig. 11.5. In case of serial filling the last should not be too low as all cavities must be filled without
filled suppositories have to be rejected. Each cavity must be reheating in between, because a premature solidification of the
filled to slightly overflowing because the suppository mass mass may impair product quality. When the mass solidifies
shrinks upon solidification. In simultaneous filling, when the prematurely, it must be reheated until it is completely homoge-
mass is poured out at once as in filling a metal mold with neous again. This is not easy to monitor and the mass may
cadre, a sufficient excess of mass has to be prepared to remain inhomogeneous or the temperature of the mass may
ensure a swift filling of all cavities. become undesirably high. Moreover, not all active substances
Preparing batches, up to about 100 suppositories, by dispersing with mortar and pestle:
a b
a dispersion of the drug substance(s) by triturating with a half to equal volume of molten base
b addition of the remaining base, followed by thorough mixing of the mass by stirring with the pestle
Preparing small batches, up to 24 suppositories to deliver, by pouring from the mortar:
c d
PRODUCT DESIGN
c waiting while stirring until the mass has reached the recommended pouring (filling) temperature (IPC → record)
d filling the mold while stirring frequently, which means stirring after every 2 or 3 suppositories
Preparing larger batches, 12–200 suppositories, by pouring from a squeeze bottle:
e f
e filling the squeeze bottle

f waiting until the mass has reached the recommended pouring (filling) temperature (in-process control (IPC)→ record)
g h
g mixing the mass by keeping the thumb in place while turning the bottle a few times upside down and back again;
h for filling the mold, the thumb is off and the fingers of the other hand squeeze the bottle; to keep the mass
homogeneous, mixing is done every 2 or 3 suppositories by replacing the thumb and turning the bottle 2 times
upside down and back again
Fig. 11.7 Small scale suppository preparation visualised. Copyright Rijksuniversiteit Groningen
212 S. Haas et al.
are sufficiently stable if heated again. Pouring from a mortar, 11.5.5.3 Filling a Composite Metal Mold
the mass meant for the last suppositories will often contain too with Cadre
much active substance, due to sedimentation. Starting with a This method may be used for 20–100 suppositories. Metal
sufficient excess of mass (see Table 11.11) the filling of the molds should be equilibrated at room temperature before
mold can be stopped when the number to be delivered is they are used, thus preventing the occurrence of fractures
reached (plus one in excess for each 20 suppositories regarding and fissures by a too rapid temperature decrease of the sup-
breaking). The content of active substance in the remaining pository mass. Keeping the mass homogeneous while filling
mass is usually too high, see Sect. 11.5.2. So never use the last the mold, being a critical point in other pouring processes, is
drop of the suppository mass! very easy to achieve when a composite metal mold with cadre
is filled. It is important, however, to fill the mold in one flow.
Immediately after having been poured out on the mold all at
11.5.5.2 Pouring from a Squeeze Bottle once, the mass must be distributed as fast as possible over the
A flexible plastic bottle with a straight nozzle, a so called cavities by the aid of a scraper. When working too slowly, the
squeeze bottle, pointed out, has been shown to be very first filled suppositories will contain too much and the latest
suitable for the serial filling of suppository molds [45]. ones too little active substance. This is caused by settling of
After dispersing active substance and excipients in the the active substance. To be able to fill the cavities fast enough
molten base, the mass is transferred to a lukewarm a sufficient excess of mass should be used.
squeeze bottle. For optimal mixing conditions, the nomi-
nal volume of the bottle may only be used for 30–80 %. 11.5.5.4 Filling Molds with a Suppository Filling
Adhesion of the active substance to the wall of the Apparatus
squeeze bottle is limited by using a bottle that is not too A suppository filling machine enables a serial filling of large
large for the volume to be poured. However, the bottle quantities of suppositories. The apparatus and its use are
should be large enough to allow mixing. After sufficient described in Sect. 28.7.2. A manually operated machine
mixing, by gently turning the bottle a few times upside- keeps the mass automatically homogeneous. The tap is
down and back again, the suppository mass can be poured operated manually as is the movement of the plastic suppos-
into the molds at about 34–35 C. The bottle is held in itory strips. An automatic machine fills the plastic molds
one hand, the thumb closing the nozzle and moving away automatically and often transits them too. The filling process
for filling, while the bottle is squeezed with the other of a suppository filling machine always has to be validated.
hand, see Fig. 11.7. The molds are slightly overfilled. The content of both the first and the last suppositories may
During the pouring process the mass must be kept homo- not meet requirements.
geneous by turning the bottle 2 times upside-down and
back again, every 2 or 3 suppositories. The squeeze bottle
method is suitable for batches of 12–200 suppositories. 11.5.6 Choice of Preparation Method
When less than 12 suppositories are prepared the loss of
mass would be too large. Tables 11.11 and 11.12 give the method of preference of
As with pouring from a mortar the filling of the mold should dispersing and pouring in relation to the batch size. Using
be stopped when the number of suppositories to be delivered is (stainless steel) mortar and (plastic) pestle for dispersing and
achieved plus 1 per 20 for loss due to e.g. breaking. pouring gives the least reliable results. This is due to the fact
For stock preparations – when no fixed number of that sufficient homogeneity of the mass is difficult to achieve
suppositories have to be dispensed - pouring may be during the filling of the molds from a mortar. Therefore, if
continued until all mass has been used, but the last filled more than 12 suppositories have to be supplied, a squeeze
suppositories will have a low active substance content (see bottle is a good choice for pouring.
Fig. 11.5). The last 2 suppositories usually do not meet the The rotor-stator disperser is better reserved for batches of
requirements and in batches of more than 100 even the last 4. 50 and more suppositories. Smaller batches frequently trig-
As in pouring from a mortar, also in pouring from a ger problems in finding appropriate utensils, in loss of mass
squeeze bottle premature solidification of the mass is a and in premature solidification.
problem. To prevent this problem occurring, the pouring
temperature has to be chosen while taking the batch size
and the ambient temperature into account. Usually 36 C is 11.5.7 Choice of Pouring Temperature
satisfactory for molding a batch of about 100 suppositories
without premature solidification and 34–35 C is high First, a proper pouring temperature has to be chosen to
enough for smaller batches. assure that the mass will not solidify during the filling
process (pouring). Moreover the pouring temperature also

determines whether the active substances will settle within happens to measure the pouring temperature at this
the suppositories or not. moment, he may suppose that there is ample time for
Choosing the lowest possible temperature for pouring filling and will be surprised by sudden solidification.
shortens the solidification time and consequently the period In practice the gradient of the curve depends on the
in which the active substance may settle. A low temperature way of cooling, the type of base and the incorporated
would also benefit the homogeneity during the filling pro- substances. See also Sect. 11.4.4 under Solidification
cess if the suppository base would be more viscous at this point or range. For hard fat the maximum is deter-
lower temperature. In practice this effect on base viscosity is mined under standard conditions and defined as solid-
not often seen (see Sect. 11.4.4) and therefore it is not a valid ification point, but in fact it is a solidification range.
issue in relation to the filling process. Melting range and solidification range of different
A great risk of a lower pouring temperature is the ten- types of hard fat are given in Table 11.3.
dency of the mass to solidify during filling. As said,
reheating the mass often leads to an unnecessarily high
pouring temperature or – in case of insufficient reheating – The choice of the pouring temperature also depends on
PRODUCT DESIGN
to an inhomogeneous mass. Therefore the pouring tempera- the pouring (filling) method:
ture should be high enough to ensure that all cavities can be • During a serial filling process with mortar or squeeze
filled without reheating. The distribution in the suppositories bottle the temperature of the molten mass decreases.
will probably not be ideal. But content uniformity goes The initial temperature should be chosen so that solidifi-
beyond a uniform distribution in the suppositories. cation starts just at the time of filling the last suppository.
The rate of solidification also depends on the material of This depends of course on working speed as well. Filling
the mold. In a metal mold the mass cools down more quickly may start at 34–35 C if using a squeeze bottle and at
than in a plastic strip. In plastic strips hanging closely 33–34 C if using a mortar.
together the mass takes even longer to cool down. • Filling a composite metal mold with cadre the pouring
temperature is chosen just high enough to prevent solidi-
fication before all cavities are filled; 34–35 C will
Solidification Range
usually do.
Choice of pouring temperature also has to do with the
• For filling from a suppository filling machine the pouring
behaviour of the suppository base upon cooling. For
temperature is chosen just above the start of the solidifi-
hard fat the temperature – time relation is shown in
cation range.
Fig. 11.8.
These pouring temperatures should be increased for large
°C batches and when the room temperature is lower than usual.
temperature
35
For small batches (required number of suppositories 6–12) the
pouring temperature should be taken lower; when using a
30 mortar a pouring temperature of about 30 C satisfies. Note:
if for a low melting point Miglyol is added to the base the
25 solidification point is also significantly lower than normal and
pouring temperature and cooling procedure should be adapted.
20
t1 t2 time
11.5.8 Cooling and Finishing
Fig. 11.8 Illustration of the temperature - time relation while
cooling a suppository base of the Adeps solidus type. Source:
Cooling suppositories should start at room temperature. As soon
as the mass has set, but before it has hardened completely, the
On cooling down of a suppository mass, the tem- excess of material should be trimmed off. This is easily done
perature first decreases until it reaches a minimum with the flat blade of a stainless steel spatula, first been dipped
(time ¼ t1) while the mass remains liquid, meanwhile into hot water and wiped dry. Sometimes a razor blade does
supercooled. From that moment the solidification pro- better. Due to settling the excess of material on top contains
cess starts and the viscosity rapidly increases. How- little active substance and can never be used for an additional
ever since solidification releases heat, the temperature suppository. After removing the excess of material the
will rise to a maximum (time ¼ t2). When the operator suppositories have to harden thoroughly. If necessary they can
be placed in the refrigerator for a more rapid hardening process,
(continued)
214 S. Haas et al.
but only after a period at room temperature of at least Any dissolved substance lowers the solidification range
15–30 min. When placed in the refrigerator earlier or poured of the base [8m] and therefore will affect the solidification
out into cold metal molds, suppositories may show a greater point of the mass. This may cause a problem when large
tendency for fractures and breaking. The rapid cooling of the quantities of lipophilic active substances are added. For
outer layers of the suppositories compared to the inner layers, example, chloral hydrate in a concentration of 5 % in hard
causes little cracks. This may happen even if the suppositories fat lowers the solidification point by more than 5 C. Some-
are placed in the refrigerator after 1 h at room temperature. The times textbooks advise the addition of a substance with a high
tendency for fractures of fatty bases is stronger when the melting point [5f]. Such an addition bears risks for bioavail-
hydroxyl value of the base is lower and thus the elasticity is less. ability however. The substance, such as beeswax, may sepa-
Suppositories containing Miglyol solidify slowly. There- rate upon cooling [8m]. Glycerol monostearate does better
fore, in addition to a lower pouring temperature but increases the viscosity of the mass as well and may
(Sect. 11.5.7) these suppositories should be placed in a therefore retard the release of the active substance. Further-
refrigerator directly after the filling of the mold. The more the increase of the solidification point may affect the
incorporated substances settle too extensively when the bioavailability as well.
suppositories cool down at room temperature.
11.7 Method of Preparation, Hydrophilic-

Based Suppositories
11.6 Method of Preparation, Fat-Based
Solution-Suppositories
The preparation of suppositories with a macrogol base
corresponds to the preparation of fat-based suppositories.
Active substances that are soluble in the suppository base at
Also suspension-suppositories and solution-suppositories
room temperature, or liquids that are miscible with the
are distinguished. And when preparing hydrophilic-based
suppository base, are incorporated into the base by
suspension-suppositories also special attention is needed to
dissolving in or mixing with the melted base. The calculation
keep the mass homogeneous at the filling process. When the
of the amount of suppository base is almost the same as with
required amount of macrogol base is calculated it should be
suspension suppositories. In solution-suppositories replace-
noted that the density of macrogol is higher than the density
ment plays a role if concentrations of active substances are
of hard fat. Therefore the dosage replacement factor is
relatively high. If a dosage replacement factor is unknown it
higher too. For most organic active substances incorporated
has to be determined experimentally. The quantity of excess
in a macrogol base a dosage replacement factor f ¼ 0.85
suppository mass needed may be somewhat smaller than for
may be used (see Sect. 11.5.1).
suspension-suppositories, because the mass can be poured
out completely and all the suppositories have the same
content. The preparation process steps are almost the same
as for fat-based suspension-suppositories, just no dispersion 11.7.1 Hydrophilic-Based Suspension-
is necessary; in summary (see also Sect. 11.5): Suppositories
• No dispersion.
• Mixing by adding the active substance to the melted base For the preparation of suspension suppositories with a
and continuous mixing until complete dissolution; espe- macrogol base the preparation process steps are compared
cially mixing of a liquid with the molten base needs with Sect. 11.5 as follows:
attention; if not done properly the suppository will show • Melting the base. Mind the higher melting range of
a solid part and a liquid layer, mostly underneath. macrogol base compared to hard fat. Furthermore
• Pouring the mass is much easier than with suspension- because of the hygroscopicity of macrogol a closed vessel
suppositories because the mass will stay homogeneous at should be used; this may be a medicine bottle, or a
the filling process, so even the last filled cavities will have squeeze bottle if used for dispersing and pouring as well.
the correct content and all the mass may be used by • Dispersing the active substance. It is performed similarly
scraping out the mortar; the pouring temperature is not to fat-based suspension-suppositories, but when
important because there are no particles to settle. triturating the active substance with a little melted base
• Cooling down and finishing the suppositories is also it should be noted that the macrogol base solidifies sooner
easier, because of the lack of sedimentation, although than a fatty base and thus it might be helpful to warm up
attention has to be paid to possible crystallisation or the mortar a little.
separation. For example in Valproic acid Suppositories • Mixing. To be performed similarly to fat-based suspen-
(see Table 11.8), fat-based solution-suppositories. sion-suppositories.
• Pouring the mass is also done in a similar manner, but uniformity of dosage units (see Sect. 32.7.2). Furthermore,
because of the higher solidification point the pouring the Ph. Eur. sets demands on dissolution (dissolution test for
temperature needs to be higher. For instance for the lipophilic solid dosage forms) or disintegration and on the
chloral hydrate suppositories of Table 11.1 the pouring softening time of lipophilic suppositories. The disintegration
temperature is 40–45 C. should happen within 30 min for a fatty base and within
• Cooling and finishing is generally similar to the fatty 60 min for a macrogol base, unless it concerns a suppository
suppositories, with a macrogol base it being even more with controlled release (‘intended for modified release’) or
important to avoid rapid cooling. Trimming off the excess for prolonged local action. With the suppository bases
mass is more difficult because fragments break off more recommended in this chapter, the softening time will always
easily. be met. And if the preparation instructions, especially about
The melting range of a number of macrogols is listed in [5h] cooling are followed accurately, the breaking resistance will
and [8n]. Rapid cooling more easily results in cracking than comply. Some of the above-mentioned controls are
with fatty suppositories. Furthermore, the density after fast discussed in the next sections. Additionally a test on the
cooling of a macrogol base may be lower than after slow deviation of the average weight from the calculated weight
cooling due to an abnormal molecular organisation. The is discussed. This control may be useful for all extempora-
PRODUCT DESIGN
consistency is less solid and the dissolution time in water is neous preparations.
shorter. The release of active substance may therefore
change as well [8p]. Fast cooling and thus facilitating the
abnormal molecular organisation must be avoided.
11.8.1 In-process Controls
The preparation steps of dispersing, mixing and pouring

11.7.2 Hydrophilic-Based Solution- determine a homogeneous distribution of the active sub-
Suppositories stance over the suppositories and thus a good content unifor-
mity. The content uniformity is quite laborious to be carried
For the preparation of a solution suppository the macrogol out as final control in pharmacy preparation, which is an
base is melted, the active substance is dissolved in the melt extra argument for in-process controls. The dispersion of the
and the mass is poured, without any additional step. Melting active substance as well as homogeneity after mixing has to
the base in a closed vessel on the water bath (see be controlled visually. The pouring temperature has to be
Sect. 11.7.1) fits better because the dispersion step is lacking. recorded. If the mass is poured from the vessel in which it
The closed vessel may be a medicine bottle or a squeeze was dispersed, the vessel has to be checked on agglomerates
bottle. The medicine bottle is to be preferred because no again after pouring. If another vessel is used for pouring,
transfer of molten base is necessary (no loss), it is transpar- such as a squeeze bottle, the dispersing vessel (e.g., a mor-
ent for controlling the dissolution process and it is suitable tar), has to be checked for agglomerates when all the mass
for pouring as there is no suspension to be kept homoge- has been transferred to the pouring vessel. In the preparation
neous. The squeeze bottle is less preferred because it is not of solution suppositories the control on agglomerates is
transparent. replaced by a control on complete dissolution of the active
substance.
11.8 Release Control and Quality

Requirements 11.8.2 Appearance
For the relevance of in-process controls, especially for Above all, suppositories should be checked visually on a
extemporaneous preparation, see Sects. 34.14.3 and 21.6.3. uniform appearance. They must show no bursts and cracks,
Critical steps in the preparation process of suppositories are, no brittle bottom (brittle blunt end) as a result of
for instance, insufficient breaking up of agglomerates, insuf- incorporated air, and no soft or brittle tip as a result of
ficient mixing and too hot or cold pouring, see further sedimentation of active substance particles. Furthermore
Sect. 11.8.1. the mold should be filled equally. A brittle or soft tip may
The specifications of the Ph. Eur. are the basis of the final be detected by rubbing lightly with a finger over the tip of the
controls. Suppositories have to comply with the test for suppository.
216 S. Haas et al.
11.8.3 Average Weight and Average Content

An Example of Large Content Variation Hardly
For small scale pharmacy preparations a suitable test for the Affecting Weight Variation
average weight and content is described as follows. The Suppose suppositories with 100 mg paracetamol are
average weight of suppositories must not deviate more than prepared, incorporated in a fatty base and with a dos-
3 % from the theoretically calculated weight. This must be age replacement factor f ¼ 0.7 and a suppository
controlled for each batch. The theoretical weight is calcu- weight of 2.00 g. Suppose also that one cavity of the
lated by the summation of the prescribed quantities of all mold has been filled completely, but as a result of
components. If the average weight deviates more than 3 % separation during pouring contains 200 mg of paracet-
from the theoretical weight the batch must be rejected. If the amol instead of 100 mg.
average weight marginally exceeds the 3 % limit and it’s The 200 mg suppository will have a calculated
concerning a large batch, it may be beneficial to check weight of 2.03 g: [(2.00 + 0.100)–(0.7 0.100)]. In
whether the average content meets the requirements of the this case of a content deviation of 100 % the weight
Ph. Eur. deviation will only be 1.5 %. Also with higher
Whenever the average weight differs more than 3 % from dosages, for instance 500 mg paracetamol per suppos-
the theoretical weight it is important to determine the cause. itory, a content variation may be missed. In the para-
Causes may be the use of a wrong sized suppository mold, a cetamol case a deviation of 100 mg (20 %) in content
miscalculation or too much incorporated air. If the average results in a weight deviation of only 1.5 %.
weight is within the 3 % limit, the average content almost
certainly complies with the Ph. Eur. requirements.
Table 11.13 shows well-known sources of deviations affect- Only if the suppository contains 25 mg or more of an active
ing the average content and also instructions to avoid substance, comprising 25 % or more, by mass, of the supposi-
them [28]. tory, the mass variation test is applicable instead of the content
uniformity test. For instance, in suppositories weighing about
2.0 g, the active substance should be 500 mg or more for the
11.8.4 Uniformity of Mass
mass variation test. A determination of the content uniformity
will be needed for most suppositories.
For the Ph. Eur. requirements and tests see Sect. 32.7.1.
For low-dosed suppositories the test on mass variation is
hardly relevant because the difference between amounts of
active substance will not be reflected in mass difference of 11.8.5 Uniformity of Content
the complete suppositories. Only if for instance, in
suppositories weighing about 2.0 g, the active substance To obtain a good uniformity of content is the greatest chal-
comprises 500 mg or more, then mass variation will indicate lenge in the preparation of suspension suppositories and can
content variation. only be achieved by a proper design of the (batch) prepara-
However a (visual) release control on equal filling of the tion instruction and properly following it. So the outcome of
molds should be performed, including removing all not determination of content uniformity is very relevant for the
entirely filled molds. monitoring of the preparation process.
Table 11.13 Sources of Error affecting the Average Content of suppositories

Source of error Measures to limit and to detect deviations
Blank weight Use suppository molds with constant volume, determine the blank weight accurately, check yield and
average weight
Dosage replacement factor Use standardised batch preparation instruction, use table for dosage replacement factors, determine
unknown replacement factors (see 11.5.1)
Loss of molten fat at transfer to Use minimum batch sizes;
dispersing vessel or melt excess of fat and fill up to weight in dispersing mortar;
Disperse with rotor-stator in melting vessel
Inclusion of air Check average weight
Settling during pouring Is of little importance for the average content, but of significant importance for the content uniformity of
separate suppositories, see 11.5.5
Settling from excess on mold Pouring should be done carefully
See Sect. 32.7.2 for the performance of the test and the 11.9.1 Active Substance: Solubility
requirements according to the Ph. Eur. These test results and Particle Size
don’t give maximal information however about the quality
of the preparation process, especially of small batches. There Rectal absorption depends on solubility and lipophilicity of
are two reasons: the sampling is random and the conclusion the active substance (see further Sect. 16.1.5), and is
of the test is either yes or no meeting the requirements. A influenced therefore by volume, pH, and buffering capacity
specific sampling, especially including the first, middle and of the enema (see Sects. 11.3 and 16.2.4).
last filled suppositories (if a serial filling) or centre and Generally the non-ionised form of an active substance is
corner filled suppositories (if filled in cadre), would give best absorbed which is in favour of water-insoluble
more information. And a standard deviation of the contents substances. However because of the equilibrium between
of randomly taken suppositories reflects homogeneity of the both forms, the absorbed (non-ionised) form of the active
mass that has been molded. substance will generate a driving force from ionised to
The validation of a new suppository formulation will bring non-ionised form. This mechanism enables the use of
about the determination of the content uniformity of a number water-soluble salts, such as dexamethasone sodium phos-
of batches. Consequently, this determination is also necessary phate and prednisolone sodium phosphate. They are much
PRODUCT DESIGN
if the preparation method is changed. For a process validation, easier to be processed than the water-insoluble parent
and probably personnel qualification, of the preparation of molecule.
suspension suppositories in general, acetylsalicylic acid is a
good test substance. Acetylsalicylic acid (180) settles easily
A poorly water-soluble active substance such as the-
and is also easy to analyse in suppositories.
ophylline becomes soluble by the addition of glycine
and sodium hydroxide. In this way a theophylline
rectal solution (Table 11.14) can be formulated with
11.8.6 Distribution of Active Substance theophylline as sodium glycinate.
in Suppositories Table 11.14 Theophylline Rectal Solution 100 mg [46]
Theophylline monohydrate 0.11 g
A homogeneous distribution of the active substance within one
Glycine 0.042 g
suppository is not important for its therapeutic effect. If the
Sodium hydroxide solution 2 M (local 0.3 g
active substance has settled to the tip, it may indicate a too high standard)
pouring temperature. If sedimentation is so extensive that the Water, purified 9.55 g
tip has become brittle and breaks, the quality is insufficient. Total 10 g (¼ 10 mL)
11.9 Product Formulation, Enemas An active substance administered as a suspension must

dissolve before it can be absorbed. This may take consider-
Formulation, volume and packaging should make an enema able time which may be a problem due to the termination of
suitable for rectal use. As with suppositories, the form of the rectal retention by defecation. For a systemic effect only a
active substance, ionised or not, is primarily chosen with few, if any, suspension enemas are in use. For a local effect a
regard to optimal effectiveness. Figure 11.1 presents an suspension enema is frequently used, for example with
overview of the choices to be made. mesalazine or beclometasone. The choice between a suspen-
The volume of enemas may vary from a few millilitres sion of the non-dissociated form of an active substance and a
(micro-enema) to more than 100 mL, mainly depending on solution of the dissociated form can in the end only be based
the intended effect: systemic or local. For large-volume on biopharmaceutical research.
enemas water is commonly used and a water-soluble form The influence of particle size on the absorption rate from
of the active substance is preferred. The solubility may be aqueous suspension enemas has probably never been
increased by addition of co-solvents, to be applied in small investigated. Dissolution of the active substance is assumed
volume enemas. If a soluble active substance or an adequate to increase with decreasing particle size (see Sect. 29.2.1).
co-solvent cannot be found, a suspension may be prepared. If For the requirements on particle size for a stable suspension
this is also not an option , a lipophilic vehicle may be chosen. enema reference is made to Sects. 29.2 and 29.3 as well as to
Choice of pH depends on the chosen form of the active Sect. 5.10 because of similarity with oral suspensions. A
substance and is important for the absorption. Excipients particle size of maximal 180 μm generally satisfies. Suspen-
may be added to correct the osmotic value, to increase the sion stability is less important than for oral use since an
viscosity, to prevent oxidation or for preservation. enema is dispensed in single-dose containers. However,
218 S. Haas et al.
suspension stability must be sufficient to assure an even Table 11.15 Choral Hydrate Rectal Solution 50 mg/mL en 150 mg/mL
distribution of the active substance at filling of the single- [50]
dose containers from a bulk suspension. In addition the 50 mg/mL 150 mg/mL
sediment must be easy resuspendable, in order to avoid Chloral hydrate 5g 15 g
active substance remaining in the enema container after Arachis oil, refined 88 g 83 g
administration. Total 93 g (¼ 100 mL) 98 g (¼ 100 mL)
For enemas with an oily vehicle, the considerations
regarding solubility of active substance and choice of parti-
cle size resemble those for fatty suppositories (see be sufficient, though less than from the macrogol base. The
Sect. 11.4.1). The process of release and absorption of the stability of chloral hydrate in sesame oil is good. Therefore
active substance is also largely comparable to that of fatty an oily vehicle is preferred. As sesame oil often causes
suppositories; just the melting step is not necessary. allergic reactions, the chloral hydrate rectal solution of
Table 11.15 presents a solution of chloral hydrate in arachis
oil [47–49].
11.9.2 Vehicle For an even better bioavailability and easier administra-
tion, a chloral hydrate suppository is often preferred. Chloral
In enemas for a systemic effect, water as a vehicle has the hydrate suppositories with a macrogol base (see Table 11.1)
great advantage of presenting only one liquid phase in the are chemically stable, this unlike the enema with macrogol
rectum, so no transition of the active substance from fat into 300.
rectal fluid is needed. The addition of co-solvents (see Sects.
18.1.3 and 23.3) to the aqueous vehicle or the use of another
vehicle, such as macrogol, is practised to bring poorly solu- 11.9.2.2 Corticosteroids Administered Rectally:
ble active substances in solution or to increase their absorp- Choice of Active Substance
tion. The solubility of an active substance in such mixtures and Dosage Form
has usually to be tried out. Co-solvents may however irritate. If a rectal dosage form for the administration of a corticoste-
For this reason, co-solvents are used for enemas up to 10 mL roid is prescribed, it is important to know if:
only, e.g. diazepam enemas. The use of a fatty vehicle is the • The physician desires a local or a systemic effect.
next option, which may improve stability as well. • This can be achieved by the prescribed form of the active
A water-insoluble active substance may be processed into substance.
an enema as a suspension. However, the dissolution rate may • This can be achieved with the dosage form indicated.
be insufficient for a systemic effect. If an active substance is If the rectal form follows oral administration a systemic
too poorly soluble in water and thus in the rectal fluid, it effect may be desired. It must be checked if the particular
cannot be absorbed at all. steroid is suitable for rectal administration, if the oral dosage
In all enemas having a volume of more than 20 mL, water may have to be adjusted, and if the rectal dosage form is
is used as the single vehicle. These enemas are intended for a appropriate.
local effect. The volume of these enemas usually exceeds A corticosteroid such as beclometasone acts almost
40 mL, see Sect. 11.9.3. exclusively locally due to a large first-pass effect in the gut
The following are three examples of considerations about wall and the liver and is therefore ideal for local application.
the vehicle that had to be made in community and hospital Beclometasone dipropionate in a suspension enema of
pharmacy practice. Some of them have been confirmed by 100 mL is used for chronic intestinal inflammations. A
biopharmaceutical investigations. These investigations are beclometasone suppository may be used to treat proctitis.
strongly recommended. There is clinical experience with beclometasone dipropionate
in an oily base, but literature is still lacking.
11.9.2.1 Choice of the Vehicle for a Chloral Dexamethasone, prednisolone and hydrocortisone are
Hydrate (Micro) Enema systemically active via the rectal route. The best chemical
Chloral hydrate is soluble in water, but the solution irritates form of the active substance must be chosen and a dosage
the mucous membrane and the active substance is rather form that provides good release of the active substance. A
unstable in water. The next choice for a vehicle may be corticosteroid as salt in solution is often optimal for an
macrogol or fatty oil. Chloral hydrate dissolves well in enema and the preparation is easy. As a solution in water it
both. The rate and extent of absorption of chloral hydrate avoids problems such as release from a fatty base and
from a macrogol base (macrogol 300) is good, but the subsequent dissolution. Dexamethasone and prednisolone
chemical stability is insufficient. The rate and extent of for instance are used as sodium phosphate salts. Conversion
absorption of chloral hydrate from sesame oil appeared to and factorisation must not be forgotten. For stability reasons
(and to obtain a physiological pH), a phosphate buffer technological aspects. Enemas for children are proportion-
should be added. ately smaller than for adults.
Hydrocortisone sodium succinate is the available salt
of hydrocortisone. It is not suitable for enemas because it
Volume of Enemas for Neonates
is very unstable in aqueous solution. Alternatives are
For a baby of 2 months a volume of 5 mL is very
hydrocortisone or hydrocortisone acetate in a suspension
suitable for systemic action. For the volume of an
enema or a suppository. For a systemic effect hydrocorti-
enema for local action, e.g., a 0.9 % NaCl solution as
sone is preferred because of its better solubility. Admin-
a laxative the general rule applies [6]: neonates <1 kg:
istration in a fatty suppository satisfies the requirements
rectally 5 mL, and neonates >1 kg: rectally 10 mL.
[51]. A suspension enema seems the better alternative, but
literature does not provide a formula for a stable product.
Therefore, in an enema the use of prednisolone or dexa- In practice, if a systemic effect is intended, usually a
methasone sodium phosphate is preferred. Local effect solution enema with a small volume is applied. The lower
may be achieved with hydrocortisone acetate, sometimes limit is 3 mL, necessary for a correct administration without
used in suppositories in the treatment of haemorrhoids. unacceptable loss. The upper limit is 20 mL, but usually a
PRODUCT DESIGN
However, for this indication hydrocortisone acetate volume of 10 mL is not exceeded. Between 3 and 10 mL
processed in a fatty cream is preferred. That dosage (eventually 20 mL) the volume is determined by the solubil-
form minimises absorption as little cream will reach the ity of the active substance.
rectum. For a local effect in the colon, the volume of an enema
generally has to be as large as possible. A volume of 100 mL
11.9.2.3 Diazepam and Temazepam in an Enema spreads over the distal part of the colon, however with a
Two vehicles have been proposed for diazepam enemas. strong inter-individual variation. An example of an enema
Both are mixtures of water and co-solvents: propylene gly- for local effect is a mesalazine enema for a distal ulcerative
col – ethanol 96 % – water (4 + 1 + 5, parts by volume, colitis or a distally localised Crohn’s disease. The volume
pH 4.8) and glycofurol – ethanol 96 % – water (5 + 1 + 4, can be even larger than 100 mL if the location of the disease
parts by volume, pH 3.6). No significant difference in irrita- and the area to be reached requires it, as for colonoscopy
tion score was observed with healthy volunteers [52]. with an X-ray contrasting agent. A smaller volume
Rectal irritation was studied also for various volumes of (40–100 mL) may be preferred for patients highly sensitive
both mixtures: 2.5 mL, 5 mL and 10 mL. Only a light to the defecation stimulating effect of an enema,. If the
irritation was observed in the first 5–10 min after adminis- disease is limited to the recto-sigmoidal area 30–60 mL
tration, lasting longer at the largest volume. As a control will be enough, and is better retained by some patients [53].
water was administered in the same volumes: all volumes
were equally well tolerated. Choosing the smallest volume
for enemas with these co-solvents seems best but may be 11.9.4 Choice of pH and Buffering
insufficient for dissolution of the active substance. Regard-
ing dissolution and irritation the optimal volume has to be The pH of enemas is important for stability and absorption of
chosen [52]. the active substance. Regarding irritation, a pH-value
Both vehicles are also usable for some other between 4 and 10 is acceptable for an enema up to 20 mL
benzodiazepines. Temazepam 10 mg in 2 mL of the [54], but preferably the pH should approach the physiologi-
glycofurol mixture, administrated to healthy volunteers, cal value (pH 7–8). In particular if the active substance is a
had a bioavailability equivalent to an orally administered weak acid or a weak base the pH may be adjusted to shift the
capsule of 10 mg temazepam [4]. In this study the enema equilibrium to the unionised form. Absorption of an active
was preserved with methyl parahydroxybenzoate (0.15 %). substance appears to be better from a buffered solution than
However, a vehicle containing such high percentages of from an unbuffered solution with equal pH, so adjusting is
glycofurol and ethanol does not need this supplementary best done by a buffer [55]. A phosphate buffer is frequently
preservation. used for this purpose.
11.9.3 Volume 11.9.5 Excipients
The volume of enemas ranges from 3 to 100 mL. The Excipients may be used to make an enema iso-osmotic, to
volume is chosen on therapeutic, biopharmaceutical and increase the viscosity and sometimes for the wetting of
220 S. Haas et al.
solids. Excipients to prevent oxidation and preservatives are Table 11.16 Beclometason 3 mg/100 g and Mesalazine 1 g/100 g
discussed under Stability (Sect. 11.9.6). Rectal Suspension [57]
Beclometasone dipropionate, anhydrous, micronised 0.003 g
11.9.5.1 Osmotic Value Mesalazine 1g
For rectal administration, the osmotic value may vary within Carbomer 974P 0.35 g
wide limits. An osmotic value corresponding to a 0–1.8 % Disodium edetate 0.1 g
sodium chloride solution is tolerated. Adjusting the Methyl parahydroxybenzoate 0.15 g
iso-osmotic value of an enema, by addition of, for example, Sodium metabisulfite 0.1 g
Trometamol 0.33 g
sodium chloride, offers no advantage regarding activity and
irritation, and can be omitted. Strong hyperosmotic solutions
must be avoided in enemas, except for those intended as Total 100 g
laxative. A strongly hyperosmotic solution, for example a
phosphate enema, induces a defecation reflex. The osmotic
value of this enema is about seven times higher than that of a vehicle (see Sect. 22.2). For the prevention of oxidation
normal saline solution. see Sect. 22.2.2. The effectiveness of an antioxidant depends
on the nature of the active substance and the vehicle, and
11.9.5.2 Viscosity must be determined experimentally. Sodium metabisulfite
For a suspension enema, the addition of a viscosity enhancer appeared to be more active than ascorbic acid in the
may be necessary. Solutions sometimes have a viscosity beclometason-mesalazine enema of Table 11.16.
enhancer added as well, based on the supposition that a Physical stability plays a role both for suspensions and
prolonged residence time is beneficial for absorption [56] solutions. A suspension may settle too fast and the sediment
but published evidence of improved efficacy does not exist. may be poorly resuspendable after standing for some time.
On the contrary, a reduced absorption may be the result of Crystal growth too may occur in suspensions (see Sect.
reduced spreading in the gut. But probably the influence of 18.4.2.3). In solutions, the active substance may crystallise
viscosity on spreading is dwarfed by the influence of the during storage (Sect. 18.1.6). These physical stability problems
intestinal pressure on spreading. resemble those of oral liquid dosage forms, see Sect. 5.4.14.
See Sect. 23.7 for the choice of a viscosity enhancer. Microbiological stability may be a problem too. Aqueous
Cellulose derivatives are often used, for example enemas are prone to microbiological contamination and
hypromellose 4,000 mPa.s 0.5–1 %, hydroxyethylcellulose growth. The Ph. Eur. sets the same requirements for
300–560 mPa·s 1–1.5 % or methylcellulose 400 mPa·s TAMC and TYMC (see Sect. 19.6.3) to rectal preparations
1–2 %. Also used are a carbomer hydrogel, 0.3 % and as to oral preparations (103 CFU/g or mL, see Sect. 19.6.2).
sometimes povidone, at a concentration of 2.5 %. Enemas, like oral mixtures, should also meet with the
requirements of preservation efficacy. For preservatives ref-
erence is made to Sect. 23.8. Generally methyl parahydrox-
11.9.5.3 Wetting
ybenzoate 0.15 % is used.
Wetting of strongly hydrophobic active substances can be so
difficult that the solid particles will not get dispersed prop-
erly and float on the water. Polysorbate 80 (0.1–0.15 %) can Prevention of Degradation
be added to the water to prevent this. Alternatively the solid The pH of a beclometasone rectal suspension with
active substance can be triturated with povidone or colloidal carbomer as viscosity enhancer has been adjusted to
anhydrous silica, see Sect. 29.3. Addition of a surfactant 5–6. That pH is lower than usual for a carbomer
such as polysorbate should be considered carefully, because hydrogel and is chosen as a compromise for two
unless in small amounts it may adversely affect the absorp- aspects: the viscosity of the carbomer hydrogel and
tion; comparable with the addition of surfactants to the stability of beclometasone dipropionate. The same
suppositories (see Sect. 11.3.2). pH is chosen for the beclometasone and mesalazine
rectal suspension of Table 11.16. As an additional
benefit mesalazine is less soluble at pH 5.5 and
11.9.6 Stability hence more stable than at a higher pH. To protect the
dissolved fraction of mesalazine against oxidation
Chemical stability may be problematic in enemas, especially sodium metabisulfite is added. Adequate storage
if the active substance is dissolved in water, hydrolysis may conditions are important to obtain a reasonable shelf
occur. Stability may be improved by a more stable form of life: protected from light and in the refrigerator.
the active substance, by a different pH or by a different
11.9.7 Containers
concentration, whereas the administered dose remains
See Sect. 24.4.4 for containers for enemas. Enemas are (almost) equal. Therefore a shorter shelf life is used:
generally dispensed in a single-dose plastic container. 12 months after filling for the syringe versus 24 months
Enemas of 3–10 mL, may be packaged in a tube-shaped or after filling for a micro-enema bottle.
bellows-shaped micro-enema bottle. Alternatively, syringes
with a rectal cannula may be used for the small volume
enemas as well. From a syringe dosing is more exact and 11.9.8 Storage
may be varied. For optimal dose flexibility at patients, the
enema can be supplied as bulk liquid in a glass bottle with a Enemas (in enema bottles or micro-enema bottles) prepared
dosage syringe with rectal cannula added (see Sect. 24.4.14). according to a standardised formula, and which are chemi-
Enemas of 20–100 mL are supplied in an enema bottle of cally and physically stable and preserved, may get a shelf
100 mL or in an enema bag (both disposable). life of 12 months in an unopened container. The same type of
These primary packaging provides insufficient light pro- enemas packaged in a glass bottle with Dose-pac, may be
tection. If light protection is desired (for instance with assigned a shelf life of 24 months and 6 months after open-
PRODUCT DESIGN
mesalazine) syringes, bottles or bags are wrapped in alumin- ing. Preserved enemas with unknown chemical and physical
ium foil or delivered in box or bag. stability cannot be stored in the pharmacy because the usage
When administering an enema, it is almost impossible to period – and thereby the shelf life is maximal 1 month and
transfer all liquid to the rectum. A small amount will always concerns the closed containers. A usage period of 1 month
remain in the bottle or giving tube. Small enema bottles are also applies to non-preserved enemas, but until use the
therefore filled with an excess of liquid. The required excess patient has to store the closed containers in a refrigerator.
depends on the model of the micro-enema bottle and on the
physical properties of the micro-enema liquid, in particular
the viscosity. The residual volume, and thus the required 11.9.9 Labelling
excess, can be determined by weighing a bottle, filling it and
emptying it by squeezing, after which it is reweighed. Enemas are dispensed with a label preferably bearing the
In enemas for a local effect, usually having a higher text ‘for rectal use only’. General requirements for labelling
volume, the residual volume is neglected. are provided in Sect. 37.3. With a suspension enema, “shake
Preferably a (micro) enema container should be filled well before use” must be stated in the label text and on a
completely, which may require adjustment of the active separate sticker. If the enema has to be kept in the refrigera-
substance concentration. A full container increases tor, the label should show the text “Bring to room tempera-
stability by reducing the air contact of the content. It also ture before use”. Up to 10 mL this can be achieved by
prevents insertion of an undesired amount of air during holding the bottle for 5 min in a warm hand. Larger enemas
application. should be taken out of the refrigerator 3 h before use. If
enemas in micro-enema bottles or syringes are dispensed in
a carton as secondary package, the primary package (con-
Packaging and Shelf Life tainer) can be provided with a flag label only, showing date,
The type of material of the primary packaging may name of preparation and shelf life.
negatively influence the shelf life of an enema. For the application of enemas, the patient is advised to lie
Diffusion through the plastic container and degra- down (in a lateral position with the upper knee flexed) and, if
dation of the container may occur during storage of a possible, not to get up before 5–10 min after administration.
solution of chloral hydrate in arachis oil packaged in The cannula, which is lubricated with soft paraffin, should be
polyethylene enema bottles or in disposable syringes brought into the rectum with a rotating movement. Deep
with a rectal cannula. The shelf life of this enema is breathing facilitates this. A syringe and a micro-enema bot-
24 months, packaged in a glass or a polyethylene tle should be emptied slowly by pressing, an enema bottle
terephthalate bottle, 3 months in a micro-enema bottle and an enema bag by rolling up. Fast insertion may provoke
and 1 month (4 weeks) in a syringe. a defecation reflex. When empty, syringe, bottle or bag
During the storage of theophylline rectal solution should be withdrawn, while still compressed [58]. As for
(Table 11.14) in disposable syringes with a rectal suppositories the method of insertion of enemas is not
cannula, water evaporates. After 12 months of storage always familiar to the patient. Providing good verbal infor-
at room temperature, the evaporation rises to 5 %, after mation and a complete and clear information leaflet as well
24 months storage to 10 %. This causes an increase in are important at the moment of dispensing, to avoid an
incorrect use.
(continued)
222 S. Haas et al.
application adhesion is not important. Also little research is

11.10 Preparation, Release Control done about the biopharmaceutics of suppository bases in
and Quality Requirements of Enemas case of vaginal application. From a preparation process
point of view the same bases can be used for pessaries as
The process steps dissolving, dispersing and mixing are dealt for (rectal) suppositories.
with in chapter 29. Micro-enema bottles are best filled using In the past a glycerinated gelatin base was often used for
a syringe with a needle (but beware of puncturing the bottle). pessaries. Glycerinated gelatin pessaries provide at body
When a bulk suspension is filled into enema bottles homo- temperature a good adhesive, softened mass and they are
geneity of the mixture should be maintained to get a good tolerated well. Because of many disadvantages however (see
content uniformity. Sect. 11.4.3), this base is not used anymore in Dutch
After preparation and packaging, enemas have to be pharmacies.
checked for appearance, labelling and packaging. The Hard fat (Adeps solidus) gives little irritation and most
final volume or the final weight must also be checked. active substances can be incorporated without any problem.
Solutions must be clear and visually free from particles. An important disadvantage of a fatty base is the incompati-
For a suspension enema the resuspendability must be bility of fat and rubber, the material of condoms and
evaluated, which may be done following the method for diaphragms. When a fatty base is used, the patient should
oral suspensions, see Sect. 32.7.2. For other quality be warned that the protective effect of a condom or dia-
requirements see Table 32.2. phragm is not reliable. A fatty base can also leak out of the
vagina, causing problems with regard to clothing.
A macrogol base is often discouraged because it would be
11.11 Pessaries irritating to the mucosa. Others report a good acceptance of
the base. Irritation is assumed to be caused by the attraction
Little is published about the biopharmaceutics of vaginal of water from the mucosa. The available amount of water in
dosage forms. The vagina is a good absorbing organ, but the vagina varies individually. A slow or incomplete release
seldom used for the systemic administration of medicines. of the active substance may result in case little liquid is
The fact that only women can benefit from this route of available. Moreover macrogol is incompatible with many
administration might have limited its use for systemic active substances, see Sect. 11.4.5.
administration of medicines and further research [59]. Vagi-
nal dosage forms are almost exclusively used for active
substances with a local effect on the vaginal mucosa. Prod- In an orientating study on the irritating properties of
uct formulation, method of preparation, release control and pessary bases, macrogol (Macrogol 1500 + Macrogol
quality requirements resemble those of suppositories (see 4000 ¼ 1:2) and hard fat (Witepsol H15) were well
Sects. 11.4, 11.5, 11.6, 11.7, and 11.8). Some specific tolerated by healthy subjects. The macrogol based
aspects of vaginal application are discussed in the following pessaries were moistened with water before insertion
sections. to prevent irritation. No difference was found between
both bases with respect to irritation. For practical
reasons the subjects strongly preferred the macrogol
base. Leakage of the melted or dissolved base from the
vagina, also mentioned in [59], was much more prob-
lematic with the fatty base than with the macrogol
High lipid solubility and low molecular weight enhance the
base, in particular with regard to spotting on clothes.
absorption through the vaginal mucosa. As for dermal
preparations absorption occurs primarily by passive diffu-
sion. Therefore active substances intended for a local effect A choice between hard fat and macrogol should depend
should have a limited lipophilicity, in order to prevent sys- on the properties of the active substance. Active substances
temic action [59]. that are insoluble in water are best incorporated in a hydro-
philic base, even when a local effect is desired [8r]. From a
lipophilic base these active substances are not or only poorly
11.11.2 Base released. Water soluble active substances can be
incorporated in both bases, but macrogol is more comfort-
A good adhesion of the base to the vaginal mucosa is needed, able for the patient [5i]. New, strongly adhesive gels as a
because a vaginal dosage form may easily be lost due to the base for pessaries are likely to be an improvement [59], but
absence of a sphincter. Little is known about the adhesion too little research is available yet for use in pharmacy
properties of suppository bases, because for rectal practice.
11.11.3 Shape and Size 11.12.1 Vehicle
Pessaries originally are egg-shaped. Other shapes are avail- Water is the only suitable vehicle.
able as well. In pharmacy practice often suppository type
molds are used. Alternatively plastic pessary molds may be
used (strips). The volume of these egg-shaped molds is about 11.12.2 Volume
equal to a suppository of 2.8 mL. Formerly used metal
pessary molds had a volume of 5 mL. In literature the size The volume of a vaginal solution varies from 150 to 200 mL.
of pessaries varies: weight values between 1.2 and 6.8 g are A concentrate for dilution will be diluted by the patient
found [8s]. No studies are available about a desirable vol- about ten times, depending on the filling marks of the avail-
ume. For a local effect 2.8 mL seems to be right. For a able irrigator.
systemic effect a smaller volume is probably adequate.
11.12.3 Choice of pH and Buffer Capacity

11.11.4 Packaging and Labelling
When the physiological pH of the vagina (pH ¼ 3.5–4.5) is
PRODUCT DESIGN
not maintained the microbiological balance in the vagina
Pessaries can be dispensed in the same way as
may become disturbed. Therefore the solution should have
suppositories. The label should contain a short indication
a physiological pH. Especially when the vaginal solution is
such as ‘for vaginal application’. See for general
intended for correction or support of the pH, for instance a
requirements for labelling Sect. 37.3. A clear indication is
lactic acid solution, a buffered solution is preferred.
needed how to use the pessary, for instance ‘insert high into
the vagina’. Especially when suppository molds were used
for the pessaries, it is important to make clear how to use
11.12.4 Sterility
these vaginal suppositories or pessaries. For macrogol
based pessaries the label may indicate: ‘moisten with
The Ph. Eur. does not require sterility for vaginal solutions.
water before insertion’. Moistening is advised in literature
However, the Ph. Eur. requires for all vaginal dosage forms a
[60], but the real effect has never been studied and is
preparation ensuring their microbiological quality. These
questionable. In the patient information leaflet, additional
requirements are the same as for cutaneous preparations:
information may be needed about use and administration of
not more than 100 CFU/g or mL. For an enema by compari-
pessaries, for instance with some figures. It is advised to
son up to 1,000 CFU/g or mL are allowed. A solution for
warn the patient to wear a sanitary napkin or panty liner to
application on a heavy damaged skin however should be
prevent spots on clothes or bed linen, especially when a
sterile according to Ph. Eur., see under ‘Liquid preparations
fatty base is used [5k]. For fat based pessaries a warning
for cutaneous application’. Sterility is also required under
about the incompatibility with rubber condoms and
‘Preparations for irrigation’ for solutions intended for irriga-
diaphragms is needed too.
tion of body cavities. In (Dutch and German) practice sterile
solutions are prepared if they are intended for vaginal use
after surgical procedures [8t]. Solutions for use on an intact
11.12 Product Formulation, Vaginal Solutions vaginal mucosa do not need to be sterile, but should have a
low bacterial count. This means that starting materials of
Vaginal solutions usually contain active substances good microbiological quality should be used and that con-
dissolved in water and are intended for a local effect. The tamination during the preparation process should be
Ph. Eur. describes solutions as well as emulsions and prevented whenever possible.
suspensions. Only solutions are seen in pharmacy practice
and just occasionally such as lactic acid solutions, with or
without sodium lactate, iodinated povidone (povidone- 11.12.5 Excipients
iodine) solutions and chlorhexidine digluconate solutions.
Accordingly, this chapter discusses the solutions only. Excipients are added to make a vaginal solution iso-osmotic.
Solutions may be prepared either ready-for-use, or as a Iso-osmosis is especially important for solutions used on a
concentrate to be diluted before use, or as a tablet to be damaged mucosa or after operations. Frequently sodium
dissolved in water shortly before use. chloride is added for iso-osmosis. Glycine is used as an
224 S. Haas et al.
alternative in chlorhexidine digluconate solutions, because 11.12.8 Storage

of a chemical incompatibility with sodium chloride. For
vaginal solutions applied to an intact mucosa iso-osmosis See Sect. 22.7 for the general approach of storage times.
is not strictly required. Sterile vaginal solutions, prepared according to a standard
formula and chemically and physically stable, may have a
shelf life of 3 years after preparation if packaged in single-
11.12.6 Stability dose containers. If prepared according to a non-standardised
formula, a sterile vaginal solution should not be stored in the
Just as in enemas (see Sect. 11.9.6) chemical stability may pharmacy because the maximal shelf life of say 1 month, may
be a problem in vaginal solutions. This cannot be avoided by be reasonably needed by the patient. After opening, a sterile
choosing a different pH or another solvent as with enemas. vaginal solution can be kept in the refrigerator for 24 h.
So the active substance should be inherently stable in water. Non-sterile but preserved vaginal solutions may have a
For the microbiological stability of non-sterile vaginal shelf life of 3 years after preparation, if prepared according
solutions which are often concentrates for multiple dosing, to a standard formula and chemically and physically stable.
preservation may be necessary if the concentrate doesn’t Once opened by the patient, such vaginal solutions can be
meet the test on preservation effectiveness (see Sect. 32.8). assigned an in-use period of 6 months. A concentrate diluted
Methyl parahydroxybenzoate can be used as a preservative. by the patient should be kept only 24 h after dilution. A
non-standardised preserved preparation should not be stored
in the pharmacy because the maximal shelf life of say
Problems with chemical or microbiological stability
1 month, may be reasonably needed by the patient. A diluted
may be avoided with a tablet or powder from which
concentrate may be kept for 24 h after dilution. Unpreserved
the vaginal solution is prepared just before use by
non-sterile vaginal solutions may have a shelf life of maxi-
dissolving it in water. An example is the Multi-Gyn®
mal 2 weeks and they have to be stored in a refrigerator.
effervescent tablet from BioClin® for the preparation
of an acidifying vaginal solution. An appropriate irri-
gator (vaginal douche) is supplied. In addition to
11.12.9 Labelling
sodium hydrogen carbonate (sodium bicarbonate),
citric acid, ascorbic acid and lactose, the effervescent
Vaginal solutions are delivered with a label showing ‘for
tablet contains an extract of Aloe barbadensis, an
vaginal use only’. It is important that the method of admin-
addition without evident function.
istration is clearly indicated. If appropriate, the word ´sterile´
A vaginal solution with iodinated povidone is
should be written on the package. An irrigator for the admin-
best delivered as a stable concentrate, for instance
istration should be delivered with the product (see Sect.
Betadine®-solution 100 mg/mL. The patient should
24.14). The patient has to be instructed how to dilute a
dilute the concentrate ten times in an irrigator. The
concentrate in the irrigator. A mark on the irrigator usually
indication is fluor vaginalis with clinically evident
indicates the amount of concentrate to be used. For dilution
inflammation but without a microbiological diagnosis.
(fresh) lukewarm tap water can be used. The patient should
A bacterial vaginosis during pregnancy can also be
be fully informed about the administration of the vaginal
treated short term with an iodinated povidone vaginal
solution.
solution.
11.13 Preparation, Release Control

and Quality Requirements
11.12.7 Containers of Vaginal Solutions
Sterile vaginal solutions are packaged in a single-dose con- Method of preparation, release control and quality
tainer that can be sterilised, for instance glass (preferably requirements of sterile vaginal solutions are the same as
class I, eventually class II) or plastic (polypropylene). Pre- for irrigation solutions (Preparations for irrigation Ph. Eur.,
served concentrates, intended to be diluted before use, are see Sect. 14.7). Preparation method and release controls of
usually packaged in a container of glass (class III) or plastic non-sterile vaginal solutions are the same as for solutions for
(polypropylene, polyethylene) meant for multiple dosing. cutaneous use (see Sect. 12.6.5).
11.14.3 Additives with a Spermicidal Effect

11.14 Semisolid Dosage Forms, Rectal
or Vaginal Sometimes information is needed about the possibility of a
(not intended) spermicidal effect of vaginal dosage forms.
For rectal application ointments and creams are common, for The viscosity enhancer hydroxyethylcellulose 250, used in
vaginal application creams and gels are used. They act the vaginal gel pH 5 (Table 11.17), might act as a barrier for
locally and the design and preparation hardly differ from sperm and also a pH 5 (or less) inhibits the mobility of sperm
corresponding dosage forms for cutaneous use. In the [63]. So this gel should not be used in case of fertility
subsequent sections some aspects of semisolid preparations problems. Surfactants and antimicrobial preservatives in a
for rectal and vaginal use will be discussed that are not cream or gel are suspected of spermicidal effects. For exam-
encountered in cutaneous use. ple, the surfactant nonoxynol-9 is the active substance in
most spermicidal creams and gels. The gel lubricant
(moisturising gel) Sensilube® that is claimed to be
11.14.1 Active Substance non-spermicidal contains methylparaben, ethylparaben and
propylparaben. Therefore these preservatives are likely to be
PRODUCT DESIGN
The possibility of absorption and systemic effects should be sperm-friendly and usable for vaginal gels. Chlorhexidine
considered with more attention than with cutaneous use. digluconate may not be spermicidal in a concentration of
Most risk of absorption theoretically exists for a lipophilic 0.1 % and lower and therefore can be used also.
active substance in a hydrophilic base, but in fact hardly
anything is known about this issue. An isosorbide dinitrate
soft paraffin cream, for instance, may already cause head- 11.14.4 Dosage Delivery Devices
ache due to systemic absorption although applied on a small
anorectal surface. Absorption from a lidocaine soft paraffin A rectal cannula is adequate for application of ointments and
cream is found when used for internal haemorrhoids and creams in the anus (see Sect. 24.4.19.12). It is about 3.5 cm
applied from a tube with a long nozzle (cannula) (see Sect. long and can be screwed onto a tube. Before insertion into
24.4.19.12). The cream easily reaches the rectum and the the anus the cannula should be lubricated with a little of the
lidocaine can then be absorbed. product. After insertion of the cannula a small amount of the
Intentional absorption at vaginal administration may be product can be brought into the anus by squeezing the tube.
attained by processing a lipophilic active substance in a For vaginal application of a cream or gel a vaginal applicator
hydrophilic base: a vaginal gel [61], see also Sects. 11.11.1 exists (see Sect. 24.4.19.11). It is a kind of syringe that
and 11.11.2. should be attached to the tube, after which about 5 g of the
cream or gel can be expelled. After aspiration of the product
the applicator is inserted into the vagina and the piston is
11.14.2 Base pressed to apply the product. For treatment of a vaginal
candidiasis during pregnancy (for instance with miconazole)
Condoms become permeable in contact with a cream or the use of an applicator bears a risk of mechanical injury.
ointment base containing fats or paraffin [62]. This may be The relevance of this risk however is uncertain and the
a problem for rectal as well as vaginal use. The same prob- vaginal administration of a cream without an applicator is
lem applies to occlusive diaphragms. For these reasons, a rather inconvenient.
hydrophilic gel is the best possible base if combination with
condoms or diaphragms cannot be excluded. An example of
a hydrophilic gel is the vaginal gel pH 5 (Table 11.17), used
as lubricant in case of vaginal dryness.
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1:243–253
Dermal
12
Antje Lein and Christien Oussoren
Contents 12.6.2 Incorporation of Active Substances . . . . . . . . . . . . . . . . . . . . 249

12.6.3 Large Batches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
12.1 Prescription Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 12.6.4 In-process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
12.1.1 Need for Cutaneous Pharmacy Preparations . . . . . . . . . . . 230 12.6.5 Release Control and Quality Requirements . . . . . . . . . . . . 251
12.1.2 Adapting Licensed Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
12.1.3 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 12.7 Specific Formulations and Preparation Methods . . . 251
12.7.1 Powders for Cutaneous Application . . . . . . . . . . . . . . . . . . . . 251
12.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 12.7.2 Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
12.2.1 Classification of the European Pharmacopoeia . . . . . . . . 231 12.7.3 Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
12.2.2 Classification in Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 12.7.4 Emulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
12.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 12.7.5 Hydrophobic Ointments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
12.3.1 Anatomy of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 12.7.6 W/o Emulsifying Ointments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
12.3.2 Release and Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 12.7.7 O/w Emulsifying Ointments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
12.3.3 Choice of the Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 12.7.8 Hydrophilic Ointments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
12.3.4 Base and Different Skin Disorders . . . . . . . . . . . . . . . . . . . . . 235 12.7.9 Lipophilic Creams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
12.3.5 Method of Application and Dosing . . . . . . . . . . . . . . . . . . . . . 237 12.7.10 Hydrophilic Creams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
12.3.6 Occlusive and Transdermal Preparations . . . . . . . . . . . . . . . 237 12.7.11 Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
12.7.12 Oleogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
12.4 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 12.7.13 Pastes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
12.5 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 12.7.14 Collodia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
12.5.1 Solid Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 12.7.15 Shampoos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
12.5.2 Lipophilic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 12.7.16 Sticks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
12.5.3 Aqueous Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 12.7.17 Sterile Cutaneous Preparations . . . . . . . . . . . . . . . . . . . . . . . . . 261
12.5.4 Interphase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
12.5.5 Physical Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
12.5.6 Chemical Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
12.5.7 Incompatibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
12.5.8 Improvement of Colour and Smell . . . . . . . . . . . . . . . . . . . . . 246
Abstract
12.5.9 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
12.5.10 Dosage Delivery Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Preparations for cutaneous (or dermal) application may be
12.5.11 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 used for local treatment as well as for transdermal adminis-
12.5.12 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 tration with a systemic effect. The chapter focuses on
12.6 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 preparations with a local effect and on design of formulation
12.6.1 Preparation Method of the Base . . . . . . . . . . . . . . . . . . . . . . . . 248 and method of preparation of those prepared in pharmacies.
The interaction between skin, active substance and base, the
anatomy of the skin and biopharmaceutical aspects of cuta-
Based on the chapter Dermatica by Christien Oussoren, Gerad Bolhuis neous preparations are discussed as well as the therapeutic
en Koen Mutsaerts in the 2009 edition of Recepteerkunde. effect of the base. Because of the important role of the
A. Lein (*) pharmacist in prescription assessment some
Pharmaceutical Laboratory of Deutscher Arzneimittel-Codex/Neues recommendations for the communication with the physician
Rezeptur-Formularium, Eschborn, Germany
are given. One aspect is how to proceed with a request for the
mixing of two licensed medicines or for the addition of an
C. Oussoren
active substance or an excipient to a licensed product. The
Department of Pharmaceutical Sciences, Utrecht University, Utrecht,
The Netherlands formulation design is generally following the several phases
e-mail: [email protected] of the multicomponent preparations. Based on the

230 A. Lein and C. Oussoren
classification of the European Pharmacopoeia additionally added to corticosteroid containing formulations to

the typical types of cutaneous dosage forms are discussed improve the penetration of the corticosteroid into the
further, with regard to formulation as well as the way of skin, which may increase therapeutic effectiveness. How-
processing. Extemporaneous preparation mostly involves ever, it should be reflected whether a stronger corticoste-
the addition of active substances to base preparations. roid may be the better choice.
Preparations standardised in European formularies are used
to illustrate special properties, design of formulation and
An example for the early incorporation of new scien-
preparation methods. Preparation processes for large scale
tific knowledge in dermatological practice by using an
require some other methods than small scale preparations.
extemporaneous preparation is the treatment of
chronic anal fissures with diltiazem hydrochloride.
Keywords
The mechanism of action is based on the reduction of
Formulation Preparation Base Semisolid Cutaneous
the pressure in the anal sphincter. In comparison to
liquid Cream Ointment Cutaneous gel Paste Skin
organic nitrates diltiazem hydrochloride causes less
Cutaneous emulsion Cutaneous powder Cutaneous
adverse effects (headache). Based on published
solution Cutaneous suspension
experiences with this treatment and the need for a
stable preparation, formulations for a gel and a cream
were developed (Table 12.1).
12.1 Prescription Assessment
Table 12.1 Hydrophilic Diltiazem Hydrochloride Rectal Gel 2 %
and Hydrophilic Diltiazem Hydrochloride Rectal Cream 2 % [1]
12.1.1 Need for Cutaneous Pharmacy
Preparations Gel Cream
Diltiazem hydrochloride 2g 2g
Licensed products are first choice in the treatment of skin Hydroxyethylcellulose gel DABa 98 g –
Cream base DACb – 98 g
disorders. However, these preparations do not always meet
the specific needs of the patient. Therefore patients are often Total 100 g 100 g
in need for individualised preparations. a
Table 12.35
b
Typical situations in which pharmacy preparations may Table 12.6
be needed are:
• If no licensed pharmaceutical preparation is available.
This may concern less common disorders. Examples
are: sodium hypochlorite solution and emulsion for the
treatment of ulcers and decubitus, dithranol cream and 12.1.2 Adapting Licensed Products
dithranol ointment in a series of increasing concentrations
for psoriasis, levomenthol or lidocaine containing In general adapting licensed preparations is problematic for
preparations for pruritus, sterile metronidazole gel for several reasons:
foul-smelling wounds and diltiazem hydrochloride • Scientific evidence of therapeutic rationality, activity and
creams and gels for the treatment of anal fissures. Many safety of the adapted product is lacking.
of these are licensed now, although not in every country. • Additives can change biopharmaceutical properties of the
• The patient is allergic to one of the excipients of the licensed product.
licensed product. If the active substance is available the • The combination of two licensed products may decrease
pharmacist may be able to formulate a preparation with- concentrations of the active substances too much.
out the allergenic excipients. • The duration of the treatment with one or the other active
• The physician or patient notifies that an individualised substance may be typically different, causing the patient
preparation is more effective. to be treated inadequate, either too short or too long. For
• The physician wants to combine two licensed products in example the combination of antibiotics and
one to ease the application for the patient. For some corticosteroids can result in bacterial resistance if the
people instructions for daily application of more than antibiotic is applied too long. Upon application of the
one preparation can be too much of an effort resulting combination of corticosteroids and antimycotics the
in non-compliance. patient may be treated too long with the corticosteroid
• The physician wants to add an extra active substance or or the treatment with the antimycotic is insufficient.
excipient to improve the effectiveness of the licensed • The qualitative and quantitative formula of licensed
preparation. For example salicylic acid and urea may be pharmaceutical preparations is often not known. Adding
12 Dermal 231
new active substances or excipients may result in patients. This may cause a conflict of interest because the
physical and chemical incompatibilities. physician wants to prescribe a tailor made preparation, but
the pharmacist may not be able to formulate and supply a
stable and effective product, for example because of
incompatibilities, toxicological or quality concerns. In
12.1.3 Recommendations order to agree on which preparations can be prescribed and
supplied it has been proven useful if pharmacists and
The following general recommendations may be helpful for physicians have access to a standardised and rationalised
handling prescriptions of cutaneous preparations: assortment of cutaneous pharmacy preparations, based on
• If suitable licensed medicinal products are available, they literature and multidisciplinary guidelines. Examples are
should be preferred. “Dermatica op Recept” in the Netherlands [2] or
• If a licensed product has to be adapted, the pharmacist “Standardisierte Rezepturen – Formelsammlung für Ärzte”
should suggest a standard pharmacy preparation with a in Germany [3]. If the physician needs a non-standardised
comparable base and chemical form of the active sub- preparation a full prescription assessment (see Sect. 2.2)
stance. For example the type of emulsion has to be the should be performed.
PRODUCT DESIGN
same or an anhydrous formulation such as a hydrophilic
or hydrophobic ointment should be replaced with a simi-
lar anhydrous preparation. 12.2 Definitions
• Is combination or adaptation of licensed products aimed at
a better adherence, it is to be preferred that physician and 12.2.1 Classification of the European
pharmacist give clear advice about the administration of the Pharmacopoeia
original products or start from a standard pharmacy formu-
lation. For the instruction of patients where, how, how often In the eighth edition of the European Pharmacopoeia cuta-
and how long to apply cutaneous preparations, a special neous preparations are classified as liquid preparations for
form with an outline figure may be helpful, see Fig. 2.5. cutaneous application, semisolid preparations for cutaneous
• Standard formulations in national formularies are to be application and powders for cutaneous application [4].
preferred. The addition of another active substance to Liquid preparations for cutaneous application are
standard formulations is possible, but the number of described as preparations with variable viscosity intended
substances has to be limited and incompatibilities must for local or transdermal application. This category comprises
be excluded. solutions, emulsions and suspensions for dermal use
• In case of non-standardised preparations the pharmacist containing one or more active substances in a suitable
should professionally improve the formulation if neces- base. As examples for liquid preparations shampoos and
sary, for instance by the addition of buffers and choosing cutaneous foams are defined in Ph. Eur.
a similar but compatible base. Semisolid preparations for cutaneous application are
To ease the communication between pharmacist and phy- subdivided in ointments, creams, gels, pastes, poultices
sician some defined agreements are useful. The pharmacist (wet dressings), medicated plasters or patches and cutaneous
has to identify the problems in the prescription and should patches.
name alternatives to the formulation if needed. The concept Ointments are cutaneous preparations consisting of one
of the treatment has to be considered. The following phase, hydrophilic or hydrophobic, in which a solid phase
measures can be agreed upon beforehand: may be dispersed. They are subdivided in hydrophobic
• Obsolete active substances or excipients should not be ointments, water-emulsifying ointments and hydrophilic
processed. ointments.
• Preservatives are added if microbial growth is expected. Hydrophobic ointments are ointments that can absorb
If a formulation should be prepared without a preserva- only small quantities of water. The base of water
tive, the physician has to note that on the prescription. emulsifying ointments is similar to the base of the hydro-
• Overdosing for therapeutic reasons has to be noted on the phobic ointments but also contains one or a few emulsifying
prescription, for example with an exclamation mark. agents, so they can absorb larger quantities of water than
• The declaration of the chemical form of steroids for hydrophobic ointments and form water-in-oil (w/o) or oil-in-
dermal use has to be clear. Some of the steroids have no water (o/w) emulsions, depending on the type of the emulsi-
effect on the skin, for example triamcinolone or fier. Hydrophilic ointments are ointments which consist of
betamethasone, but the esters do. only a hydrophilic phase. They are miscible with water.
Prescribing extemporaneous cutaneous preparations is a Creams are described as preparations comprising a lipophilic
privilege that many physicians appreciate as well as some and an aqueous phase. Creams with the aqueous phase as
Table 12.2 Definition of cutaneous preparations

Standard
Ph. Eur. terms Synonyms Examples
Powders for cutaneous
application
Cutaneous Base for cutaneous powder (Table 12.18)
powder
Liquid preparations for
cutaneous application
Solution Cutaneous Salicylic acid cutaneous solution 10 % (Table 12.10), Tretinoin cutaneous solution
solution 0.05 % (Table 12.11)
Suspension Cutaneous Mixture, Zinc oxide cutaneous suspension (Table 12.21)
suspension lotion
Emulsion Cutaneous Liniment, Cetomacrogol cutaneous emulsion (Table 12.24)
emulsion milk, lotion
Semisolid preparations for
cutaneous application
Lipophilic gel Gel Oleogel Hydrophobic base gel DAC [43]
Hydrophilic gel Mucilago, Hydroxyethylcellulose gel DAB (Table 12.35)
hydrogel
Lipophilic cream Cream W/o cream Cooling ointment FNA (Table 12.31), Hydrophobic cream base DAC (Table 12.32)
Hydrophilic cream O/w cream Nonionic hydrophilic cream SR DAC (Table 12.33), Lanette cream I and II
(Table 12.34)
Hydrophobic ointment Ointment Coal tar soft paraffin ointment (Table 12.25)
Water-emulsifying ointment Emulsifying hydrophobic base gel DAC (w/o emulsifying) (Table 12.26),
Cetomacrogol ointment base (o/w emulsifying) (Table 12.27)
Hydrophilic ointment Macrogol ointment DAC (Table 12.29)
Paste Cutaneous Zinc oxide cutaneous paste DAB (stiff paste) (Table 12.38), Zinc oxide calcium
paste hydroxide weak paste (Table 12.39)
continuous phase are classified as hydrophilic. Lipophilic be found. For example a physician usually associates cream
creams are creams with a lipophilic continuous phase. with a hydrophilic base and ointment with a lipophilic one.
Gels are defined as fluids that form a gel because of the In the German Pharmacopoeia the Hydrophilic ointment
presence of a suitable gelling agent. Gels are subdivided in with water (Unguentum emulsificans aquosum) is not an
hydrophilic and lipophilic gels. ointment as the Latin term Unguentum suggests. It is on
Pastes are semisolid preparations containing a large the contrary a hydrophilic cream by Ph. Eur. definition.
amount of solids, dispersed in the base. Emulsions in the sense of liquid preparations with a high
Poultices (wet dressings) are hydrophilic heat-retentive amount of water are often named lotions, liniments or milks.
bases in which one or more active ingredients, solids or As the pharmacist has a lot of different bases for cutaneous
fluids, are dispersed. Generally, they are heated before use preparations it makes sense to communicate the therapeutic
and applied on the skin in a thick layer. goal, the skin conditions and the area of application with the
Medicated plasters are flexible preparations with one or physician to find the right formulation. Knowledge of the
more active substances that should be slowly absorbed, or characteristics and properties of cutaneous preparations
they have protective or keratolytic properties. helps to make an appropriate choice. Table 12.2 shows the
Cutaneous patches are intended for local effects. official terminology in Ph. Eur. EDQM standard terms [5],
Powders for cutaneous application consist of solid, loose, synonyms used in physicians’ practice and European
dry particles with a varying fineness. They may contain one formularies and formulations to be found in this chapter as
or more active substances and excipients. references for each type of preparation.
12.2.2 Classification in Practice 12.3 Biopharmaceutics
Official definitions for the different types of cutaneous In cutaneous preparations the base as such has an influence
preparations are given in the European Pharmacopoeia on the therapeutic effectiveness. It also very much
(Ph. Eur.). But in the physicians practice, in licensed influences the therapeutic effect of the active substance
preparations and in formularies various terminologies can by influencing its release and penetration into the skin. To
12 Dermal 233
Fig. 12.1 Anatomy of the skin. stratum

Source: Recepteerkunde 2009, hair corneum
# KNMP sensory nerve
sebaceous gland
capillaries
epidermis
dermis
hair follicle
loose connective
tissue subcutaneous tissue
(subcutis, hypodermis)
fat tissue sweat gland artery and vein
PRODUCT DESIGN
understand how penetration of active substances and the tissue from infection, dehydration, chemicals, radiation and
therapeutic effect are related to the formulation, it is neces- mechanical stress. During the process of division, migration
sary to have knowledge on the anatomy of the skin and skin and death of the epidermis cells the percentage of water
biopharmaceutics. Release and penetration into the skin is decreases from approximately 70 % in the stratum
generally described in Sect. 16.2.5. As the therapeutic germinativum to 10–20 % in the stratum corneum. How-
effectiveness of cutaneous preparations also depends on ever, the stratum corneum can absorb more water (up to
the frequency of application and the amount to be dis- 50–75 %), for example under occlusion or while bathing.
pensed, these aspects are also dealt with. Hydrated the stratum corneum has a better permeability and
the protecting function is decreased. The pH is 7.1–7.3 in the
stratum germinativum and 5.4–5.9 in the stratum corneum.
12.3.1 Anatomy of the Skin The dermis has a thickness of about 3–5 mm. In contrast
to the epidermis it contains blood vessels and nerves. The
From the outside to the inside the skin consists of the dermis is divided into two layers. The outer layer, the papil-
following layers (see Fig. 12.1): lary region contains a network of capillaries and has a
• The epidermis, which has mainly a protecting function supplying function for the epidermis. The inner layer, the
• The dermis (corium), which has a supplying and reticular region lies under the papillary region and is usually
stabilising function much thicker. Because of the high concentration of collage-
• The subcutis, a layer which has an insulating and nous and elastic fibers imbedded in dense connective tissue,
protecting function and works as an energy storage it gives the dermis mechanical strength and elasticity.
The epidermis consists of a multi-layered epithelium that The subcutaneous tissue mainly contains fat tissue. It has
varies in thickness from 0.03 mm on the eyelids up to an insulating and buffering function.
2.0–4.0 mm on the palms of the hands and soles of the Hairs stand loose in hair follicles. Each root of a hair is
feet. The cells are gradually and continuously renewed by connected with a sebaceous gland that is secreting sebum
being moved from the inside to the outside of the skin. into the follicle. Sebum consists of short chain fatty acids,
During this outward migration the cells change. They waxes and emulsifiers, such as cholesterol. Sweat glands are
keratinise and disintegrate and become denucleated forming coiled tubes that range from the dermis and subcutis into the
a firm cornified layer. From the outside to the inside the surface of the skin. The fluid produced by the glands, the
epidermis consists of five layers: the stratum corneum, the sweat, is a hypotonic salt solution with a pH of approxi-
stratum lucidum, the stratum granulosum, the stratum mately 5. Beside salts, it contains small quantities of other
spinosum and the stratum germinativum. In the stratum substances such as lactic acid and urea. The most important
germinativum, the cell division takes place. The interior function of sweat glands is temperature regulation by loss of
four layers are called the living epidermis. water vapour. The mixture of sebum and secreted products
The outer layer of the epidermis, the stratum corneum, of sweat glands and the loose dead cells of the stratum
consists of dead, mainly keratine containing cells that are corneum form a greasy layer, which covers the skin. This
continuously scaled off. It is considered as a membrane, lipid film can absorb water because of the presence of
built from a dense lipid protein matrix. The function of the emulsifying agents. However it remains water resistant and
stratum corneum is to form a barrier to protect underlying protects the skin against dehydration. The short chain fatty
acids originating from sebum and sweat components and the into the skin more rapidly than hydrophilic substances.
low pH are responsible for its protecting effect against Additionally, lipophilic substances are released more rapidly
pathogenic micro-organisms. from aqueous than from lipophilic bases because of their
higher affinity to the stratum corneum.
The base of a cutaneous preparation also influences the
12.3.2 Release and Penetration rate and extent of absorption. The base can be simple, such
as an aqueous solution, but can also be very complex such as
See Sect. 16.5.1 at first. The rate and extent of penetration of an emulsion. The base can alter the skin conditions, for
the active substance into the skin mainly depends on the example by hydration. As a result, the penetration of the
partition of the active substance in the base and the stratum active substance into the skin may be modified.
corneum. Other factors such as skin conditions, the area and Ultimately, the release and penetration of active substances
method of application play a role as well. from cutaneous preparations is difficult to predict.
Hydrocortisone and the acetate and butyrate esters Lidocaine is applied on the skin in its non-ionic form
are often used for cutaneous application. In the skin because this form penetrates best. To anaesthesise
the esters hydrolyse rapidly and the active substance mucous membranes the hydrochloride salt of lidocaine
hydrocortisone is formed. Usually the concentration of is more suitable because the charged form dissolves
hydrocortisone acetate in creams is 10 mg/g. The usual better in the mucous membranes than the base.
concentration of hydrocortisone butyrate is 1 mg/g, Cutaneous preparations for the skin should contain the
10 times lower than the hydrocortisone acetate ester. base as such or the base has to be formed from lidocaine
Glucocorticosteroids for external use are classified hydrochloride. Three concepts may be followed:
by their potency. Two systems of classification exist 1. Lidocaine hydrochloride is dissolved in an aqueous
that must not be mixed up. One is depicted in the WHO gel. As only non-dissociated molecules can pene-
Model prescribing information [6]: The steroids for trate into the skin, and lidocaine is slightly soluble
external use are assorted there in four groups with in water, the pH is adjusted to 6.5. At this pH only a
seven classes from class I (ultra high potency) to VII small amount of lidocaine (pKa ¼ 7.9) is in the
(low potency). The more common and well known lipophilic form, but dissolved anyway.
system of Niedner [7] has only four categories from 2. Lidocaine is dissolved in a lipophilic phase by
class I (low potency) to class IV (very high potency). warming. An aqueous phase is added last.
Criteria for this classification system are the local effect 3. Lidocaine is added by deliquescing lidocaine
in the vasoconstriction test, the anti-inflammatory and crystals and levomenthol together. The eutectic
the anti-proliferative effectiveness. mixture is than emulsified in an aqueous gel. The
Preparations with hydrocortisone acetate are classi- biopharmaceutic advantage of this principle is that
fied in activity class I, preparations with hydrocorti- a molecular dispersion of the lipophilic lidocaine
sone butyrate in class II. Although the active substance base in a hydrophilic preparation is formulated.
in both preparations is the same, the therapeutic effec-
tiveness of the butyrate ester is stronger. This is the
Penetration into the skin can be enhanced by penetration
consequence of the higher lipophilicity of the butyrate
enhancers. These excipients diffuse into the stratum
ester that leads to better skin penetration.
corneum and interact with components of this layer. The
barrier function of the skin decreases. The effect of penetra-
If substances are in a dissolved state near the skin surface, tion enhancers is based on two mechanisms. The penetration
they will penetrate into the skin rapidly after application. enhancer can change the structure of the stratum corneum or
Dissolved molecules in the preparation firstly have to diffuse the solubility of the active substance in the skin. Penetration
towards the skin surface. If the rate of diffusion through the enhancers should not damage the underlying skin layers and
base is low, the penetration will be impeded. The rate of should not be toxic or allergenic. Moreover, the effect must
diffusion through the base depends on the properties of the be reversible. Because of the different properties and
active substance and the base. mechanisms of action of penetration enhancers it is difficult
If the active substance is suspended in the base, it must to predict which enhancer will be most effective for the
dissolve first. This process depends on its solubility in the penetration of a specific active substance. Substances such
base. A small particle size increases the dissolution rate. as dimethyl sulfoxide (DMSO), salicylic acid, urea, propyl-
The properties of the active substance influence skin ene glycol, ethanol, isopropyl alcohol and many acids can
penetration as well. Generally lipophilic molecules penetrate act as penetration enhancers.
12 Dermal 235
Table 12.3 Basic preparations for different skin conditions and skin types
Skin Form Effect Base
Wet skin Water or wet dressing Drying, astringent Water, physiological saline solution, black tea as wet dressing
#
#
# Cutaneous suspensions Drying Zinc oxide cutaneous suspension (Table 12.21)
(commonly with zinc oxide)
Pastes (commonly with zinc Drying Zinc oxide aqueous paste (Table 12.41)
oxide)
Hydrophilic cream Neutral Nonionic hydrophilic cream SR DAC (Table 12.33), Lanette cream I/II
(Table 12.34)
Soft paraffin cetomacrogol cream (Table 12.4), Cream base DAC
(Table 12.6),
Dry skin Lipophilic cream Hydrating Hydrophobic cream base DAC (Table 12.32)
Strong Ointment Strongly Emulsifying hydrophobic base gel DAC (Table 12.26), White soft paraffin
keratotic hydrating,
disorders occluding
PRODUCT DESIGN
Greasy (oily) Hydrophilic gel Hydroxyethylcellulose Gel DAB (Table 12.35)
skin Solution Blends of ethanol/isopropyl alcohol, propylene glycol and water
Scalp Hydrophilic gel Hydroxyethylcellulose Gel DAB (Table 12.35)
(seborrheic) Solution Blends of ethanol/isopropyl alcohol, propylene glycol and water
Scalp (dry) Solution (washable, oily) Vegetable oils, octyldodecanol, triglycerides medium-chain blended with
surfactants (for example macrogol lauryl ether)
Open wounds Solution (sterile) Physiological saline solution
Hydrophilic gel (sterile) Isotonic carbomer gels
skin is neither dry nor wet the choice of the base is much
To be effective, a locally applied corticosteroid must less important than the active substance. The classifica-
penetrate into the skin. The rate and extent of penetration of a number of bases appropriate for several skin
tion is determined for a large extent by the formulation conditions has been summarised in Table 12.3 for a
of the base. By adding penetration enhancers such as gradual transition from wet to dry skin and for specific
salicyl acid or urea the penetration of the active sub- skin conditions.
stance is enhanced. In this way a class I or II corticoste- Usually the base of a cutaneous preparation is prescribed
roid containing preparation becomes more effective. by the physician. But sometimes the pharmacist is free to
choose it on his own authority. Both, physician and pharma-
cist, have to take the following factors into consideration:
A particular way to enhance the penetration of substances
• The base should not irritate or sensitise.
into the skin is iontophoresis, see also Sects. 12.7.11 and 16.2.5.
• The base should not adversely influence the active
substances.
• The base has to be cosmetically acceptable, preferably
12.3.3 Choice of the Base not shiny and not sticky after spreading on the skin.
• The choice of the base depends on the skin conditions
The base of cutaneous preparations does not only influ- (whether the disease is in an acute or chronic state) and
ence the release of the active substance, it can contribute the skin type.
to the therapeutic effectiveness of the preparation itself.
In some cases the base alone may sufficiently influence
healing, by which the addition of an active substance is 12.3.4 Base and Different Skin Disorders
unnecessary. In such cases the physical properties of the
base are utilised, such as: cooling; dehydration or protec- 12.3.4.1 Acute Skin Disorders
tion by indifferent solids; prevention of dehydration by Acute exsudative skin disorders are usually treated with wet
hydrophobic components. The correct choice of the base packs first, for example with black tea because of the astrin-
is very important for wet and dry skin disorders. If the gent effect of the tannin content. Dressings wetted with
physiological saline solutions or water are used as well. As a 12.3.4.3 Strong Keratotic Disorders
result of evaporation of water the dressings will absorb fluid A strong keratotic skin is treated with hydrophobic ointments.
and purulence from the skin. The dressings have to be Hydrophobic anhydrous bases cover the skin and prevent
changed a few times a day. They should not be wrapped in evaporation of water, the skin becomes hydrated. Examples
plastic because that prevents water from evaporating and the for such disorders are ichthyosis or psoriasis.
dressings will not be effective. The treatment with wet
dressings results in cooling and drying of the skin. 12.3.4.4 Greasy (Oily) Skin
Not recommended for the treatment of acute exudative For a seborrheic skin hydrophilic bases have to be chosen:
skin disorders are: hydrophilic gels, emulsions or creams. Especially for acne
• Hydrophilic suspensions, because the powder that remains treatment bases without or with only a small percentage of
on the skin after drying can irritate and damage it lipophilic components are indicated.
• Powders for cutaneous application for the same reason,
except powders consisting of absorbable sterile lactose 12.3.4.5 Itching Skin Disorders
For the acute state of the disorder, if without strong Hydrophilic suspensions (liniments, lotions) are suitable for
exudation, hydrophilic suspensions are appropriate. They application on large itching areas if the skin is not damaged.
typically contain a relatively high amount of water and The evaporation of the liquid components will cool the skin
solid substances. Solid substances act as a drying agent on and reduce the itch.
the skin because of their water absorbing property. The
combination of a solid substance and water increases the 12.3.4.6 Scalp
evaporation surface area of water. This increases the cooling For the treatment of the scalp hydrophilic solutions and
effect. Examples for such preparations are zinc oxide cuta- hydrogels, liquid emulsions and washable liquid oils are
neous suspensions. used. Examples are olive, almond or refined castor oil, as
When the skin has become dryer and is changing to a well as fatty alcohols such as octyldodecanol, all in combi-
subacute state it can further be treated with a hydrophilic nation with a surfactant, for instance macrogol lauryl ether
cream. 4. The decision for one or the other base depends on the skin
conditions. A seborrheic scaling scalp is often treated with
12.3.4.2 Normal Skin hydrophilic preparations, a dry and scaling one is treated
For patients with normal skin conditions and also for patients with liquid oils.
with a subacute dermatosis hydrophilic creams are fre-
quently used. If a preparation with more fat is needed for a 12.3.4.7 Piles
slightly drier skin, hydrophilic creams with a higher amount Hydrophilic creams with a high amount of lipophilic
of lipophilic components are applied. For an example a components are appropriate for the treatment of
cream with added soft paraffin (Table 12.4). haemorrhoids. These creams cover the painful, damaged
A slightly dry skin may be treated with an extra fat mucous membrane. Soft Paraffin Cetomacrogol cream
containing hydrophilic cream. Patients with a very dry skin FNA or Cream base DAC (Tables 12.4 and 12.6) are two
use cutaneous preparations with a high amount of lipophilic examples for suitable bases. Thinner creams may flow off
components. Lipophilic creams are suitable for the treatment easily. A more lipophilic base is not desirable because of the
of the chronic state of atopic eczema. Hydrophobic chance on maceration: the weakening of the skin by long
ointments or saturated hydrocarbons are not indicated time exposure to moisture.
because they have an occlusive effect, which causes heat Preparations intended for application to other mucous
accumulation and enhances itching. membranes are described in Chaps. 6 Pulmonary, 7 Oro-
pharynx, 8 Nose, 11 Rectal and vaginal, 14 Irrigation and
dialysis.
12.3.4.8 Open Wounds

Table 12.4 Soft Paraffin Cetomacrogol Cream [8] In modern wound management aqueous solutions
Cetomacrogol emulsifying wax (BP) 15 g
(irrigations) and hydrogels are mentioned to be applied on
Paraffin, liquid 12.5 g deep and chronic wounds. Other preparations such as creams
Paraffin, white soft 22.5 g ointments and powders are described as well but have some
Propylene glycol 10 g disadvantages. Components of these preparations may not
Water, purified 40 g be removed from the wound easily and lipophilic
Total 100 g
compounds can hinder secretion. Cutaneous preparations
with zinc oxide should not be used on open wounds because
12 Dermal 237
they dry out the edges of the wound. The consequence is Table 12.5 FTU dosing
delayed wound healing. Talc can cause the formation of Head Arm Leg Torso
granulomas and should therefore be avoided as well. As a and and and (front Back and Whole
typical powder base for wound powders absorbable sterile neck hand foot side) bottom body
lactose is often used. In general cutaneous preparations that Age Number of FTU (fingertip units)
are applied to large damaged areas of the skin (wounds) must 3–12 1 1 1½ 1 1½ 40
months
be sterile, because the natural barrier of the skin against
1–2 1½ 1½ 2 2 3 24
micro-organisms is lacking. The specific formulations are years
described in Sect. 12.7.17. 3–5 1½ 2 3 3 3½ 18
years
6–10 2 2½ 4½ 3½ 5 14
12.3.5 Method of Application and Dosing years
adults 2½ 4a 8b 7 7 8
a
12.3.5.1 Method of Application For one hand of an adult one FTU is necessary
b
For one foot of an adult two FTU are necessary
In general hydrophilic creams (o/w-creams) and emulsions
PRODUCT DESIGN
are used without a bandage. Whether to cover the applica-
tion site after application of lipophilic creams (w/o-creams) For the treatment with corticosteroids several options of
and ointments depends on the skin conditions. To soften a therapy are established:
skin area with a strong keratinisation covering the • Interval therapy implies treatment with the corticosteroid
lipophilic preparation with a bandage is effective. Fatty containing preparation for some days alternating with the
pastes and pastes with a cooling effect can be put on lint base for some days.
first. Thereafter the application site is dressed with a • Gradual therapy starts with a stronger corticosteroid in
bandage. the initial phase for up to 7 days. Then step by step
weaker corticosteroids are used.
12.3.5.2 Quantity to Be Applied • Proactive therapy: After the symptoms have disappeared,
If the cutaneous preparation is going to be applied because of the application of the corticosteroid will be continued
its physical properties, such as the prevention of dehydra- with a frequency of two times a week.
tion, ample application is desirable. If the preparation is
mainly acting by its active substance, the amount to be
applied is expressed in fingertip units to prevent underdosing
12.3.5.4 Duration of Therapy
How long a cutaneous preparation has to be used depends on
when the patient is told “to apply thin”, as well as
the disorder and the typical period in which an active sub-
overdosing [9].
stance reaches its therapeutic effect. Usually corticosteroids
The FTU reflects a stripe of cream or ointment with a
or antibiotics should be applied for only a few days if applied
length from the tip of the index finger of an adult to its first
every day. The treatment with an antimycotic may take a
crease. One FTU is approximately 0.5 g of cream or oint-
longer time. In general the physician should see the patient
ment. This is sufficient to cover 300 cm2 of skin. Depending
regularly to assess the effectiveness of the therapy. The
on the body part to be treated more FTU’s can be applied
preparation should therefore be prescribed in a limited
(see Table 12.5).
amount appropriate to the treatment scheme.
Another approach is that for hydrophilic creams the
amount should be limited to as much as the skin can absorb.
Lipophilic creams and hydrophobic ointments should be
applied in a thin layer until the skin feels slightly fatty. 12.3.6 Occlusive and Transdermal Preparations
12.3.5.3 Application Frequency Cutaneous preparations are inefficient formulations since

Neutral bases should be applied at least twice a day, but may only small amounts of the applied active substance penetrate
be applied as often as desired. Cutaneous application of the skin and reach the site of action. The first attempts to
corticosteroids results in the formation of a depot of the understand the mechanism of skin permeation and formula-
active substance in the stratum corneum. As a consequence tion effects of cutaneous preparations were described in
the frequency of application may be reduced after some 1960 [10]. Since then more research has been performed
time. Application once a day is generally sufficient for on rational design of dermal formulations. Much research
effective therapy. is focused on improved skin penetration [11, 12]. Skin
penetration is discussed in detail in Sect. 16.2.5 Dermal and 12.3.6.3 Transdermal Patches
transdermal administration. In contrast to cutaneous patches and medicated plasters,
Relatively new developments of enhanced skin penetra- transdermal patches are designed for delivery of an active
tion are cutaneous and transdermal patches. The European substance into the systemic circulation and consequently to
Pharmacopoeia distinguishes medical plasters and cutaneous achieve a systemic effect.
patches which are classified as ‘Semisolid Preparations for According to the European Pharmacopoeia “transdermal
Cutaneous Application [4] and transdermal patches which patches are flexible single-dose preparation intended to be
are described in a separate monograph [4]. applied to the unbroken skin to obtain a systemic delivery
over an extended period of time”. Manufacturers design
patches in a variety of ways. However, in general patches
12.3.6.1 Cutaneous Patches
can be categorised in two main types: the reservoir and the
According to the European Pharmacopoeia ‘cutaneous
matrix systems. In reservoir systems the active substance
patches are flexible preparations containing 1 or more active
may be dissolved or dispersed in a semisolid basis or in a
substances. They are intended to be applied to the skin. They
solid polymer matrix, which is separated from the skin by a
are designed to maintain the active substance(s) in close
rate-controlling membrane. Matrix systems contain the
contact with the skin such that these may act locally’. Cuta-
active substance in a solid or semisolid matrix, the properties
neous patches consist of an adhesive basis spread as a
of which control the diffusion pattern to the skin. The matrix
uniform layer on an appropriate support made of natural or
system may also be a solution or dispersion of the active
synthetic material. The adhesive basis is not irritant or
substance in the pressure-sensitive adhesive. The releasing
sensitising to the skin. The adhesive layer is covered by a
surface of the patch is covered by a protective liner to
suitable protective liner, which is removed before applying
be removed before applying the patch to the skin. The
the patch to the skin.
principles of different types of transdermal patches are
Skin permeation of the active substance after application
given in [13]. To improve drug delivery to the systemic
of cutaneous patches is enhanced compared to conventional
circulation transdermal patches often contain excipients to
cutaneous preparations because of the occlusive effect of the
enhance penetration into the skin.
patch. In this way relatively high concentrations in the skin
Transdermal patches are an alternative for patients that
are obtained. In contrast to transdermal patches plasma
are not able to take oral medication. Advantages of transder-
concentrations will be low and no systemic side effects are
mal patches are that they are easily applied and may prevent
observed.
more painful and arduous parenteral administration. More-
Examples of cutaneous patches are lidocaine containing
over, transdermal administration is advantageous for active
patches that sometimes contain a second local anaesthetic.
substances that undergo extensive first-pass metabolism,
After applying the patch, lidocaine penetrates deep into the
active substances with narrow therapeutic window or active
skin where it has a local anesthetising effect. Capsaicin
substances with a short half-life, which cause noncompli-
containing patches are used in the treatment of peripheral
ance due to frequent dosing.
neuropathic pain in non-diabetic adults. Following exposure
For transdermal drug transport the active substance
to the patch, capsaicin penetrates the skin and interacts with
should have appropriate physico-chemical and pharmaco-
the cutaneous transient receptor potential vanilloid 1 receptor
logical properties. Although different requirements are
(TRPV1) resulting in pain relief.
described in literature, in general the molecular weight of
the active substance should not exceed about 500 Da, the
12.3.6.2 Medicated Patches partition coefficient (log P(octanol/water)) should be
The European Pharmacopoeia also defines medicated between 1.0 and 4.0 and the dose should be low (less than
plasters as semisolid preparations for cutaneous application. 20 mg/day). Recent research focusses on transdermal deliv-
According to the European Pharmacopoeia “medicated ery of active substances that do not meet these requirements,
plasters are flexible preparations containing 1 or more active such as relatively large molecules.
substances. They are intended to be applied to the skin. They Transdermal patches registered at present are patches
are designed to maintain the active substance(s) in close containing active substances such as buprenorphine, estra-
contact with the skin such that these may be absorbed diol, fentanyl, glyceryl trinitrate, nicotine, oxybutynine,
slowly, or act as protective or keratolytic agents”. rivastigmine, rotigotine and scopolamine. These transdermal
5-Aminolevulinic acid medicated plasters represent this dos- patches are used in the treatment of a variety of diseases.
age form. They are used in photodynamic/radiation therapy. They release the active substance during a period of 24 up to
The plasters are applied to mild to moderate actinic keratosis 72 h, depending on the type of patch used and the active
lesions. Four hours after application the plasters are removed substance. After application of the patch plasma concentra-
and the lesions are exposed to red light. tion slowly rises until a steady concentration is reached.
12 Dermal 239
During application a depot of the active substance is formed example of an irritating active substance is tretinoin. The
in the skin. After removal of the patch plasma concentrations decrease of the concentration can lead to better tolerance.
will gradually but slowly diminish. Because of the absorption Some patients have to get used to the irritating effect in order
of the active substance from the depot in the skin even after to be able to tolerate later during the treatment higher or
the patch has been removed, elimination from the plasma will more irritating concentrations. Some active substances that
be slower than anticipated based on i.v. or oral elimination are known to be irritating in cutaneous preparations are
data. Therefore, when switching from transdermal patches to benzoyl peroxide, dithranol, hydroquinone, iodine,
oral medication it should be taken into account that the active capsaicinoids and salicylic acid.
substance is still present in the systemic circulation. The oral An allergic reaction is an immunogenic reaction that may
dosing time and dose should be adapted accordingly. be limited to redness of the skin but may also be severe. An
Well known as transdermal patches are those containing allergic reaction occurs if the patient is sensitised against the
fentanyl. Fentanyl is used in the treatment of severe chronic substance. The risk of getting sensitised via the skin is rela-
pain. Fentanyl is rapidly metabolised in the liver resulting in tively high. Once a person is sensitive to a substance, he or she
low bioavailability after oral administration. After application will never tolerate the substance anymore. If the allergic
of the patch, 90 % of the released amount reaches the systemic reaction is caused by an excipient, the active substance can
PRODUCT DESIGN
circulation. After first application the plasma concentration still be used, but in a base with different excipients. Excipients
increases gradually, stabilises after 12–24 h and is stable up that are known to be sensitising are methyl parahydroxy-
to 72 h [14]. Fentanyl transdermal patches often offer an benzoate and propyl parahydroxybenzoate, wool alcohols
adequate alternative to parenteral opioid administration in and cetostearyl alcohol. Examples for sensitising active
patients who are not able to take their medications orally. substances are neomycin, tetracain and clioquinol.
A photosensitisation or phototoxic reaction occurs if the
skin is exposed to sun light or artificial sun light
12.4 Adverse Effects (e.g. solarium). Examples of substances that are known to
cause such reactions are benzoyl peroxide, coal tar,
Adverse effects of cutaneous preparations may be: undesirable methoxsalen and essential (volatile) oils. Intensive exposi-
systemic effects, (photo) toxicity, irritation or (photo) allergic tion to (artificial) sunlight has to be avoided while and after
responses after sensitisation. Substance monographs [15], using these substances. Appropriate clothing and sunscreen
package leaflets or SmPCs of licensed products and medicine are recommended. Methoxsalen and in special cases coal tar
databases give information about these adverse effects. are applied for a treatment with ultraviolet light. It is moni-
Toxic systemic effects have been reported for salicylic tored by the physician and the photosensitisation is desired.
acid, resorcinol, lindane or mercury substances. These Some medicines can cause abnormal reactions to sun
effects are related to the substance, the amount of prepara- light or artificial light equally whether they are intended
tion and the body surface area to which it is applied, the skin for oral or dermal administration. The phototoxic reaction
conditions and duration of treatment. Symptoms for sys- may be toxicological or immunological. It is very difficult to
temic intoxications are for example headache, nausea and distinguish a phototoxic reaction from a photoallergic one.
vomiting, convulsions, fall in blood pressure, kidney dam- Moreover, a combination of these reactions also occurs. The
age or metabolic acidosis. Apart from salicylic acid the substance is than phototoxic as well as photoallergic.
mentioned substances are no longer used because of these
systemic adverse effects and the limited therapeutic signifi-
cance in cutaneous preparations. Especially infants and 12.5 Product Formulation
toddlers are susceptible for systemic adverse effects because
their skin is thinner. Additionally, the relative body surface Cutaneous preparations may consist of a simple or a more
area in relation to body contents in children is larger than in complex formulated base in which one or more active
adults. For salicylic acid in infants and toddlers the only substances can be dissolved, dispersed or mixed. Bases
indication is psoriasis. It should be used in low often contain several phases: a solid phase, an aqueous, a
concentrations and on a limited body surface area. lipophilic phase and an interphase. In this section the
Irritation is induced by active substances that chemically properties, function and excipients of each phase are
damage cells of the skin. The strength of the effect depends discussed. Active substances or excipients may make up
on the concentration of the irritating substance. Irritation is the solid phase. The aqueous phase may contain the active
expressed by redness, itching and sometimes erosion of the substance, excipients that improve the microbiological sta-
skin. Decreasing the concentration can prevent irritation. bility or sometimes excipients that improve physical stabil-
However, the therapeutic effect will be reached later as ity of the preparation. The lipophilic phase influences and
well. As irritation also depends on the individual sensitivity improves the consistency of the cutaneous preparation. If
of the patient´s skin the tolerance differs individually. An there is an aqueous and a lipophilic phase in the preparation,
there is also an interphase. In cutaneous preparations a

number of specific emulsifying agents are applied, which small particles microcrystalline tetracycline hydro-
are described. Because of the presence of several phases, the chloride is easier to process in cutaneous preparations
physical and chemical stability and potential incompat- than the ponderosum quality. The disadvantage of the
ibilities have to be considered in the design of the formula- microcrystalline quality is that during storage epi- and
tion. Last but not least the preservation and packaging which anhydro degradation products may be formed. Only
can play a role in the chemical, physical and microbiological 1 % of these substances are allowed in tetracycline
stability and shelf life of cutaneous preparations are impor- hydrochloride [16]. The degradation is visible as a
tant issues of this section. discolouration to a darker yellow. Generally a cream
prepared with the ponderosum quality has a lighter
colour than a cream containing the microcrystalline
quality.
12.5.1 Solid Phase In practice the more stable ‘ponderosum’ quality
can be dispersed in cutaneous preparations anyway by
The solid phase contains solid substances which are dis- firstly triturating with water in a mortar with a pestle. It
persed in a liquid phase or a semisolid base. Powders for is likely that due to the water the outer layer of the
cutaneous application consist only of a solid phase. The solid tetracycline hydrochloride particles dissolves causing
substances can be active substances or excipients. the particles to disperse.
12.5.1.1 Particle Size

The particle size of solid substances of both excipients and
12.5.1.2 The Function of Solid Excipients
active substances is important not just for biopharmaceutical
Sometimes it is not clear whether an excipient is solely an
properties (see Sect. 12.3.2) but also for the physical and
excipient or has active substance properties.
chemical properties of cutaneous preparations. If the solid
In dermal bases indifferent solid substances may:
is dispersed in a liquid base, the particles must be suffi-
• Act as filler material: powders for cutaneous application
ciently fine to obtain a physically stable suspension (see
sometimes need a filler
Sect. 18.4.2). However decrease of particle size may
• Increase the consistency
increase the rate of degradation. Additionally processing
• Cause cooling and drying of the skin; finely divided solid
small particles may lead to agglomerates.
excipients enlarge the surface of the skin resulting in
Solid particles should be small enough not to be felt when
increased evaporation of water and increased loss of
being applied onto the skin of the patient. The Ph. Eur. doesn’t
warmth
give detailed guidance for particle size in the chapters for
• Act as an adhesive; some solid excipients, such as talc
cutaneous dosage forms (see Sect. 12.2) just that it has to be
result in an improved adherence of the preparation on the
suitable for application. A maximum particle size of 90 μm in
skin
powders, hydrophobic and hydrophilic ointments and in
• Act as astringent; salts, aluminium oxide and zinc oxide
creams is generally accepted and therefore recommended.
cause the skin to astringe; the blood capillaries contract
Many solid raw materials are meant to be used in cutane-
and slow down the exudation
ous preparations are processed in their micronised state (see
• Prevent agglomeration (anhydrous colloidal silica)
Sect. 23.1.8 for definitions) mainly for improving the release
Apart from the general descriptions in Chap. 23, some
of the active substance (see Sect. 12.3.2).
details, also on function, are given on the most important
In case of solutions small particles may increase the speed
solid excipients for cutaneous preparations:
of dissolving.
Talc is a silicate often used in powders and suspensions
for cutaneous application. It is a fine substance that consists
Tetracycline hydrochloride is in the Netherlands mainly of magnesium silicate, but also contains some alu-
available in two qualities, microcrystalline and minium silicate. It has good flow properties and adheres well
‘ponderosum’ (‘heavy’). Tetracycline hydrochloride to the skin. It has a very low water absorbing capacity. A
ponderosum consists of agglomerates of the micro- disadvantage of talc is the chance on formation of
crystalline substance and has a shelf life of 3 years, granulomas if it ends up in wounds. The combination of
has a better flowability and is much less susceptible to talc and zinc oxide in combination with water or other
degradation than the microcrystalline form. It is volatile solvents results in cooling of the skin. The cooling
mainly used for capsule preparation. Because of the is the result of an increased surface area which allows water
to evaporate more easily.
(continued)
12 Dermal 241
Zinc oxide is an astringent. It dries, cools and protects the 12.5.2.3 Fatty Alcohols
skin and is weakly antibacterial. It may be used in nearly all Fatty alcohols such as cetostearyl alcohol and wool alcohols
types of cutaneous preparations. However, it is unsuitable are lipophilic chains with a hydroxyl group at the end. Because
for the hairy skin because it cannot be washed out. of the combination of the lipophilic chain and the hydrophilic
Calamine is a mixture of zinc oxide, basic zinc carbonate hydroxyl group these structures reduce the surface tension (see
and zinc silicate with a small amount of ferric oxide. Cala- Sect. 18.4.3). Cetostearyl alcohol is a mixture of cetyl alcohol
mine gives a salmon colour to preparations. and stearyl alcohol. It is a weak water-in-oil emulsifying agent
Magnesium stearate and zinc stearate cool and cover the and it is a component of self-emulsifying waxes.
skin and in combination with fatty oil, such as arachis oil,
they form magnesium oleate and zinc oleate. These oleates 12.5.2.4 Waxes
act as thickening agents and render the oil into oleogels (see Waxes such as bees wax, wool fat and decyl oleate are esters
Sect. 23.7.3 and Table 23.20). of fatty alcohols and fatty acids (see Sect. 23.3.5). The solid
Potato starch or rice starch is generally used as a compo- waxes are mainly used to improve the consistency of semi-
nent of cutaneous powders and pastes with a high amount of solid preparations. Due to the presence of impurities such as
solids. Starch absorbs a high percentage of water. As a result it fatty alcohols some waxes are weak w/o emulsifying agents.
PRODUCT DESIGN
swells. This may lead to the formation of a crust on wounds. It Although wool fat is classified as a wax it has different
is therefore not suitable for acute exsudative skin disorders. characteristics due to its ‘impurities’. Wool fat is extracted
from the wool of sheep by water. It consists of a complex and
variable mixture of several esters and polyesters of alcohols
12.5.2 Lipophilic Phase (wool fat alcohols) of high molecular weight and fatty acids.
Wool fat is a stronger emulsifier than other waxes because of
The lipophilic phase consists of hydrophobic, oily semisolid the presence of these esters. It can absorb water in a range up
and liquid substances. With regard to chemistry only to 25 % of its weight. Hydrous wool fat (lanoline) is a w/o
triglycerides are defined as fats. Hydrophobic substances emulsion consisting of 75 % wool fat and 25 % water. Decyl
such as hydrocarbons, waxes and fatty alcohols are not fats. oleate is a liquid and is used as a component of the lipophilic
However, the hydrophobic phase is often named as ‘fat phase in o/w creams.
phase’. It covers the skin and prevents the evaporation of The liquid isopropyl myristate is closely related to the
water. As a result the skin becomes hydrated. The degree of waxes. However it is not a wax as it is not an ester of a fatty
hydration depends on the properties of the hydrophobic alcohol and fatty acid. It has similar characteristics to fatty
components. Hydrophobic substances that do not penetrate oils. It is mainly used to enhance the spreadability of oil-in-
the skin generally have a stronger hydrating effect as those water emulsifying ointments.
that penetrate.
Hydrophobic substances are classified based on their
structure: 12.5.3 Aqueous Phase
12.5.2.1 Hydrocarbons (Paraffin Waxes) The aqueous phase may contain, apart from water, water-
Hydrocarbons such as liquid paraffin and white soft paraffin miscible liquids as humectants, co-solvents or penetration
are also called mineral oils. They hardly penetrate the skin enhancers. The aqueous phase has to be preserved. If
and in cutaneous preparations they are mainly used for substances are dispersed in the aqueous phase they are con-
protection of the surface of the skin or occlusion. They sidered part of the solid phase (see Sect. 12.5.1). For the
absorb little or no water. Because they cover the skin they substances reference is made to appropriate sections of
prevent evaporation of water and hydrate the skin. Chap. 23 Raw materials. Just some functional details are
Hydrocarbons are used in lipophilic creams, hydrophobic mentioned here.
ointments and pastes.
12.5.3.1 Water
12.5.2.2 Fatty Oils and Fats The use of purified water is recommended to keep the initial
In chemical terms fatty oils and fats are esters of glycerol contamination low and thereby to hold the Ph. Eur.
and fatty acids. Arachidis oil and Miglyol 812 (medium requirements for microbiological quality of non-sterile phar-
chain triglycerides) are examples of often used fatty oils. maceutical preparations. The requirements of the chemical
In contrast to hydrocarbons they are biodegradable. They and microbiological purity of purified water are well
hardly absorb water but cover the skin less extensive than the defined, see Sect. 23.3.1. The concentration of ions in
hydrocarbons. Fatty oils and fats reduce the viscosity of purified water is low, which is an advantage as they may
semisolid cutaneous preparations and improve their spread- catalyse degradation of active substances and excipients and
ability. They are used in soft pastes for example. form complexes with active substances and excipients.
12.5.3.2 Co-solvents emulsions). In hydrophilic emulsions microbiological con-

Ethanol (see Sect. 23.3.2), propylene glycol (see Sect. tamination can easily spread throughout the whole prepara-
23.3.3) and glycerol (see Sect. 23.3.3) are often used as tion. Moreover, the outer phase has contact with the
co-solvents (see Sect. 18.1.3). environment where microbiological contamination
The formula should allow hydrophilic active substances originates.
and excipients to dissolve completely in the aqueous phase. To ensure the microbiological quality of cutaneous
Information on solubility of substances can be found in preparations the following measures should be taken:
several reference works [15, 17, 18]. However, the solubility • Ingredients should have a low initial microbiological
in mixtures of solvents is only rarely to be found. It is not contamination (see Sect. 23.1.7). Specifically ingredients
identical to the solubility in separate solvents because it is of natural origin and water may contain relatively high
influenced by the interaction between the solvents. amounts of micro-organisms.
• The aqueous phase has to be preserved by the addition of
12.5.3.3 Prevention of Water Loss (Humectants) preservatives or other substances with a preserving func-
Water easily evaporates from warm skin. Due to evaporation tion. Many preservatives are sensitising; sorbic acid and
a cutaneous preparation looses its characteristics. To prevent methyl parahydroxybenzoate are commonly used. Con-
water loss humectants are added. Humectants are non-volatile sideration should be given to not using preservatives if
solvents that prevent water loss during storage as well as after the preparation is intended for large skin surfaces, in
application to the skin. Examples are propylene glycol, glyc- order to reduce the risk of sensitisation.
erol 85 % and sorbitol 70 %. Humectants are often used in
cutaneous suspensions, hydrophilic creams and hydrogels.
If the aqueous phase is emulsified in the lipophilic
phase (w/o system) it is not always necessary to add a
12.5.3.4 Viscosity Enhancement
preservative. Theoretically, in w/o systems micro-
Increasing the viscosity of the aqueous phase will result in
organisms die inside the small water droplets due to
the formation of a gel, which may be applied easier to the
a lack of oxygen and nutrients. If the initial contami-
skin than water. In creams the increase of the viscosity may
nation is low, if contamination during preparation is
improve the physical stability of the emulsion, see
prevented and the microbiological quality is moni-
Sect. 12.5.5. Carbomers 0.2–0.3 % (see Sect. 23.7.3.5) and
tored at release, this theory may be applicable. If
cellulose derivates (see Sect. 23.7.3.2) are used for this
preservation is required in a w/o system propylene
purpose. A gel with carbomers is clear and leaves no residue
glycol could be added to the aqueous phase.
on the skin. The disadvantage of carbomers is that the
Microbiological challenge tests for a w/o ‘cooling
viscosity of the aqueous phase increases only at pH 6 or
ointment’ (Table 12.31) showed that the addition of
higher. Active substances that require a low pH, for example
10 % propylene glycol gave the formulation some
because of solubility or stability, are not compatible with
preservative properties. The addition of 20 % would
carbomer gels. Additionally, the negative charge on the
be even better, however in that formulation a compro-
carbomer molecule causes many incompatibilities with cat-
mise had to include improvement of microbiological
ionic substances. Cellulose derivates show less incompati-
stability without decreasing physical stability or
bility than carbomer but a disadvantage is the formation of a
increasing penetration too much.
thin layer on the skin, a so called xerogel, after evaporation.
This gives the patient a tightening sensation.
Enhancing the viscosity of an aqueous suspension is often Preservatives need to be hydrophilic as they act in the
necessary to obtain a reasonable physical stability (see Sect. aqueous phase where micro-organisms live. To penetrate the
18.4.2.2). Apart from the already mentioned viscosity cell wall of the micro-organism and interfere with the cell
enhancers, also mineral viscosity enhancing substances, life cycle preservatives need to be hydrophobic as well.
such as anhydrous colloidal silica (2–4 %, usually 2 %), Because of the partly hydrophobic characteristics
and colloidal aluminium magnesium silicate (2–4 %, usu- preservatives may diffuse into the lipophilic phase or will
ally 2 %) or bentonite (1–2 %) are used. All percentages be solubilised in the aqueous phase. In this way the concen-
refer to the final amount of the preparation. tration of the preservative in the aqueous phase may become
lower than required. Formulations of hydrophilic emulsions
12.5.3.5 Preservation therefore will contain higher concentrations of preservatives
Pharmaceutical preparations that contain water are suscepti- than those of hydrophilic solutions.
ble of microbiological contamination. This applies specifi- Table 23.21 gives an overview of preservatives. For cuta-
cally to preparations in which water is the outer phase (o/w neous preparations as said sorbic acid and methyl
12 Dermal 243
Table 12.6 Cream Base DAC [19] glycol (150 mg/g) (Table 12.21). Another option is the
Glycerol monostearate 60 4g increase of the glycerol 85 % concentration up to 30 %.
Cetyl alcohol 6g Ethanol acts as a preservative when present in a concen-
Triglycerides, medium-chain 7.5 g tration above 15 %. If sufficient ethanol is present other
Paraffin, white soft 25.5 g preservatives are not needed.
Macrogol 20 glycerol monostearate 7g
Water, purified 40 g 12.5.4 Interphase
Total 100 g
The interphase is the phase between the aqueous and the
lipophilic phase. For the integration of the aqueous phase
and the lipophilic phase a surfactant is needed (see Sect.
parahydroxybenzoate are mostly used. Antimicrobial 18.4.3). Surfactants reduce the surface tension between both
properties of ethanol and propylene glycol are often made phases resulting in the formation of an emulsion, see
use of. Sect. 12.5.5. Surfactants are used in emulsions for cutaneous
PRODUCT DESIGN
The activity of the preservative depends on the concen- application such as creams and water emulsifying ointments.
tration in the aqueous phase and therefore on the partition The emulsifying capacity of the surfactant is determined by
coefficient (n-octanol/water). Because of its relatively the HLB value (see Sect. 18.4.3). These characteristic and to
favourable partition coefficient sorbic acid is a suitable pre- a certain degree the ratio water-fat determines whether an
servative for o/w emulsions. Therefore it is often used in emulsion will be an oil in water (o/w) or a water in oil (w/o)
hydrophilic cream bases. Sorbic acid holds a carboxyl group emulsion. Surfactants are described in Sect. 23.6. In this
that is deprotonated above pH 4–5. Sorbic acid only takes section their function in cutaneous emulsions is summarised.
effect in the non-ionised form that means only in acidic
solutions. However, at relatively low pH sorbic acid is 12.5.4.1 Oil- in-Water Emulsions
degraded by oxidation. To prevent oxidation sorbic acid is In o/w emulsions often combinations of o/w and w/o
often used in combination with potassium sorbate in order to substances are used because the combination gives a more
obtain a pH value of 4–5. stable emulsion than only one o/w emulsifier (see Sect. 18.4.3).
Methyl hydroxybenzoate has an unfavourable partition The following emulsifiers are used for cutaneous o/w
coefficient. Therefore it is not a suitable preservative for emulsions:
o/w emulsions. It is mainly used in hydrogels. In some • Cetomacrogol emulsifying wax BP [20] – non-ionic,
countries a combination with propyl hydroxybenzoate is containing 20 % of macrogol cetostearyl ether, a strong
used as ‘Preserved water’. A typical mixture contains o/w emulsifier and 80 % cetostearyl alcohol, a weak w/o
0.075 % of methyl parahydroxybenzoate and 0.025 % of emulsifier
propyl parahydroxybenzoate in purified water. • Emulsifying wax BP [20] (Lanette emulsifying wax) –
Propylene glycol acts as a preservative in concentrations anionic, containing 10 % of sodium laurylsulfate, a
above 20 % of the aqueous phase. However, it is less active strong o/w emulsifier and 90 % cetostearyl alcohol
than sorbic acid and methyl hydroxybenzoate. It is most • Sodium cetostearyl sulfate
effective in combination with surfactants (especially hydro- • Polysorbate 80
philic) and other components of creams and emulsions. • Cetrimide
Cream Base DAC (Table 12.6) is an example. It contains The selection of the surfactant is mainly based on the
20 % of propylene glycol in the aqueous phase and macrogol compatibility with the active substance. Sodium lauryl sul-
20 glycerol monostearate as hydrophilic surfactant. It is well fate is an anionic surfactant and therefore incompatible with
preserved in this way. cationic active substances. Cetomacrogol emulsifying wax
Propylene glycol can also be used in o/w emulsions with a BP is incompatible with high concentrations of phenolic
pH higher than 5, because it is effective independent from substances due to an interaction of the phenolic group with
pH. It has to be considered, that propylene glycol may be the polyethylene glycol chains in the macrogol cetostearyl
irritating and may act as a penetration enhancer. ether. It is compatible with acids, high concentrations of
Glycerol 85 % is a less potent preservative than propyl- electrolytes and cations.
ene glycol. It acts as a preservative above 30 %. In lower
concentrations it is less effective. Microbiological challenge 12.5.4.2 Water-in-Oil Emulsions
tests of a zinc oxide cutaneous suspension for example In water-in-oil (w/o) emulsions and hydrophobic creams,
showed an insufficient effect in a concentration of 110 mg/g glycerol mono-oleate and wool fat are mainly used as
Glycerol 85 %. Therefore it was replaced with propylene emulsifiers. These substances are part of the lipophilic
Table 12.7 Lauromacrogol Hydrophilic Emulsion 5 % [21] Table 12.8 Dimethyl Sulfoxide Paraffin Cream 50 % [22]
Lauromacrogol 400 5g Dimethyl sulfoxide 50 g
Propylene glycol 20 g Carbomer 974P 1g
Carbomer 980 or 974 p 0.25 g Soft paraffin Cetomacrogol cream FNAa 46 g
Trometamol 0.2 g Paraffin, white soft 3g
Cream base DACa 10 g Total 100 g
a
See Table 12.4
Total 100 g
a
See Table 12.6
Table 12.9 Calamine Cutaneous Suspension [23]
phase and are weak emulsifiers. If a stronger w/o surfactant Calamine BP 15 g
is needed sorbitan esters of fatty acids, such as sorbitan Aluminium magnesium silicate 3g
oleate (span 80), can be used. Triglycerol diisostearate is a Glycerol (85 %) 6.1 g
w/o surfactant used in a lipophilic cream with a high content Phenol, Liquefied BP 0.5 g
of water (Table 12.32). Sodium citrate 0.5 g
Zinc oxide 5g
12.5.5 Physical Stability Total 121 g (¼ 100 mL)
12.5.5.1 Emulsions
Emulsions consist of hydrophilic and hydrophobic percentage of the solid particles. The addition of a viscosity
ingredients. Therefore emulsions are not physically stable enhancer may cause a decrease of the cooling effect of the
and the phases may separate into a water layer and a fatty preparation.
layer. The physical stability of emulsions can be increased Resuspendability can be increased by increasing the
by decreasing the size of the droplets of the inner phase, by degree of flocculation of the particles (see Sect. 18.4.2.1)
increasing the viscosity of the outer phase and first of all by by the addition of a flocculating agent. An example of such is
decreasing the surface tension between the aqueous and the sodium citrate which is used in a cutaneous suspension with
lipophilic phase. The presence of an active substance can calamine (Table 12.9).
influence the stability of an emulsion negatively. Enhancing
the viscosity of the aqueous phase may increase the physical
stability of an emulsion. Thereby sometimes the percentage 12.5.5.3 Solutions
of fatty phase can be decreased. An example is the emulsion Dissolved substances (whether active substances or
base in Table 12.7, where carbomer has been used for the excipients) may crystallise during preparation or storage.
viscosity enhancement. Crystallisation may occur if the solvent (mixture) has not
Another example of the use of carbomer for enhancing the potential to dissolve all solid or if the solubility changes
the viscosity is a 50 % dimethyl sulfoxide paraffin cream by mixing several bases or by the addition of a solution to a
(Table 12.8). Dimethylsulfoxide is commonly needed in base. The storage temperature plays an important role as
high concentrations in creams, which cause destabilisation well. Crystallisation may lead to crystal growth (see
of the cream base. With the formulation of Table 12.8 a Sect. 18.1.6) leading to faster settling and having biophar-
stable cream with a fine emulsion structure is created. The maceutical consequences.
physical stability of emulsions can be tested by temperature The solubility of salicylic acid for example depends on its
cycles, see Sect. 22.5.3. concentration, on the type of oil used as vehicle, or on the
ratio in the solvent mixture. Fatty oils except castor oil have
12.5.5.2 Suspensions limited solubilising properties for salicylic acid
Liquid suspensions are physically unstable as well due to (Table 12.10). Higher concentrations in oily solutions usu-
settling of the solid particles. The settling rate can be ally need the addition of castor oil to avoid crystallisation
decreased (see Sect. 18.4.2.1) by: and crystal growth.
• Decreasing particle size
• Diminishing the difference in density between the inter-
nal and the external phase (fluid) 12.5.6 Chemical Stability
• Increasing the viscosity of the external phase
Zinc oxide cutaneous suspensions are usually stable without Chemical degradation in cutaneous preparations usually
a viscosity enhancer because of the fineness and the high concerns oxidation (see Sect. 22.2.2) and hydrolysis (see
12 Dermal 245
Table 12.10 Salicylic Acid Cutaneous Solution 10 % [24] Table 12.11 Tretinoin Cutaneous Solution 0.05 % [25]
Salicylic acid 10 g Tretinoin 0.05 g
Castor oil, raffinated 60 g Butylhydroxytoluene 0.055 g
Octyldodecanol 30 g Propylene glycol 50 g
Total 100 g Ethanol (96 %) 49.9 g
Total 100 g
Sect. 22.2.1). Oxidation occurs in the presence of oxidising Table 12.12 Dithranol Cream 0.1 % [26]
agents and hydrolysis in the presence of water. Therefore the Dithranol 0.1 g
components of the base and the pH influence the chemical Ascorbic acid 0.1 g
stability of active substances. The chemical form of the Salicylic acid (90) 1g
active substance can affect the biopharmaceutical Lanette cream I FNAa 98.8 g
characteristics of the preparation which should be taken Total 100 g
into account before adjusting the pH.
PRODUCT DESIGN
a
See Table 12.34
12.5.6.1 Oxidation
Oxidising agents in cutaneous preparations may be active Table 12.13 Betamethasone Valerate Cream 0.1 % [27]
substances (benzoyl peroxide), peroxides from the base, Betamethasone valerate 0.1 g
oxygen from the air, light and ions of heavy metals. Oxida- Triglycerides, medium chain 0.4 g
tion is promoted by an increase in pH and temperature. Citric acid 0.025 g
Purified water 4.95 g
Benzoyl peroxide is explosive and incompatible with Cream base DACa 94.5 g
active substances that can easily be oxidised. The raw Total 100 g
material is moisturised with water and supplied as
a
hydrous benzoyl peroxide. It contains at least 20 % See Table 12.6
of water. Benzoyl peroxide containing products should
not be heated above 60 C. It is recommended to use aqueous phase sodium metabisulfite or ascorbic acid are
the content of one package with benzoyl peroxide often used as antioxidants.
completely to prevent evaporation of water upon An example of a cutaneous preparation in which an
repeated opening of the container. antioxidant - butylhydroxytoluene - is added to prevent
oxidation of the active substance is a tretinoin cutaneous
Peroxides occur and may be generated in fat and oil but solution (Table 12.11). During preparation tretinoin has to
also in hydrocarbons, waxes and macrogols. Macrogol be protected from light and no metal utensils should be used.
ointments (Table 12.29) are therefore not appropriate for Dithranol is oxidised rapidly in aqueous bases. Usually,
active substances which are susceptible to oxidation. ascorbic acid is added to the aqueous phase of hydrophilic
To prevent oxidation the addition of an antioxidant (see creams containing dithranol (Table 12.12). Salicylic acid is
Sect. 22.2.2) may be helpful but is not always necessary. The added to the lipophilic phase. In hydrophobic dermal bases
following measures may avoid or decrease risk of oxidation: the addition of just salicylic acid is sufficient.
• Use of excipients of high quality, for instance fats and oils
with a low peroxide value 12.5.6.2 Hydrolysis
• Choosing the right storage conditions, for instance in the Hydrolysis is catalysed by water and is typical for water
refrigerator containing bases. pH influences hydrolysis as such and also
• Storage in the right container, such as airtight containers by changing the fraction of dissolved substance that is avail-
that protect from light and heat able for degradation.
• Removal of air from the container in which the prepara- If an acidic environment is required for the stability of the
tion is stored active substance the pH may conveniently be adjusted to
If the addition of antioxidants is expected to be necessary 3.5–5.5 with a citric acid-citrate buffer (Table 12.13).
the effectiveness always has to be tested, see Sect. 22.2.2. For instance in creams with the easily hydrolysing tetra-
All-rac- alfa-tocoferol or butylhydroxytoluene (BHT) may cycline hydrochloride the pH is adjusted with a citric acid-
be suitable antioxidants for the lipophilic phase. In the citrate buffer to keep it undissolved.
12.5.7 Incompatibilities A too low pH has to be adjusted with an alkaline agent, for
example trometamol; a too high one with an acid, for exam-
The complexity of many cutaneous preparations may cause ple citric acid.
incompatibilities. This may lead to an excipient not func-
tioning and an active substance being not effective anymore.
To increase the penetration of ketoconazole into the
In literature [28, 29] many excipients and their incompat-
skin the prescriber sometimes requires the addition of
ibilities are described.
3 % salicylic acid to ketoconazole 2 % cream. Keto-
conazole however is unstable in an acid environment
12.5.7.1 Cation/Anion [30]. Addition of salicylic acid to ketoconazole cream
A known incompatibility by charge differences is the reac- leads to an immediate degradation of ketoconazole,
tion of anionic surfactants with cations. Sodium cetostearyl causing a blue discolouration.
sulfate (as compound of emulsifying cetostearyl alcohol
type A, also known as Lanette N) and sodium lauryl sulfate
Zinc oxide gives an alkaline reaction in water which leads
(as compound of emulsifying cetostearyl alcohol type B,
to chemical incompatibilities in cutaneous preparations. One
also known as Lanette SX) may cause this incompatibility.
of the best known is the interaction with salicylic acid which
As a result the lipophilic and hydrophilic phases separate
is turned into salicylate. The keratolytic or penetration
and the cream becomes almost fluid. An example of this
enhancing effect of salicylic acid is based on the acid func-
effect is the incorporation of chlorhexidine gluconate in
tion. Salicylate does not have these effects. The incompati-
lanette creams. The anionic part of the emulsifier
bility may be prevented by replacing zinc oxide by titanium
precipitates with the chlorhexidine gluconate, which not
dioxide. Titanium dioxide is in comparison to zinc oxide
only decreases the physical stability of the cream but also
only soluble in very strong acids. Therefore no interaction is
the effectiveness of chlorhexidine.
expected.
12.5.7.2 Polyethylene Glycol Chains/Phenolic

Groups 12.5.8 Improvement of Colour and Smell
An often used o/w emulsifier in hydrophilic creams is
cetomacrogol wax. This emulsifier is incompatible with
Colour correction of cutaneous preparations that have a
high concentrations of phenols. It may cause immediate
covering colour (zinc oxide or titanium dioxide), may be
separation of the lipophilic and aqueous phase. The phenol
desired for cosmetic reasons. The colour of the skin can be
group and the polyethylene glycol (PEG) chain of
approximated by a mixture of ferric oxides. Zinc oxide
cetomacrogol interact rendering the PEG-chain less hydro-
mixtures can be made skin coloured with a mixture of
philic and decreasing the emulsifying power of
yellow, red and brown or yellow, red and black ferric
cetomacrogol. But not every cream base containing an emul-
oxide. Because of the large variation in skin colours it is
sifier with PEG-chains will become unstable with phenolic
only possible to give some suggestions for such mixtures.
excipients. An example is Nonionic Hydrophilic Cream SR
For instance for 100 mL zinc oxide cutaneous suspension,
DAC (Table 12.33). It shows physical stability with salicylic
1 g of an iron oxide concentrated orange-like blend
acid up to 50 % and hydroquinone up to 2 %. That makes it
(Table 12.14) will probably do.
difficult to assess the relevance of this incompatibility in
A calamine cutaneous suspension (Table 12.9), that is
advance.
coloured pink by the ferric oxide in the calamine, may be
adapted to the skin colour with water-soluble chlorophyll.
12.5.7.3 pH Shift
Incompatibilities may also be created by a change in pH
caused by addition of an excipient or active substance, for
example salicylic acid. Degradation, dissolution or precipi- Table 12.14 Iron Oxide Concentrated Blend [31]
tation of other substances may be the unintentional result. Yellowish Orange-like Reddish
For example erythromycin is only stable under weak alka- Iron oxide red 15 g 20 g 25 g
line conditions. It is inactivated quickly if processed with Iron oxide yellow 75 g 70 g 65 g
acids or acidic bases or stronger alkali. The pH value has to Iron oxide black 10 g 10 g 10 g
be adjusted within a close range. The choice of the Total 100 g 100 g 100 g
stabilising agent depends on the pH value in the preparation.
12 Dermal 247
Table 12.15 Containers of cutaneous preparations Table 12.16 Triamcinolone Salicylic Acid Cutaneous Solution
10 % [32]
Type of dosage form Container with dosage delivery devices
Collodion Bottle with brush or spatula Salicylic acid 2g
Creams and gels Aluminium tube with internal coating, dose Triamcinolone acetonide 0.1 g
dispenser Benzalkonium chloride solution 0.09 g
Drops (external) Bottle with dropper or another dosage device Alcohol denaturated 70 % V/V 86 g
Solutions, Bottle, possibly with roll-on or dabbing Total 88.2 g (¼ 100 mL)
suspensions, applicator or another dispensing cap (for
emulsions example flip top cap with spray orifice)
Pastes Jar with spatula
Shampoos Plastic squeezing bottle (shampoo bottle) Fluid cutaneous preparations and cutaneous preparations
Sticks The lower part in aluminium foil, the whole with volatile substances such as ether or ethanol require a
stick in a jar
tightly closable container to prevent evaporation.
Powders for cutaneous Sifter-top container
application
The alternative is to adjust (shorten) storage time to the
Ointments Aluminium tube with internal coating; for increase of evaporation by opening. A triamcinolone
thick ointments jar with spatula salicylic acid cutaneous solution (Table 12.16) may be kept
PRODUCT DESIGN
2 years in a closed container, and just 6 months after
opening.
Surprisingly the green colour of chlorophyll compensates
Evaporation from collodion may be diminished by dis-
the excessive red of calamine.
pensing, if only 20 mL bottles are available, 20 mL instead
Skin disinfection preparations sometimes get a signal
of 10 mL and by turning the bottle upside down after closing
colour to mark the disinfectant on the skin. Patent blue V
so that the cap is sealed with the collodion.
(10 mg/L, for aqueous solutions) or azorubine (for alcoholic
solutions) are suitable for this.
Smell correctors are only exceptionally added to derma-
tological preparations because of possible allergic reactions. 12.5.10 Dosage Delivery Devices
Usually volatile oils are being used. The risk of an allergic
reaction is supposed to be small for rose oil and lavender oil. See also Table 12.15. Those dosage delivery devices are
An example of a smell corrector in a skin preparation is rose described in Sect. 24.4.19.1. Physically unstable cutaneous
oil in a cooling ointment (Table 12.31). preparations that have to be stirred before use by the patient
should be dispensed with a plastic spatula (for example a
tongue spatula). On the label the text ‘stir before use’ should
12.5.9 Containers be written. Wooden spatulas are not suitable, because micro-
organisms may grow on the spatula especially when the
The selection of a container is determined by the consis- spatula is wet.
tency, the purpose, the compatibility with the packaging For the administration of cutaneous solutions a dabbing
materials and the degradation type (oxidation!) of the active or roll-on applicator may be very useful.
substance. Many substances, active substances as well as
excipients such as sorbic acid, may degrade under the influ-
ence of light. Cutaneous preparations are preferably pack- 12.5.11 Labelling
aged in a primary container that does not transmit light.
General guidelines for packaging pharmaceutical dosage The container of cutaneous preparations is labelled with “not
forms can be found in Chap. 24. Table 12.15 gives an to be taken” or “for external use”. If next to a primary
overview of the containers and dosage delivery devices for container also a secondary container is used, such a label
cutaneous preparations. should be fixed to both containers. The label should meet the
Semisolid preparations that are prepared in stock and requirements that are mentioned in Sect. 37.3. On all sterile
stored ‘in bulk’ may be packaged in well closable cutaneous preparations the word “sterile” should be men-
containers of polypropylene or brown glass. The size of tioned. A label with the words “shake well before use”
the stock container is chosen in connection with the storage should be fixed onto the container of emulsions and
time, the speed of turnover of the preparation and in con- suspensions for dermal use.
nection with the number of times the container will be If a preparation contains flammable substances, such as
opened (see Sect. 22.3.1). ethanol, acetone or ether, there should be a warning for the
As tubes may get dented, they can be packaged in a patient. Which H(azard) statement warning sentence (Sect.
secondary container such as a tube folding box. 26.3.4) and which symbol should be put on the label,
depends mainly on the flash point of the flammable sub- Therefore raw materials already having a particle size of
stance. If labelling of flammable preparations with a specific less than 90 μm should be preferred.
symbol is not legally required, an advice should be given The solid phase of suspensions and paste bases is dis-
anyhow. persed in the aqueous or lipophilic phase. The method of
Some active substances such as clioquinol, dithranol and dispersing depends on the amount of the solid and the con-
methylrosaline hydrochloride (gentian violet) stain clothes sistency of the aqueous or lipophilic phase.
and bedding. A label for example with the text “Stains
clothing and bedding” can warn of this property. In the 12.6.1.2 Lipophilic Phase
case of benzoyl peroxide the text “Bleaches hair, textile A lipophilic phase is prepared by mixing the components.
and bedding” is more appropriate to warn of its bleaching Basically it is possible to mix compatible liquids or semi-
effect. Also for active substances that irritate strongly if they solid substances at room temperature, but mixing is easier if
are spilled accidentally on mucous membranes or in the they are heated on a water bath (see Sect. 29.6). Stirring the
eyes, such as capsicum, there should be a warning. mixture while it is cooling down is important for getting a
homogeneous product and for prevention of recrystallisation
of substances with a relatively high melting point, such as
12.5.12 Storage cetostearyl alcohol. White wax, solid paraffins and high
molecular macrogols always have to be heated for further
Cutaneous preparations can usually be stored at room tem- processing because of their consistency.
perature. In case of chemical instability or microbiological
vulnerability storage in the fridge (2–8 C) may be neces- 12.6.1.3 Aqueous Phase
sary. For example a hydrophilic cream with diltiazem hydro- Bases consisting of only an aqueous phase are prepared by
chloride for rectal application (Table 12.1) and preparations mixing the hydrophilic fluids and dissolving the solid
that contain tretinoin are kept at low temperature to reduce substances in this mixture. See also Sects. 29.5 and 29.6.
the degradation rate. A zinc oxide cutaneous suspension Preservatives are in general slightly soluble in water
(Table 12.21) is microbiologically vulnerable and therefore because the molecules are partly hydrophobic which prop-
has to be stored in the fridge. erty is needed for the function as a preservative. Therefore,
Dissolved substances may recrystallise in large crystals the concentration at which they are used is relatively high
when kept too cool. Preparations should thus not be stored in compared to their solubility in water (see Sect. 12.5.3). They
the fridge unnecessarily. dissolve slowly in the desired concentration. To increase the
dissolution rate preservatives are generally dissolved while
heating. Sorbic acid needs boiling water to dissolve, in a
closed vessel because of its volatility with water vapour. It is
easier to work with the combination of potassium sorbate
and an acid, such as citric acid, to form sorbic acid while
General methods of mixing, solving and dispersing are
preparing. Both substances are freely soluble in water with-
described in Chap. 29. This section shows typical procedures
out heating.
in the preparation of dermatological medicines. It includes
The dissolution rate of methyl hydroxybenzoate can be
the preparation of the bases and the different phases. It is
increased by heating which may be advantageous through
followed by methods for incorporating active substances
simultaneously killing micro-organisms already present in
into the base.
water. If large volumes have to be dealt with, heating
brings about the risk of boiling retardation and bursting
of glass vessels. A safer way for processing is the prepara-
12.6.1 Preparation Method of the Base tion of a concentrate in advance, such as a solution in
propylene glycol (Table 12.17). This solution should com-
The preparation method of the base depends on the phases of monly be added to the main part of the aqueous phase; if
which it is composed. A base with only one phase can be using too little water precipitation of methyl parahydroxy-
prepared by mixing the components. If more than one phase, benzoate will occur. Up to batch sizes of 500 mL prepared
each phase has to be prepared separately. Finally they have by hand, it is manageable to add the concentrate in one
to be mixed. portion and shake immediately after. With larger batches
the concentrate has to be added in smaller portions under
12.6.1.1 Solid Phase continuous stirring.
Solids with particles larger than 90 μm are ground and For Preserved water (see Sect. 12.5.3) methyl and propyl
sieved. Sieving with sieve 90 may be very laborious. hydroxybenzoate (0.075 % / 0.025 %) are dissolved by
12 Dermal 249
Table 12.17 Methyl Parahydroxybenzoate Solution 150 mg/mL [33] 12.6.2.1 Processing the Active Substance
Methyl parahydroxybenzoate 15 g with the Base
Propylene glycol 91 g There are several methods to process the active substance
Total 106 g (¼ 100 mL) with the base. The method of choice depends on the
substance’s properties (particularly solubility) and the for-
mulation of the base.
Solids can be triturated with the base or with an appropri-
heating. A special order of addition to the preparation is not ate liquid excipient. If agglomerates are present, they may be
needed. dispersed in this way, but the effectiveness always should be
The method of processing viscosity enhancing substances validated. That liquid excipient should be part of the base or
in the aqueous phase depends on the type of substance. The added in a negligible percentage. It must not dissolve the
general rule is: The viscosity enhancer has to be wetted active substance, because of the risk of subsequent recrystal-
completely at first. Otherwise lumps may occur that cannot lisation. For trituration the solid active substance should
swell anymore because they are insulated by the outer, have the required primary particle size, often being
swollen part. Section 23.7.2 gives elaborate information on micronised. Substances with larger primary particles than
different preparation methods.
PRODUCT DESIGN
required have to be ground and sieved for further processing.
As an alternative method, the active substance, whether
12.6.1.4 Aqueous and Lipophilic Phase existing of agglomerates or too large primary particles,
Preparations consisting of an aqueous and a lipophilic phase may be mixed with a small amount of the base, and passed
(creams and emulsions) usually contain an emulsifier. The through an ointment mill. Afterwards the remainder of the
preparation method depends on the type of the emulsion: base is added and mixed.
w/o or o/w. For preparing water-in-oil-emulsions the Dispersion of agglomerating substances, as most
substances that build the lipophilic phase are melted on the micronised substances are, requires much attention, see
water bath and stirred until the mixture reaches room tem- Sect. 29.3. In small batches of cutaneous preparations it is
perature. The aqueous phase with the dissolved substances is common practice to use a minimal amount of base for the
added in portions. For preparing oil-in-water-emulsions both first phase of dispersion.
phases are separately heated to 70–80 C. They are mixed by Subsequently the triturate has to be mixed with the remain-
continuous stirring. The temperature at which the emulsion der of the base by geometrical dilution, see Sect. 29.7.2.
becomes stable is about 45 C. Afterwards it is adequate to If an active substance is soluble in the base, it can be
stir occasionally until it is cooled down to room temperature. dissolved in a small amount of an appropriate solvent which
is compatible with the base. If the incorporation of an addi-
tional (amount of) solvent is not desired, freely soluble
substances can be directly mixed with the base. The sub-
12.6.2 Incorporation of Active Substances stance dissolves during the dispersion so mixing has to be
continued to cover complete dissolution; this has to be
Active substances can be incorporated during the prepara-
validated. Liquids which are miscible with the base can be
tion of the base or they can be mixed with the completed
directly mixed with it as well.
base. Only active substances that are soluble in the lipophilic
As an illustration of several preparation methods the
or aqueous phase can be directly dissolved in it. Insoluble
processing of triamcinolone acetonide in different bases is
substances have to be dispersed in the base. In pharmacies
given.
often the cream and ointment bases or gels are kept on stock
Triamcinolone acetonide is a low dose active substance,
as such. In this case the active substances can only be
usually micronised and thus agglomerised as well. For
incorporated into the base, not into the appropriate phase.
homogeneous dispersion in a base the use of a concentrate
is recommended: a trituration of triamcinolone acetonide
Examples for substances that are soluble in the with rice starch 1:10 or a semisolid trituration with a cream
lipophilic phase in a limited concentration are benzyl or ointment base. In this way a better mixing ratio as well as
benzoate, lidocaine, levomenthol and triclosan. deagglomeration can be achieved (see Sect. 29.3).
Dithranol is soluble in vegetable oils by warming. If the substance or the powder trituration should be
But because degradation rate is increased by tempera- processed in ointments or creams it has to be triturated
ture and dithranol may recrystallise after cooling, it is with an appropriate liquid that is preferably a part of the
not recommended to process dithranol in this way. base. Subsequently the trituration is mixed with the ointment
or cream base.
In liquid emulsions it can be triturated with a small temperature and pressure in the mixing device have to
amount of the base and subsequently be mixed with the be specified.
remainder of the base. In solutions (typically alcoholic) the • Air may easily be included during mixing. This is to be
substance has to be used not the powder trituration. It is prevented by mixing in vacuum. If this is not possible
soluble in alcoholic bases and needs no special measures for limits have to be set to the maximal amount of air
processing. inclusion.
• Sometimes pre-processing is necessary, for example
melting the solid substances or dissolving active
Active Substances with Special Processing
substances or excipients in one of the components, or
Methods
dispersing agglomerates.
Isosorbide dinitrate is used in the treatment of anal
The following examples give an explanation to these
fissures. The substance is explosive. For safety reasons
guidelines.
it is used as a 40 % dry mixture with a powder base.
According to Ph. Eur. it may contain mannitol or
lactose monohydrate. Commercially available
12.6.3.1 Processing of Sorbic Acid
Sorbic acid has to be dissolved in boiling water due to slow
mixtures usually contain lactose monohydrate and
dissolution in cold water. But because sorbic acid is volatile
isosorbide dinitrate in a crystalline or amorphous
with water vapour, loss of sorbic acid has to be prevented by
form. They are mixed with the cutaneous base via
immediately closing the vessel after the addition of the
geometrical dilution (see Sect. 29.4.1).
boiling water. When the preparation is processed in a
Viscous tar products such as ichthammol (ichthyol,
Stephan mixer in vacuum the sorbic acid may evaporate
Sulfobituminosum ammonicum) and coal tar (Pix
fast as well. An alternative is to use potassium sorbate
lithantracis) should be weighed onto a small portion
instead of sorbic acid and to adjust the pH of the preparation
of fat or ointment base because there is no other way to
subsequently.
remove it quantitatively from a weighing dish.
12.6.3.2 Processing of Low-Dosed Substances

Trituration of low-dosed, solid substances directly with the
base may lead to insufficient homogeneity. These substances
12.6.3 Large Batches may therefore be pre-dispersed in a small amount of fluid. Or
they may be dissolved at first and then mixed in very con-
The focus in this chapter is on small scale preparation: with a trolled circumstances with the rest of the base preparation to
mortar and a pestle, a rotor stator mixer or an ointment mill. get a fine precipitate.
For preparation on a larger scale pharmacies in several Lipid soluble substances can be dissolved separately in an
countries use the mixing-dispersing apparatus Stephan extra amount of a fluid component of the base and subse-
mixer. This mixer exists in various models and is suitable quently added to the lipid phase. The extra amount is
for the preparation of almost all cutaneous preparations (see subtracted from the amount of cream base to be used. A
Sect. 28.6.1). well water soluble substance can be dissolved separately in
The formulation of cutaneous preparations and the extra water and subsequently added to the aqueous phase.
excipients to be used are usually independent of the scale The amount of water that is used is again subtracted from the
of preparation. Upscaling brings about natural differences in amount of cream base to be used.
the practical performance. A main difference is that on a
small scale often a base is used into which active substances 12.6.3.3 Air Inclusion and Lumps
are dispersed. For large scale preparation the product is Air inclusion occurring with the preparation of creams may
usually prepared from the individual substances. The active be reduced by mixing just until the cream forms. At cooling
substance is processed as one of the substances. Some prac- down the mixture should only be stirred occasionally. Com-
tical guidelines are: bining the oil and the aqueous phase should occur at a
• The equipment and utensils should be based on the batch minimum temperature difference between those phases
size. Lifting and weighing of large amounts of starting (not more than several degrees). A too large difference
materials may lead to physical problems. Sometimes may cause lumps of fat and emulsifier and leads to an
extra tools may be necessary. inhomogeneous appearance. To avoid long mixing and
• For validation of the mixing process the mixing equip- thus air inclusion the phases should be mixed at a minimum
ment, the sequence of adding starting materials, the temperature but well above the temperature at which the
mixing time and speed, physical parameters such as emulsion is formed.
12 Dermal 251
12.6.4 In-process Controls The extent of quality control of stock and extemporaneous
preparations depends on a risk assessment, see Sect. 21.6.3.
For the control of the process steps (unit operations, see Sect.
17.6) of pharmacy preparation the following in-process 12.6.5.1 Quality Requirements
controls are recommended: For cutaneous preparations the following quality
• Recording the tare of the devices (mortars, bowls, pestles, requirements may apply (see also Table 32.2)
vessels et cetera) • Identity
• Re-weighing the weighing dishes or weighing papers • Appearance (homogeneity, clarity of solutions,
(used for small amounts of solids) (see Sect. 29.1.6) resuspendability of suspensions)
• Macroscopic control on agglomerates and homo- • Microbiological stability
geneity in manually as well as mechanically prepared • Content of active substance(s)
products • Sterility (for preparations applied on wounds)
• Parameters in the use of mechanical mixing systems
(speed and duration)
• Clarity and homogeneity of solutions; inhomogeneity of 12.7 Specific Formulations and Preparation
PRODUCT DESIGN
solutions may look like trails or strings Methods
• Temperature (important for the preparation of hydro-
philic emulsions, formulations with thermolabile This section describes more detailed how to design the
ingredients and sterilisation processes) formulation and preparation method of specific groups of
• pH measuring (for an in-process control pH measuring cutaneous preparations. Examples show how general
paper or indicator sticks may be used) methods and rules (as given in Sect. 12.5 for formulation
• Control and recording of the total amount (important for design and Sect. 12.6 for method of preparation) are
hydrophilic creams, gels and alcohol containing implemented in practice.
formulations)
The in-process controls for stock preparations are generally
the same as those for small scale. Usually the preparation 12.7.1 Powders for Cutaneous Application
method is validated and the parameters for processes are
known. 12.7.1.1 Formulation
Powders for cutaneous application are consisting of one or
more solids forming the base (see for example Table 12.18).
12.6.5 Release Control and Quality As said in Sect. 12.5.1 different excipients are used as
Requirements filler, for cooling and drying the skin, as astringent or to
prevent agglomeration. Specific for cutaneous powders may
For quality requirements and tests reference is made to be the addition of substances that improve the adhesiveness
Chap. 32. on the skin, for example wool fat or white soft paraffin or
The release control includes at least the appearance, substances that enhance the binding capacity for liquids, for
packaging and labelling. example kaolin.
Texture, colour, smell, clarity (solutions) and particle size
(suspensions) may also have to be controlled. 12.7.1.2 Preparation Method
Appropriate tests for liquid preparations (suspensions, See Sect. 12.6.1 for general information. The substances in
emulsions or shampoos) are homogeneous appearance, sta- cutaneous powders usually have a very small particle size
bility of the emulsion (after shaking), resuspendability of and will thus cause dust, static charge and agglomerates.
suspensions and their particle size. Cutaneous powders have to be sieved by sieve 90, leaving
Ointments, creams and gels with dispersed solids are not more than one percent remaining on the sieve. After
tested by putting a small amount of the preparation between sieving of mixtures, mixing is necessary because separation
two microscope slides or other glass slides with only small may have taken place.
pressure. In transmitted light agglomerates must not be
found in the preparation. To determine the particle size in Table 12.18 Base for Cutaneous Powder [34]
a larger sample a grindometer can be used. Zinc oxide 10 g
If the consistency of specific preparations is relevant for Talc 90 g
therapeutic use, it could be easily checked by using an Total 100 g
extensometer.
Lipophilic substances can be added, after melting, in Table 12.19 Salicylic Acid and Triamcinolone Acetonide Oily Cuta-
small portions by mixing and passing through sieve 180. neous Solution [36]
Sieve 90 is not suitable, because the particles are too large. 2% 5% 10 %
The powder that remains on the sieve is dissolved in a Salicylic acid 2g 5g 10 g
volatile solvent, added and mixed with the bulk. Triamcinolone acetonide 0.1 g 0.1 g 0.1 g
2-Propanol 9.9 g 9.9 g 9.9 g
Castor oil, refined – – 50 g
12.7.2 Solutions Octyldodecanol 88 g 85 g 30 g
Total 100 g 100 g 100 g
Solutions for dermal use are liquid hydrophilic or lipophilic
bases with dissolved active substances and excipients.
Table 12.20 Salicylic Acid and Triamcinolone Acetonide Washable
12.7.2.1 Formulation Oily Cutaneous Solution [37]
The formulation of hydrophilic solutions is discussed in 2% 5% 10 %
Sect. 12.5.3 comprising co-solvents, humectants, viscosity Salicylic acid 2g 5g 10 g
enhancers and preservation. The formulation of lipophilic Triamcinolone acetonide 0.1 g 0.1 g 0.1 g
solutions is discussed in Sect. 12.5.2 which elaborates on the Macrogol lauryl ether 10 g 10 g 15 g
functions of the various ‘fatty’ excipients. Octyldodecanol 87.9 g 84.9 g 74.9 g
As an example of a lipophilic solution a salicylic acid
Total 100 g 100 g 100 g
and triamcinolone acetonide oily cutaneous solution is
shown in Table 12.19. It is a lipophilic solution based on
octyldodecanol, a fatty alcohol. Salicylic acid is soluble up
to approximately 8 % in this base. For higher concentrated suspensions. These (Table 12.21) are often used without any
solutions castor oil is needed. Triamcinolone acetonide is (other) active substance.
practically insoluble in the oily base. To dissolve it about
10 % of isopropyl alcohol has to be added to the solution
12.7.3.1 Formulation
base. The preparation method is such that triamcinolona-
See Sect. 12.5.3. The liquid phase of hydrophilic
cetonide is dissolved in isopropyl alcohol at first. The for-
suspensions generally consists of water, a humectant, a pre-
mulation is applied to the scalp. It has to be washed out after
servative and a viscosity enhancer to decrease the settling
a certain time. An additionally processed surfactant eases
rate.
this and reduces the amount of shampoo which is usually
If the concentration of solids, for instance zinc oxide, is
necessary. Therefore the DAC/NRF [35] has a second for-
high enough, the suspension is relatively stable and the
mulation with macrogol lauryl ether as surfactant
addition of viscosity enhancers is not necessary. Further-
(Table 12.20). Because of the dissolving properties of
more viscosity enhancers may be unsuitable if they ruin
macrogol lauryl ether neither isopropyl alcohol nor castor
specific effects such as the cooling effect from evaporation
oil is needed. Both formulations play a role in the
of water or alcohol. If the addition of preservatives is not
dermatologists practice. The decision for one or the other
desirable, e.g. in case of a large skin area that is affected, the
depends on the patient´s skin conditions. Surfactants may
preparation should be dispensed in single-use (or at least few
irritate a sensitive skin. In that case the formulation without
times use) containers and the use period should be restricted
surfactant may be preferred.
to a few days.
Typical active substances in zinc oxide cutaneous sus-
12.7.2.2 Preparation Method
pension are levomenthol (Table 12.22) and ichthammol
See Sects. 12.6.1 and 29.5 for the preparation method of
(Table 12.23). Levomenthol dissolves completely only in
lipophilic and hydrophilic solutions. Volatile solvents
an alcohol containing base. Therefore a zinc oxide suspen-
should be processed in a closed vessel or added at the end.
sion with ethanol is the right base for it. Ichthammol may be
Warming is only appropriate for substances which remain
formulated in an aqueous as well as in an ethanol-containing
completely dissolved at room temperature.
one.
12.7.3 Suspensions 12.7.3.2 Preparation Method

If the suspension does not contain a viscosity enhancer the
Suspensions for dermal use generally are hydrophilic. Well- insoluble solid (after grinding and sieving if necessary) is
known as pharmacy preparations are zinc oxide cutaneous dispersed in the mixture of the hydrophilic liquids in which
12 Dermal 253
Table 12.21 Zinc Oxide Cutaneous Suspension [38] Table 12.24 Cetomacrogol Cutaneous Emulsion [41]
Zinc oxide 16.7 g Cetomacrogol emulsifying wax (BP) 3g
Propylene glycol 16.7 g Decyl oleate 4g
Talc 16.7 g Potassium sorbate 0.09 g
Water, purified 61 g Sorbic acid 0.13 g
Total 111.1 g (¼ 100 mL) Sorbitol, liquid (crystallising) 0.8 g
Total 100 g
Table 12.22 Levomenthol Zinc Oxide Cutaneous Suspension [39]

Levomenthol 1g 12.7.4.1 Formulation and Preparation Method
Ethanol (95 %) 23 g For formulation see Sect. 12.5.4. Emulsions usually have an
Zinc oxide 13.83 g aqueous phase/lipophilic phase ratio of about 4. The aqueous
Propylene glycol 13.83 g phase usually contains a preservative and a humectant (see
Talc 13.83 g
Sect. 12.5.3).
PRODUCT DESIGN
For the preparation method see Sect. 12.6.1.4. The prepa-
Total 111.1 g (¼ 100 mL) ration method resembles that of hydrophilic creams (see
Sect. 12.7.10).
A specific preparation method for cutaneous o/w
emulsions is a dilution of hydrophilic creams. These are
Table 12.23 Ichthammol Zinc Oxide Cutaneous Suspension [40]
typically diluted in a ratio of 1:2 up to 1:6 with water (with
2.5 % 5% 10 % added preservative), the ratio depending on the properties of
Ichthammol 2.5 g 5g 10 g the cream, the consistency that is desired and the location of
Bentonite 1g 1.5 g 2g
application. Warming is not necessary for diluting the cream
Zinc oxide 20 g 20 g 20 g
base with water. In some cases the use of a rotor-stator-mixer
Talc 20 g 20 g 20 g
is recommended to get finer emulsions and thereby a higher
Glycerol 85 % 30 g 30 g 30 g
viscosity.
Water, purified 26.5 g 23.5 g 18 g
For the incorporation of active substances see
Total 100 g 100 g 100 g
Sect. 12.6.2. Solids that do not dissolve in the base, such as
corticosteroids, are preferably dispersed by triturating with
an equal amount of the emulsion. Water soluble solids, such
as urea, will dissolve when mixed with the aqueous phase
soluble ingredients already have been dissolved. See long enough (to be validated). Fluids that are miscible with
Sects. 12.6.2 and 29.7 for dispersion methods. the base, such as coal tar solution, are added by simply
If a viscosity enhancing agent is used, a gel has to be mixing with the base.
prepared first (see Sect. 23.7). Soluble substances are
dissolved in the gel or added as solution to the gel.
If a rotor-stator mixer is used, its mixing time and speed
12.7.5 Hydrophobic Ointments
have to be limited in order to minimise the inclusion of air.
As the inclusion of air cannot be completely avoided, the
Hydrophobic ointments, frequently called fatty ointments,
preparation has to be prepared by weight not by volume.
are plastic lipogels, in which active substances and
excipients may be dissolved or dispersed. A hydrophobic
ointment can absorb only a small quantity of water or water-
12.7.4 Emulsions miscible fluids. They are not washable.
Emulsions for cutaneous application are usually oil-in-water 12.7.5.1 Formulation

emulsions. The formulation resembles hydrophilic creams See Sect. 12.5.2. Suitable substances for hydrophobic
(see Sect. 12.7.10). The only difference is the higher content ointments are white soft paraffin, liquid and solid paraffin,
of water (Table 12.24). Water-in-oil emulsions are not com- vegetable and animal fats and fatty oils, synthetic esters of
mon and therefore not described. glycerol or alcohols or mixtures of these substances.
Table 12.25 Coal Tar Soft Paraffin Ointment [42] Table 12.26 Emulsifying Hydrophobic Base Gel DAC [44]
5% 10 % 20 % Isopropyl palmitate 8g
Coal tar topical solution DAC 5g 10 g 20 g Triglycerol diisostearate 10 g
Carbomer 50,000 1g 1g 1g Hydrophobic base gel DAC 82 g
Paraffin, white soft 94 g 89 g 79 g Total 100 g
Total 100 g 100 g 100 g
Table 12.27 Cetomacrogol Ointment Base [45]

12.7.5.2 Preparation Method Cetomacrogol emulsifying wax (BP) 30 g
See Sect. 12.6.1.2. Hydrophobic ointments are usually Paraffin, liquid 25 g
prepared by melting all lipophilic ingredients and stirring Paraffin, white soft 45 g
the mixture while it is cooling down. The consistency of the Total 100 g
product depends on the speed of the cooling down and the
stirring speed.
For the incorporation of active substances see
See Sect. 23.6 for descriptions of these surfactants.
Sect. 12.6.2. Coal tar is miscible with white soft paraffin
White soft paraffin and wool fat are commonly used
and can be added directly without melting. Insoluble active
excipients for w/o emulsifying ointments. Emulsifying
substances are best triturated with an equal amount of an
Hydrophobic Base Gel DAC (Table 12.26) is an ointment
ingredient of the base (wool fat or paraffin) or an appropriate
base free of wool fat and wool alcohols. It consists of
lipophilic liquid. For the dispersion of high amounts of
plastibase (also named as Hydrophobic Base Gel DAC
insoluble solid substances (such as zinc oxide) passing the
[43]: polyethylene processed with liquid paraffines), isopro-
preparation through an ointment mill is recommended.
pyl palmitate and triglycerol diisostearate.
Hydrophilic liquids are not appropriate as dispersing agents
because they are not miscible with the base or only miscible
in a very small amount, depending on the emulsifying 12.7.6.2 Preparation Method
properties of the ingredients of the ointment base. Just glyc- Basically the preparation of w/o emulsifying ointments and
erol 85 % is miscible in a reasonable amount. Alcoholic the processing of active substances are similar to hydropho-
liquids usually are insufficiently miscible with hydrophobic bic ointments. Whether heating is meaningful depends on
ointment bases, but small amounts can be added drop wise. the properties of the ingredients. Emulsifying Hydrophobic
The hydrophilic coal tar solution can be mixed (up to 10 %) Base Gel (Table 12.26) for example is prepared by mixing
with hydrophobic bases (Table 12.25.) with the help of all substances at room temperature. The Hydrophobic Base
carbomer (1 %) that increases its viscosity. Gel does not tolerate temperatures above 70 C.
Insoluble active substances are usually incorporated by
trituration into a paste with wool fat or a lipophilic liquid if it
is a component of the base. Afterwards this paste is mixed
12.7.6 W/o Emulsifying Ointments with the other lipophilic ingredients.
W/o emulsifying ointments consist of a lipophilic phase

containing w/o emulsifiers. Because of these properties the 12.7.7 O/w Emulsifying Ointments
water binding capacity is much higher than in hydrophobic
ointments. O/w emulsifying ointments consist of a hydrophobic base
with an o/w surfactant (Tables 12.27 and 12.28). Addition of
12.7.6.1 Formulation water to these ointments leads to an oil-in-water-emulsion,
The ingredients used in w/o emulsifying ointments are the which makes them somewhat washable.
same as in hydrophobic ointments, but a w/o surfactant is
added such as: 12.7.7.1 Formulation
• Wool fat The lipophilic base is formulated in the same way as hydro-
• Wool alcohols phobic ointments, see Sect. 12.5.2. The o/w emulsifiers are
• Sorbitan esters usually the same as in o/w creams: for example
• Monoglycerides cetomacrogol emulsifying wax and lanette emulsifying
• Fatty alcohols wax (lanette wax SX or N). As these bases are anhydrous
12 Dermal 255
Table 12.28 Lanette Ointment Base [46] Table 12.29 Macrogol Ointment DAC [47]
Cetostearyl alcohol (type B), emulsifying 30 g Macrogol 300 50 g
Paraffin, liquid 25 g Macrogol 1500 50 g
Paraffin, white soft 45 g Total 100 g
Total 100 g
Macrogol ointments can absorb up to 5 % of water and up

no preservatives or humectants are needed. By addition of to 5 % of ethanol. If 5 % of macrogol 4000 is replaced by
appropriate substances these ointments can be modified for stearyl alcohol or cetyl alcohol the ointment base can absorb
different applications. Examples for additives are: up to 25 % of water.
• 15 % of isopropyl myristate to Cetomacrogol Ointment
Base and Lanette Ointment Base (Tables 12.27. and 12.7.8.2 Preparation Method
12.28). These preparations are known as Cetomacrogol Hydrophilic ointments are prepared by melting the
Ointment and Lanette Ointment in the FNA (see Sect. ingredients on the water bath and stirring while the mixture
39.4.5). These water emulsifying ointments have better is cooling down. Soluble active substances are dissolved in
PRODUCT DESIGN
spreading properties than the parent ointment base. macrogol or another solvent which is contained in the for-
• 25 % of decyl oleate to Cetomacrogol Ointment Base and mulation. Insoluble active substances have to be dispersed
Lanette Ointment Base which makes them applicable to in the melted cooling base. If formulated, water and alcohol
the scalp and easy to be washed off. are added after the base has cooled down completely.
By the addition of water the o/w emulsifying ointments
are turned into hydrophilic creams with a relatively high
content of lipophilic ingredients and good application 12.7.9 Lipophilic Creams
properties (Table 12.4). Propylene glycol is added for
preservation. Lipophilic creams or w/o-creams are emulsions with a
lipophilic outer phase. Active substances are dissolved in
12.7.7.2 Preparation Method the aqueous or lipophilic phase or are dispersed.
O/w emulsifying ointments are prepared by melting all
ingredients on a waterbath and stirring while the preparation 12.7.9.1 Formulation
is cooling down. Stirring has to occur continuously to pre- The lipophilic phase comprises usually about 70–75 % of
vent crystallisation of cetostearyl alcohol whereby the oint- the total amount of the cream base. The lipophilic phase may
ment would become granulous. Active substances are consist of fatty oils (usually arachis oil), waxes such as decyl
incorporated in the same way as in hydrophobic and w/o oleate, wool fat and white wax or hydrocarbons such as
emulsifying ointments (see Sects. 12.7.5 and 12.7.6). Water liquid paraffins or white soft paraffin (see Sect. 23.3.5 for
soluble substances can be easily processed in o/w descriptions). They determine consistency and spreadability.
emulsifying ointment bases, for example urea as an aqueous A w/o surfactant is added (see Sect. 12.5.4). The emulsifying
solution. properties of w/o surfactants are weaker than those of o/w
surfactants. Therefore they are often used in a higher quan-
tity. The physical stability of w/o creams is limited. For
instance the addition of phenols, acids and alcoholic fluids
12.7.8 Hydrophilic Ointments
may lead to phase separation. Most hydrophobic creams
only include less than 5 % alcohols.
Hydrophilic ointments consist of a water miscible base,
A specific hydrophobic cream base is Cooling Ointment.
usually containing a mixture of liquid and solid macrogols
A cooling ointment should be unstable, separate on the skin
(polyethylenglycols or PEGs, see Sect. 23.3.4).
and cool the skin through evaporation of water.
The Cooling Ointment given in Table 12.30 does not
12.7.8.1 Formulation contain any physical stabilisers. The aqueous phase is only
An example of a hydrophilic ointment base is Macrogol physically bound. It is not very suitable for the addition of
Ointment (Table 12.29). The consistency can be modified active substances that affect the physical stability such as
by variation of the ratio between liquid and solid macrogols. lauromacrogol 400, coal tar solution or urea. After a rela-
Sometimes water is added to make the ointment less hygro- tively short time water can separate. Only a limited number
scopic and irritating. Being anhydrous, no preservation is of substances can be added often in a low concentration.
necessary. Solid substances such as glucocorticosteroids, salicylic acid
Table 12.30 Cooling Ointment DAB [48] Table 12.32 Hydrophobic Cream Base DAC [50]
Arachis oil, refined 60 g Citric acid, anhydrous 0.07 g
Beeswax, yellow 7g Glycerol (85 %) 5g
Cetyl palmitate 8g Hydrophobic base gel DAC 24.6 g
Water, purified 25 g Isopropyl palmitate 2.4 g
Total 100 g Magnesium sulfate heptahydrate 0.5 g
Triglycerol diisostearate 3g
Table 12.31 Cooling Ointment FNA [49] Total 100 g
Arachis oil, refined 57.5 g
Beeswax, white 12.5 g
Glycerol mono-oleate 5g substances that tolerate 70 C) and subsequently stirring to
Rose oil (USP/NF) 1 drop
cool. The hydrophilic phase is added in portions to the
cooled lipophilic mixture and mixed. Hydrophobic Base
Total 100 g Gel, which is a component of Hydrophobic Cream Base
(Table 12.32) should be processed without heat because it
does not tolerate temperatures of more than 70 C.
and sulfur usually can be processed directly without any
influence on physical stability.
Another cooling ointment is depicted in Table 12.31. The 12.7.10 Hydrophilic Creams
name Cooling Ointment is actually not correct anymore for
that formulation. In the course of time different formulations Hydrophilic creams or o/w creams are emulsions whereby
have been used. In practice the physical instability was not the outer phase is the aqueous phase.
appreciated anymore because it made the addition of active
substances impossible. The formulation is too stable to be a 12.7.10.1 Formulation
good cooling ointment, because it contains glycerol mono- Hydrophilic creams are preferably formulated with
oleate, a w/o surfactant. But addition of active substances is combinations of emulsifying agents (mixed layer
possible and this Cooling Ointment functions firstly as pre- emulsifying agents or emulsifying agent complexes, see
servative free cream base. Sect. 18.4.3). For examples of o/w surfactants see
Although cooling ointments are w/o systems, they are Sect. 12.5.4. Generally hydrophilic creams may be anionic-
microbiologically vulnerable to bacteria, fungi and yeasts active or non-ionic-active. Because of incompatibilities of
(see Sect. 12.5.3.5). But the preservation is often not desired. active substances with anionic or non-ionic-active
Cooling ointments are regarded as bases that are well surfactants mixtures of these types of emulsifiers have to
tolerated on the skin and preservatives may cause be avoided. The lipophilic excipients improve the consis-
sensitisation and irritation. Typically they are not preserved tency of the cream. These may be hydrocarbons such as
and thus the shelf life has to be shortened. white soft paraffin or waxes such as decyl oleate.
An example for a physically stable w/o cream base is The outer phase of hydrophilic creams consist of water,
given in Table 12.32. It consists of Emulsifying Hydropho- dissolved active substances, preservatives and humectants
bic Base Gel (Table 12.26) and an aqueous phase preserved see Sect. 12.5.3.
with sorbic acid (using a combination of potassium sorbate The formulation in Table 12.33 represents a non-ionic-
and citric acid). The base contains 65 % of water and is free active hydrophilic cream base. It contains a liquid wax
of wool fat. It is for example an appropriate base for (ethylhexyl laurate), which is well absorbed by the skin.
corticosteroids, urea, tretinoin and triclosan. The active sub- The robust cream base tolerates processing of organic
stance lauromacrogol 400 can only be added to a base with solvents and of phenols such as salicylic acid, in spite of
less water. Otherwise the preparation becomes physically its nonionic character. Lanette creams 12.34 are anionic-
unstable. active bases. The two formulations differ in their consis-
tency. The higher amount of emulsifying cetostearyl alcohol
12.7.9.2 Preparation Method in Lanette cream II leads to a more stiff cream. It is espe-
Lipophilic creams are usually prepared by melting the lipid cially suitable for preparations with a larger quantity of
components and the surfactant (and possibly lipid soluble liquids.
12 Dermal 257
Table 12.33 Nonionic Hydrophilic Cream SR DAC [51]

Nonionic emulsifying alcohols DAC 21 g Specific Processing Method
Ethylhexyl laurate DAC 10 g Sometimes the active substance may best be dispersed
Citric acid, anhydrous 0.07 g by precipitating during preparation. Tetracycline hydro-
Glycerol (85 %) 5g chloride dissolves readily causing a pH of 2.5 at which it
Potassium sorbate 0.14 g is degraded by more than 10 % after 1 month. In a
Water, purified 63.79 g tetracycline hydrochloride cream (Table 18.4) tetracy-
Total 100 g cline hydrochloride is added to a cream base after being
dispersed in a small amount of water. Mixing with the
cream base causes tetracycline hydrochloride to dis-
solve completely. Immediately sodium citrate solution
is added which causes fine precipitation of tetracycline,
Table 12.34 Lanette Cream I and II [52]
as well as an increase of the shelf life to 6 months.
I II
Cetostearyl alcohol (type B), emulsifying 15 g 24 g
Decyl oleate 20 g 16 g 12.7.11 Hydrogels
PRODUCT DESIGN
Sorbic acid 0.2 g 0.15 g
Sorbitol, liquid (crystallising) 4g 4g Hydrogels consist of a hydrophilic fluid (such as water,
Water, purified 60.8 g 55.85 g glycerol, propylene glycol and alcohol) or a mixture of
Total 100 g 100 g hydrophilic fluids in which a viscosity enhancing substance
has been incorporated.
Table 12.35 Hydroxyethylcellulose Gel DAB [53] The most often used viscosity enhancers in hydrogels are
Hydroxyethylcellulose 10,000 2.5 g carbomer salts and the cellulose derivates hypromellose and
Glycerol 85 % 10 g hydroxyethyl cellulose (see Sects. 12.5.3 and 23.7.3).
Water, purified 87.5 g Carbomer gels (see Table 23.17) tolerate the addition of
Total 100 g ethanol or isopropyl alcohol without losing the gel structure,
although the extent depends on the type of neutralising sub-
stance (see further Sect. 23.7.3). They have a limited compati-
bility with salts and cations depending on their concentration;
the viscosity may be decreased. Zinc oxide disturbs the gel
12.7.10.2 Preparation Method structure by cross-linking the polymer. If any addition causes
For the preparation of the hydrophilic cream base the the pH to decrease under 6, the gel structure will be lost as well.
excipients have to be divided into hydrophilic and lipophilic If processing of a substance in Carbomer gels is not
ones, forming the aqueous and lipophilic phase respectively. possible because of incompatibilities, a gel with cellulose
The aqueous phase consists of: water, often sorbitol solution derivates may be prepared (Table 12.35). Hypromellose and
70 %, glycerol 85 %, propylene glycol or sorbic acid hydroxyethylcellulose are nonionic and compatible with
and other dissolved substances as far as they are not volatile salts, acids and bases.
or degrade while being warmed. The lipophilic phase Depending on their viscosity type cellulose derivates
consists of: fats, fatty oils, surfactant(s) and oil-soluble create firm gels in concentrations of 2.5–8 %.
substances. The two phases are warmed separately to about Salicylic acid, erythromycin and calcium gluconate are
70–80 C. The aqueous phase is added to the lipophilic incompatible with carbomer gels and may be formulated
phase, usually in one time or sometimes in portions. The with a hypromellose gel. An alcoholic gel of erythromycin
mixture is stirred immediately after the addition and (Table 12.36) for example is based on a mixture of ethanol,
continued until the structure of the cream is built. Then glycerol 85 % and water thickened with hypromellose. For
stirring can be slowed down to prevent too much air being stability of erythromycin, citric acid is used to adjust pH to
included in the cream. The evaporated water has to be 8–8.5. Glycerol 85 % functions as humectant.
compensated for. Because of the presence of water a preservative should be
The way of processing active substances follows general added to hydrogels, see Sect. 12.5.3. Suitable preservatives
recommendations for the incorporation of active substances are sorbic acid, glycerol and propylene glycol. Methyl
(see Sect. 12.6.2). hydroxybenzoate or a combination of methyl and propyl
Table 12.36 Erythromycin Alcohol Gel [54] viscosity. The addition of alkali and the stirring is done by
0.5 % 1% 2% 4% hand and not with the rotor stator mixer because otherwise
Erythromycin, anhydrous 0.50 g 1g 2g 4g too much air would be entrapped.
Citric acid, anhydrous 0.038 g 0.075 g 0.15 g 0.30 g
Ethanol (96 %) 45 g 45 g 45 g 45 g 12.7.11.3 Preparation Method of Gels
Glycerol (85 %) 2g 2g 2g 2g with Cellulose Derivatives
Hypromellose 4,000 3g 3g 3g 3g
For the preparation of gels containing cellulose derivatives,
Water, purified 49.462 g 48.925 g 47.85 g 45.7 g
the following methods are known, see also Sect. 23.7.2.
Total 100 g 100 g 100 g 100 g • Cellulose derivatives are triturated in a mortar with a
viscous hydrophilic fluid in which it will not swell, such
hydroxybenzoate (Preserved water, see Sect. 12.5.3) can be as propylene glycol, glycerol 85 % or sorbitol solution
used as well because there is no lipophilic phase that 70 %.
removes part of these substances. • The gelling agent is mixed with hot water. For some types
of cellulose derivates this technique leads to a fast disper-
sion and gelling while cooling down.
Gel for Iontophoresis • The gelling agent can be sprinkled on the liquid base
Iontophoresis is a technique whereby ionic active while stirring continuously and vigorously.
substances are transported into the skin with the help Generally gels may also be prepared with the use of a
of an electric field. Gels for iontophoresis should not Stephan mixer (see Sect. 28.6.1). Lumps will be dispersed
contain charged excipients because these excipients immediately in this way. Processing with a Stephan mixer
may penetrate into the skin as well and reduce the under vacuum has another advantage. It results in an air
penetration of the charged active substance. Gel bubble free (and thereby transparent) gel.
bases for iontophoresis may contain hypromellose as Active substances that are sufficiently soluble in the gel
gelling agent (Table 12.37). base may be added to the finished base by dissolving them in
water or in another fluid that can be mixed with the base.
Table 12.37 Base Gel for Iontophoresis [55]
However, addition of a large amount of fluid to the finished
Hypromellose 4,000 mPa.s 2g base leads to a less viscous preparation. If this is undesirable,
Propylene glycol 30 g direct mixing is to be preferred if the active substance is well
Water, purified 68 g soluble, or the gel should be prepared from the single
Total 100 g components and not with the finished product.
For example in the alcoholic erythromycin gel
(Table 12.36) erythromycin is dissolved in ethanol first.
Hypromellose has to be dispersed in this water free solution.
12.7.11.2 Preparation Method of Carbomer Gels Finally water and glycerol 85 % are added and the gelling
Carbomer dust irritates the eyes, mucous membranes and agent starts to swell. The gel can be prepared in a flask
respiratory tract. Therefore this substance should be because it is relatively thin. Substances that are insoluble
processed carefully avoiding any handling that causes dust. in water such as corticosteroids and metronidazole are dis-
Small batches of carbomer gels (up to 300 g) can be prepared persed in an equal volume of gel and subsequently geomet-
with a mortar and pestle. First the carbomer is partially rically mixed with the rest of the base.
ionised by dry mixing with the neutralising substance (for
instance trometamol), which makes it hydrophilic. Then
disodium edetate is added to remove by cross-linking biva-
lent ions (for example calcium ions) that can hinder the 12.7.12 Oleogels
creation of the gel. Subsequently this mixture is triturated
with fluid. Dispersion and creation of the gel in this case Oleogels or hydrophobic gels consist of an oil like or fatty
takes place at the same moment. fluid in which a viscosity enhancer is processed.
For the preparation of batches up to 500 g a rotor stator
mixer is recommended. With the rotor stator mixer carbomer 12.7.12.1 Formulation and Preparation Method
is moistened and dispersed in the aqueous phase in which Oleogels may be mixtures of liquid paraffin with polyethyl-
water soluble substances such as disodium edetate have ene (Hydrophobic Base Gel DAC [43]) or fatty oils com-
already been dissolved. Herewith a somewhat viscous solu- bined with anhydrous colloidal silica, aluminium or zinc
tion is created. Adding an alkali reacting substance causes soaps as viscosity enhancer. Hydrophobic gels are prepared
deprotonating of carbomer and thereby an increase of by mixing the oil phase with the viscosity enhancer. If the
12 Dermal 259
Table 12.38 Zinc Oxide Cutaneous Paste DAB [56] Table 12.40 Zinc Oxide Cutaneous Paste [58]
Zinc oxide (90) 25 g Zinc oxide (90) 60 g
Paraffin, white soft 50 g Arachis oil, refined 39.3 g
Wheat starch 25 g Oleic acid 0.7 g
Total 100 g Total 100 g
Table 12.39 Zinc Oxide Calcium Hydroxide Weak Paste [57] base. Sometimes it may be helpful to melt the base before
adding the solid. Because of the large percentage of solid
Zinc oxide (90) 33 g
Arachis oil, refined 33 g
substance it is difficult to remove all agglomerates by hand.
Beeswax, white 1g Therefore stiff pastes are commonly passed through an
Calcium hydroxide solutiona 33 g ointment mill. Additional mixing has to take place
Oleic acid q.s. afterwards.
Total 100 g
PRODUCT DESIGN
a
12.7.13.2 Weak Pastes
Contains at least 1.4 mg dissolved calcium hydroxide per
mL. Preparation is according the monograph Solutio calcii hydroxidi.
Weak pastes may have a liquid or a weak semisolid base.
In: Nederlandse Farmacopee, Zesde uitgave, 2e druk. ‘s-Gravenhage: They are used for wetting skin disorders. Formulations differ
Staatsuitgeverij, 1966:600 in their potential to adhere to a very wet skin. The weak zinc
oxide paste containing a calcium hydroxide solution
(Table 12.39) for example adheres much more on wet skin
oleogel contains a solid substance it is being dispersed in the than a paste based only on an oil (Table 12.40). The phases
fatty base. of the former, water containing, preparation separate after
application and as a result the cooling effect is intensified.
The weak paste with zinc oxide and calcium hydroxide
12.7.13 Pastes solution in Table 12.39 is actually a lipophilic cream, but
because of the large amount of solid substance it is classified
Pastes are semisolid preparations that consist of a lipophilic as a paste. The w/o emulsifiers calcium oleate and zinc
phase in which a high percentage of solid substance is oleate are created during the preparation process in the
dispersed. The range of solid substances is typically presence of oleic acid. The amount of oleic acid necessary
30–50 % or more. The consistency varies dependent on the for emulsifying depends not only on the acid value of the
formulation of the base. In connection with the amount of used arachis oil (corresponding to the amount of fatty acid
solids this classifies the preparations into stiff and weak already present), but also on the method of preparation.
pastes. Another kind of paste is an aqueous paste containing When mixed and dispersed well usually no oleic acid is
the solid in a hydrophilic base. Zinc oxide is the most needed. When too much oleic acid is added, the emulsion
frequently processed solid in pastes. Zinc oxide containing will break.
formulations are used as examples of these different kinds of The viscosity of the zinc oxide cutaneous paste depicted
paste. in Table 12.40 is increased by zinc oleate that is formed from
zinc ions with free fatty acids from the fatty oil. The prepa-
12.7.13.1 Stiff Pastes ration may be considered as a cutaneous oleogel of zinc
Stiff pastes typically have a semisolid base with a high oleate in arachis oil in which the excess zinc oxide is
percentage of solid (50 % or more) dispersed in it (see suspended. During preparation the product is still fluid.
Table 12.38). Their main function is to protect the skin, for During storage more zinc oleate is created and the product
instance around a stoma, from body exsudates and humidity. thickens into a semisolid preparation that may be called a
The absorptive capacity is determined to be not relevant weak paste. This paste is used in subacute and chronic
[59a]. eczemas and in intertrigines.
Stiff pastes usually are based on white soft paraffin. Weak pastes are prepared by dispersing the insoluble
Sometimes a part of white soft paraffin is replaced by liquid components (e.g. zinc oxide) (after grinding and sieving if
paraffin to improve the applicability, as for example in zinc necessary) in the base. Stable weak pastes such as Zinc oxide
oxide pastes. Zinc oxide pastes contain wheat starch and zinc cutaneous paste (Table 12.40) may be passed through an
oxide as the solid phase. ointment mill. Sieving of the zinc oxide is not necessary in
Stiff pastes are prepared by dispersing insoluble that case. Active substances, for example corticosteroids,
substances (after grinding and sieving if necessary) in the lidocaine, miconazole nitrate and sulfur, can be added to
Table 12.41 Zinc Oxide Aqueous Paste Table 12.42 Lactic Acid Salicylic Acid Collodion 10 % [60]
Zinc oxide (90) 22.5 g Salicylic acid 10 g
Aluminium magnesium silicate 2.5 g Lactic acid 11.1 g
Propylene glycol 10 g Collodion, elastic DAC (containing castor oil, refined) 78.9 g
Talc 22.5 g Total 100 g
Total 100 g
Table 12.43 Shampoo Base

Hypromellose 4,000 mPa.s 1g
this paste by dispersing them in an equal weight of propylene
glycol and subsequently mixing them with the paste.
In Zinc Oxide Calcium Hydroxide Weak Paste (Table 12.39) Sodium lauryl ether sulfate 28 % m/m (local standard)a 60 g
active substances may be processed by dispersing them Water, purified 37.3 g
in a similar volume of the paste and subsequently mixing
Total 100 g
with the remainder of the paste. However, the paste is
a
unstable as such and every added (active) substance may Texapon NSO®
disturb the physical stability. Therefore no extra liquid
should be added to dissolve active substances nor should
they be triturated. the skin. It enables an intensive contact between active
substance and skin. The flexibility of the membrane is
12.7.13.3 Aqueous Pastes improved by adding castor oil. Collodia contain a high
Aqueous pastes, also called hydrophilic pastes, consist of a concentration of alcohol and ether. In this environment no
hydrophilic base with 40–60 % solid substance. This type of micro-organisms will grow. Therefore preservation of a
paste may consist of water only, made viscous by a viscosity collodion is not necessary.
enhancer (see Table 12.41) or by the addition of a hydro-
philic cream or emulsion. They are supposed to have a good 12.7.14.2 Preparation Method
absorptive capacity and are therefore used in the treatment of Active substances are dissolved. Speeding up the dissolution
wetting skin disorders [59b]. process by warming is not possible because of the high
The formulation of aqueous pastes strongly resembles the inflammability of collodion (due to the presence of ether
formulation of cutaneous suspensions (see Sect. 12.5.5.2). and ethanol). Ventilation should be sufficiently effective as
Aqueous pastes contain, however, a higher percentage of to prevent the concentration of their vapours exceeding
solid substances which makes them semisolid. For typical critical limits (see Sect. 26.11).
excipients see Sect. 12.5.1. The formulation of an aqueous
paste with colloidal aluminium magnesium silicate as vis-
cosity enhancer is described here. Propylene glycol
preserves the aqueous phase. 12.7.15 Shampoos
Aqueous pastes are prepared by dispersing insoluble
substances (after grinding and sieving if necessary) in the Shampoos are semisolid or fluid preparations for the scalp.
mixture of liquids that may be thickened to a gel first. They contain foaming surfactants and often additives for
‘hair care’.
12.7.14 Collodia 12.7.15.1 Formulation

Shampoos are hydrophilic solutions, hydrophilic
A collodion is used when a prolonged contact of the active suspensions or hydrogels with a high percentage of
substance with the skin is required, for example salicylic surfactants (Table 12.43). Active substances may usually
acid in the treatment of warts (see Table 12.42). be processed without problems in a neutral base shampoo,
available as a mild or everyday shampoo. The addition of
12.7.14.1 Formulation coal tar solution or coal tar alcoholic solution may decrease
A collodion is a solution of cellulose nitrate (4 %) in a the viscosity slightly.
mixture of alcohol and ether. The cellulose nitrates increase Shampoos are packaged in a plastic squeezing bottle
the viscosity of the alcohol-ether mixture. After evaporation (shampoo bottle) and not in a glass bottle because of the
of the solvents a stiff cellulose nitrate membrane remains on risk of breakage in the bathroom.
12 Dermal 261
12.7.15.2 Preparation Method 12.7.17.1 Sterile Cutaneous Powders

The processing of active substances in shampoos is in prin- Sterile cutaneous powders usually contain lactose as the
ciple similar to the one in aqueous suspensions base, because lactose is absorbable and does not cause gran-
(Sect. 12.6.2). Because of foam formation the mixture uloma, as talc does.
should not be stirred firmly. Salicylic acid (up to 3 % m/m, The raw materials should preferably purchased sterile.
dissolved in a threefold amount of alcohol 95 % v/v) and The substances to be processed are ground and sieved if
coal tar alcoholic solution (up to 10 % m/m) may be directly necessary. They are dried and when they are resistant they
mixed with the base shampoo of Table 12.43. Coal tar (Pix may be sterilised with dry heat (see Sect. 30.5.2). Lactose
lithanthracis) may be mixed with the shampoo base after can be dried and sterilised (drying 1 h 130 C, sterilisation
trituration with some sodium lauryl ether sulfate solution. 3 h 140 C).
The substances should be spread out in a thin layer so that
the heat can penetrate well. If they can be sterilised at the
same regimen and no interactions will take place during
12.7.16 Sticks
sterilisation, then they should be mixed before sterilisation.
Otherwise they should be mixed after sterilisation, asepti-
Sticks, also called ointment sticks, are meant to be used
PRODUCT DESIGN
cally. The mixture is not sieved anymore. The powders are
on lips.
packaged in a sterile sifter-top container.
12.7.16.1 Formulation 12.7.17.2 Irrigations for Wounds

The consistency of ointment sticks has to be high enough to To rinse large wounds, non-intact skin or non-intact mucous
prevent deformation while being used, but it should enable membranes sterile aqueous solutions have to be used. Also
for active substances to be abraded. A suitable base is made dressings that are applied to non-intact skin should be sterile.
from equal amounts of cocoa butter, white wax, wool fat and Additionally, irrigations for wounds have to be pyrogen free.
cetyl palmitate (synthetic spermaceti) or cocoa butter only. Sterile dressings may also contain macrogols. Aqueous
Ointment sticks with cacao butter only are used for cracked macrogol solutions may be steam sterilised. In Chap. 14
lips or to prevent lips cracking. Ointment sticks are packaged other aspects of the formulation and preparation are
in aluminium foil and dispensed in a glass or synthetic jar. discussed.
They can also be placed in lipstick holders.
12.7.17.3 Sterile Hydrophobic Ointments

12.7.16.2 Preparation Method The preparation of sterile hydrophobic ointments is similar
The preparation of the base and the processing of the active to that of eye ointments, see Sect. 10.7.3. The base however
substances is similar to the preparation of suppositories with does not have to be filtrated until particle free.
a fat base (see Sect. 11.5). The melted mass is preferably Insoluble active substances are processed as in eye
poured into molds for ointment sticks. ointments (Sect. 10.7.3).
12.7.17.4 Sterile Creams

12.7.17 Sterile Cutaneous Preparations Sterile creams are prepared aseptically from sterile
components, similar to eye creams, see Sect. 10.7.3.
Sterile cutaneous preparations undergo sterilisation in the Some components that are usually warmed with the oil
final container if possible. Many active substances, base phase of cutaneous preparations are not resistant to 140 C.
preparations and package materials for cutaneous These substances are sterilised with the aqueous phase. An
preparations however are not resistant to the common example is sodium lauryl sulfate (and also lanettewax SX).
sterilisation methods, see also Sect. 30.8. If sterilisation in Cetomacrogol wax is resistant to 140 C.
the final container is not possible, cutaneous dermal With sterile lipophilic creams the cooled aqueous phase is
preparations should be prepared aseptically and packaged added drop wise to the oil phase and mixed in aseptic
in sterile packaging materials, see Chaps. 30 and 31. On the circumstances. With sterile hydrophilic creams the prepara-
label of sterile cutaneous preparations the word sterile has to tion method should be planned as such that both phases are
be mentioned. After opening, these preparations can only be cooled to around 70 C at the same time. The aqueous phase
stored for 24 h. is aseptically processed with the oil phase to a hydrophilic
emulsion by firstly stirring continuously and later every now 10. Higuchi T (1960) Physical chemical analysis of percutaneous
and then. absorption process from creams and ointments. J Soc Cosmet
Chem 11:85–97
Insoluble active substances are processed as in eye 11. Wiechers JW, Kelly CL, Blease TG, Dederen JC (2004)
creams (Sect. 10.7.3). Formulating for efficacy. Int J Cosmet Sci 26:173–182
12. Lane ME, Hadgraft J, Oliveira G, Vieira R, Mohammed D, Hirata K
(2012) Rational formulation design. Int J Cosmet Sci 34:496–501
12.7.17.5 Sterile (Wound) Gels 13. Williams AC (2013) Topical and transdermal drug delivery. In:
For the formulation of sterile wound gels reference is made Aulton M, Taylor K (eds) Aulton’s pharmaceutics the design and
manufacture of medicines, 4th edn. Churchill Livingstone, London,
to Sect. 12.7.11. If the gel has to be iso-osmotic, for example
pp 675–98
when used in wounds, then mannitol may be used for that 14. Geneesmiddel Informatie Centrum (2014) Informatorium
purpose. Medicamentorum. Den Haag: Koninklijke Nederlandse
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15. Sweetman SC (ed) (2009) Martindale – The complete drug refer-
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ence, 36th edn. Pharmaceutical Press, London
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Maatschappij ter bevordering der Pharmacie (KNMP) Pharmazeutischer Verlag, Eschborn
42. LCD-Vaselin 5% / 10%/ 20% NRF 11.87. Fassung 2013/1. In: 57. Zinkoxidekalkwaterzalf FNA. Jaar 2009. Formularium der
Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium. Nederlandse Apothekers. Den Haag: Koninklijke Nederlandse
Govi-Verlag Pharmazeutischer Verlag, Eschborn. Deutscher Maatschappij ter bevordering der Pharmacie (KNMP)
Apotheker Verlag, Stuttgart 58. Zinkoxidesmeersel FNA. Jaar 2012. Formularium der Nederlandse
43. Hydrophobes Basisgel DAC B-024. Fassung 2011. In: Deutscher Apothekers. Den Haag: Koninklijke Nederlandse Maatschappij ter
Arzneimittel-Codex/Neues Rezeptur-Formularium. Govi-Verlag bevordering der Pharmacie (KNMP)
Pharmazeutischer Verlag, Eschborn. Deutscher Apotheker Verlag, 59. Juch RD, Rufli T, Surber C (1994) Pastes: what do they contain?
Stuttgart How do they work? Dermatology 189:259 (59a), 377 (59b)
44. Emulgierendes hydrophobes Basisgel DAC B-023. Fassung 2011. 60. Milchsäure-haltiges Salicylsäure-Collodium 10 % (NRF 11.18.).
In: Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium. Fassung 2012/2. In: Deutscher Arzneimittel-Codex/Neues
Govi-Verlag Pharmazeutischer Verlag, Eschborn. Deutscher Rezeptur-Formularium. GOVI-Verlag Pharmzeutischer Verlag,
Apotheker Verlag, Stuttgart Eschborn. Deutscher Apotheker-Verlag, Stuttgart
45. Basis voor cetomacrogolzalf FNA. Jaar 2009. Formularium der
Nederlandse Apothekers. Den Haag: Koninklijke Nederlandse
Maatschappij ter bevordering der Pharmacie (KNMP)
Parenteral
13
Marija Tubic-Grozdanis and Irene Krämer
Contents 13.5.9 Preservatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

13.5.10 Excipients Used in Freeze-Drying . . . . . . . . . . . . . . . . . . . . . . 277
13.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 13.5.11 Packaging and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
13.1.1 Advantages and Disadvantages of the Parenteral Route 266 13.5.12 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
13.1.2 Type of Parenteral Administration . . . . . . . . . . . . . . . . . . . . . 266 13.5.13 Storage Temperature and Shelf Life . . . . . . . . . . . . . . . . . . . . 277
13.1.3 Availability of Parenteral Administration Forms . . . . . . 267 13.5.14 Quality Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
13.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 13.5.15 Special Parenteral Preparations . . . . . . . . . . . . . . . . . . . . . . . . . 278
13.2.1 Definitions of the European Pharmacopoeia (Ph. Eur.) 267 13.6 Product Formulation of Infusions . . . . . . . . . . . . . . . . . . . . 279
13.2.2 Colloidal Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 13.6.1 Types of Infusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
13.2.3 Routes of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 13.6.2 Buffer Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
13.2.4 Specific Routes of Administration . . . . . . . . . . . . . . . . . . . . . . 268 13.6.3 Osmolarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
13.2.5 Administration Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 13.6.4 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
13.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 13.6.5 Container and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
13.3.1 Rapid Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 13.6.6 Quality Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
13.3.2 Prolonged Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 13.7 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
13.4 Side Effects and Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 13.7.1 Starting Material and Equipment . . . . . . . . . . . . . . . . . . . . . . . 280
13.4.1 Protein Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 13.7.2 Preparation of the Bulk Solution . . . . . . . . . . . . . . . . . . . . . . . 281
13.4.2 (Thrombo)phlebitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 13.7.3 Control of Bioburden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
13.4.3 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 13.7.4 Purging with Inert Gas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
13.4.4 Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 13.7.5 Filling and Closing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
13.4.5 Damage by Foreign Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 13.7.6 Sterilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
13.7.7 Visual Inspection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
13.5 Product Formulation of Injections . . . . . . . . . . . . . . . . . . . 272 13.7.8 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.1 Active Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 13.7.9 In-process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.2 Solubility of the Active Substance . . . . . . . . . . . . . . . . . . . . . 272 13.7.10 Release Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.3 Vehicle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
13.5.4 pH and Buffer Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 13.8 Reconstitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.5 Osmotic Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 13.8.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.6 Viscosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 13.8.2 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
13.5.7 Excipients for Suspensions and Emulsions . . . . . . . . . . . . 276 13.8.3 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
13.5.8 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 13.8.4 Control and Quality Requirements . . . . . . . . . . . . . . . . . . . . . 286
13.9 Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
13.9.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
13.9.2 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
13.9.3 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
13.9.4 Release Control and Quality Requirements . . . . . . . . . . . . 290
13.9.5 Administration of Parenteral Nutrition Admixtures . . . 291
13.10 Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
13.10.1 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Based upon the chapter Parenteraal by Yvonne Bouwman-Boer and 13.10.2 Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
András Vermes in the 2009 edition of Recepteerkunde. 13.10.3 Infusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
13.10.4 Infusion- and Administration Systems . . . . . . . . . . . . . . . . . 295
M. Tubic-Grozdanis (*) I. Krämer
13.10.5 Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Hospital pharmacy, University Medical Centre of the Johannes
13.10.6 Management of Parenteral Administration . . . . . . . . . . . . . 297
Gutenberg University Mainz, Mainz, Germany
e-mail: [email protected]; References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
[email protected]

266 M. Tubic-Grozdanis and I. Krämer
Abstract • There is a chance of tissue damage in the injection area.

This chapter gives an overview of parenteral dosage • Possible mistakes in the route of administration.
forms and the rational for their use. Parenterals are sterile • Side effects or allergic reactions can appear fast, require
preparations that are injected intravascularly, adminis- immediate action and cause major damages compared to
tered into body tissues or into visceral cavities. The other routes of administration.
parenteral route of administration is often chosen for • Accidentally injected air may produce an embolism.
active substances that are poorly absorbed via the oral • Administration requires specific knowledge and skills of
route or when rapid systemic availability and effects are an authorised and qualified person.
required, or both. An introduction to the formulation and • An infusion brings along specific problems:
preparation of parenteral dosage forms is provided. Par- – Occlusion of the infusion set
enteral medicines can be formulated as solutions, – Formation of a biofilm in the infusion line which
emulsions or suspensions. Products, such as implants increases infection risk
and microspheres are only briefly discussed. Knowledge • Infusion is not patient friendly, because the mobility of
about these types of products is a prerogative for the the patient is reduced and inserting and maintaining the
sound education of patients and caregivers in using the infusion line is aggravating.
products. • Inserting and maintaining the infusion line is labour-
Formulation strategies for reconstitution of ready to intensive.
administer medicines are described in detail. Poorly prepared or administered parenterals can cause
This chapter includes formulation considerations, patient harm such as thrombus formation, severe hypersen-
preparation and quality control of parenteral nutrition. sitivity reactions and infection. Because of the disadvantages
An overview of the administration methods of the paren- of the parenteral route other administration routes are pre-
teral dosage forms is also discussed ferred. The parenteral route is only considered when other
routes cannot be used or when the active substance can only
Keywords be administered parenterally. This is often the case for
Injections Infusions Parenterals Parenteral nutrition patients in the hospital and especially for intensive care
Administration Reconstitution Infusion systems patients and other critically ill patients.
RTA Formulation Preparation Phlebitis
13.1.2 Type of Parenteral Administration

13.1 Orientation
The appropriate type of parenteral dosage form and admin-
13.1.1 Advantages and Disadvantages istration site has to meet the medical needs of the patient.
of the Parenteral Route Criteria that have to be considered are: onset and duration of
pharmacological activity, site of therapeutic action, the vol-
Common reasons for parenteral administration of medicines ume to be administered, inpatient or outpatient.
are: The site of the pharmacological action of an active sub-
• A need to rapidly achieve therapeutic concentrations and stance is not always known. In most cases the active sub-
effects of the active substances. stance can reach the site of action when it is injected
• A poor bioavailability when given orally. subcutaneously or intramuscularly, or into the venous or
• The plasma concentration of the active substance needs to arterial bloodstream. Sometimes it is necessary to inject the
be carefully controlled to avoid under or overdosing. medicine directly into a deep compartment such as the
• The patient is unconscious or resists cooperation, or when central nervous system. Some active substances can only
enteral route is not possible (following major abdominal reach a specific compartment with a transport carrier.
surgery or a critical illness). Some charged or large molecules can reach specific tissues
Some medicines are administered parenterally for a combi- incorporated in liposomes (see also Sect. 13.2.2).
nation of these reasons. The pharmacokinetic and pharmacodynamic characte-
The parenteral route also has some disadvantages: ristics of the active substance mainly determine whether a
• The production is expensive. bolus (¼ a high quantity at once) injection or a continuous
• There is always a risk of infection. administration via infusion or injection pump is appropriate.
• An injection is an inconvenient way of administration for An active substance with long duration of action or long
most patients. half-life can be administered via bolus injection. Active
13 Parenteral 267
substances with a short duration of action or short half-life

are to be administered continuously if a continuous action For example noradrenalin is commercially available in
is required. The administration route of parenterals ampoules of 1 mL containing a solution of 1 mg/mL.
depends also on the type, i.e. solution, emulsion, suspension For intensive care patients 50 mL of noradrenaline
and vice versa. Aqueous solutions and emulsions from solution in a diluted concentration is used for continu-
the O/W type (particle size of the disperse phase <1 μm) ous infusion with a syringe pump. Prefilled 50 mL
can be administered intravenously. Injection volumes usu- vials with noradrenaline injection solution (prepared
ally amount to 5–10 mL. Larger volumes of aqueous from raw material, packaged, sterilised and labelled in
solutions or emulsions are usually administered by infusion the hospital pharmacy) reduce risks due to dilution
over time intervals from 15 min up to continuously. Some errors or infection.
toxic (antineoplastic, vasoconstrictive agents) or tissue-
injury causing medicines can only be administered
intravascularly.
Parenteral suspensions and oil-based parenterals must be
administered either subcutaneously or intramuscularly (see 13.2 Definitions
PRODUCT DESIGN
Sect. 13.5.3). The volume of subcutaneous injection typi-
cally amounts to 1 mL. To increase the applicable volume at 13.2.1 Definitions of the European
the subcutaneous application site, hyaluronidase can be Pharmacopoeia (Ph. Eur.)
added to the formulation [1]. The volume of intramuscular
injection is also small, usually 1–3 mL or up to 10 mL in The Ph. Eur. defines parenteral preparations as “sterile
divided doses. In practice the pharmacist also may dispense preparations intended for administration by injection, infu-
special injections (see Sect. 13.5.15). sion or implantation into the human or animal body”. They
The availability and competence of a caregiver also are categorised as:
influences the choice of the parenteral form. Only 1. Injections (solutions, emulsions or suspensions)
specialised nurses or physicians are allowed to administer 2. Infusions (aqueous solutions or emulsions with water as
medicines by intravenous injection. In addition nurses are the continuous phase, mostly isotonic with blood, meant
qualified to administer medicines subcutaneously and intra- for administration in a large volume)
muscularly or to connect the administration set of an infu- 3. Concentrates for injections or infusions (meant to be
sion solution to the already inserted peripheral or central administered per injection or per infusion after dilution)
venous access. 4. Powders for injections or infusions (sterile solids that
result in a solution when mixed with the right amount of
the recommended reconstitution solution; to this category
13.1.3 Availability of Parenteral Administration belong freeze-dried preparations)
Forms 5. Gels for injections (extended release of the active sub-
stance after injection) (see Sects. 13.3.2 and 13.5.15.2)
Many medicines coming to the market during the last 6. Implants (solid administration forms that release the
decade are formulated for parenteral administration. The active substance over a prolonged period of time) (see
main reason is the (glyco)protein structure of the active Sects. 13.3.2 and 13.5.15.3)
substances and the lack of bioavailability after oral adminis- In the European countries volumes larger than 10 mL are
tration. Parenteral formulations with ‘common active rarely administered as an injection. But it is difficult to define
substances’ (also called ‘small molecules’) are available as a strict limit for volumes to be injected or to be infused.
licensed pharmaceutical preparations across Europe. In the According to the United States Pharmacopeia (USP) par-
countries where those preparations are not on the market or enteral formulation can be divided into two categories,
not available, mostly for economic reasons, preparation of namely Small Volume Parenterals (SVP) up to a volume of
parenteral formulations can be done in the (hospital) 100 mL and Large Volume Parenterals (LVP) with a volume
pharmacies. >100 mL.
To decrease the delay required to draw up the medicine in
emergency, and to reduce the risk due to dilution errors or
infection or both, hospital pharmacy also supplies ready-to- 13.2.2 Colloidal Forms
administer (RTA) preparations (see Sect. 13.8) [2, 3]. Hos-
pital pharmacy preparation of RTAs should be limited to Poorly soluble active substances can be administered as
clinically approved products not commercially available in a colloidal solutions such as micelles, liposomes or
practical form. microspheres (see also Sect. 18.4.1).
Micelles are spherical or laminar colloidal aggregates would be injected). By this route the active substance is
consisting of 50 monomers. Micelles are not rigid spread very fast through the circulatory system.
particles, but there is a constant exchange between the Subcutaneous injections are injected into the subcuta-
monomers in the solution and bound in the micelles. neous connective tissue of the upper arm, the upper leg,
Micelles do not have an aqueous phase within the particle below or above the waist or the upper area of the buttock.
as it is the case in liposomes. Taxanes are formulated as Absorption of the active substances takes place through
micellar solutions for intravenous administration [4]. the vascular wall of the small vessels in the connective
Liposomes are microstructures composed of one or more tissue. Heparins and insulins are usually injected
concentric spheres of (phospho)lipid bilayer, separated by subcutaneously.
water or aqueous buffer compartments. Those particles can Intracutaneous injection is done into the dermis layer of
encapsulate and deliver both hydrophilic and lipophilic the skin, which is the tissue located under the epidermis. It is
substances. Water soluble substances can be entrapped in frequently done as a diagnostic measure, such as for tuber-
the central aqueous core, lipid soluble substances in the culin testing (screening test for tuberculosis referred to as a
membrane and peptide and small proteins at the liquid aque- Tine test) and allergy testing (placing very small amounts of
ous interface. The size of such a particle can differ from the suspected antigen or allergen in a solution under
20 nm to 10 μm. Liposomes are in general made syntheti- the skin).
cally e.g. by the lipid hydration method. Liposomal Intramuscular injections are administered into the deltoid
medicines are on the market for the treatment of systemic muscle of the upper arm or vastus lateralis muscles in the
fungal infections, tumours and for vaccination. anterolateral aspect of the middle or upper thigh.
Microspheres consist of natural and synthetic polymers
such as Eudragit®, chitosan, ethyl cellulose and egg albu-
min, which can be loaded with active substances.
13.2.4 Specific Routes of Administration
13.2.3 Routes of Administration Other more specific routes are employed for the administra-
tion of the active substance directly to the therapeutic site.
Commonly used parenteral administration routes are (see For administration into the central nervous system the intra-
Fig. 13.1): thecal, epidural or intracisternal injection route is used.
• Intravenous Intrathecal injection is an injection into the spinal canal,
• Subcutaneous more specifically into the sub-arachnoid space so that it
• Intracutaneous reaches the cerebrospinal fluid and is useful in spinal anaes-
• Intramuscular thesia, chemotherapy, or pain management applications.
Intravenous injections are injected into the vein, so in the This route is also used for antibiotic treatment of infections,
direction of the heart to diminish chance of bleeding on the particularly post-neurosurgical. Medicines given intrathe-
puncture place (as would occur easily if intra-arterially cally must not contain any preservative.
Fig. 13.1 The most frequently

used parenteral administration
routes. Source: Recepteerkunde
2009, #KNMP
intravenous
subcutaneous
epidermis utaneous
intrac
dermis intramuscular
vein
subcutis
muscle
13 Parenteral 269
Fig. 13.2 Epidural and dorsal

intrathecal administration route. epidural administration
Source: Recepteerkunde 2009,
#KNMP intrathecal administration
dorsal vertebra
periost
epidural space
dura mater
subarachnoidal space
with cerebrospinal fluid
spinal nerve
ventral
PRODUCT DESIGN
Epidural anaesthesia is a technique whereby a local
Since intravenous solutions have been accidentally anaesthetic is injected through a catheter placed into the
applied into intrathecal space, international guidelines epidural space, see Fig. 13.2.
have been issued to prevent this occurring. A major Spinal and epidural techniques are shown to provide
recommendation is to use a non-luer connector (see effective anaesthesia for caesarean section. Spinal block
Sect. 13.10.2) in neuraxial procedures. The first differs from an epidural block in a number of ways:
non-luer connectors for intrathecal administration • A smaller needle is used to perform a spinal block com-
were launched in UK. However, standardisation of pared to an epidural block.
these connectors is required [5]. • With the spinal technique the medicines are injected into
the cerebrospinal fluid that bathes the spinal cord; with an
epidural block, the medicines are delivered outside the
Spinal anaesthesia (spinal block or sub-arachnoid block) is
dura, in the epidural space.
used to administer the injection into the subarachnoid space.
• With the spinal technique small doses of local anaesthetic
Several local anaesthetics are used for spinal anaesthesia such
are required because they spread more easily in the spinal
as procaine, lidocaine, tetracaine, and bupivacaine.
fluid.
Vasoconstrictors such as adrenaline (0.1–0.2 mg) and phenyl-
• A spinal block is a single injection of local anaesthetic
ephrine (0.5–2 mg) can be added to subarachnoid blocks to
medications and so there is only one opportunity to
decrease vascular uptake and prolong duration of action.
deliver the medications; in an epidural, an indwelling
Local anaesthetics are synergistic with intrathecal opioids
catheter may be placed that avails for additional
and intensify sensory block without increasing sympathetic
injections.
block. The combination makes it possible to achieve spinal
Intraventricular administration is used for antineoplastic
anaesthesia with otherwise inadequate doses of local
treatment of gliomas or delivering the therapeutic agents to
anaesthetic.
different areas of central nervous system.
Intracisternal injection is used to deliver therapeutic
The difference in density between the cerebrospinal fluid agents to the cisterna magna.
(CSF) and local anaesthetic solutions should be consid- Intraocular (or intravitreal) injections, containing active
ered to restrict their distribution to the subarachnoid substances such as triamcinolone, antivascular endothelial
space. The relationship between the density of the local growth factor (VEGF) inhibitors, antibiotics, antivirals, or
anaesthetic solution and the density of the CSF is called antifungals, are administered into the eye.
baricity. Solutions of anaesthetic substances, which have By intraarticular injection medicines, e.g. containing
a greater density than CSF, are hyperbaric. Hyperbaric corticosteroids, local anaesthetics as active substances, are
solutions are especially practical in small doses for uni- administered into the joint.
lateral anaesthesia. Several commercially available In case of cardiac emergency medicines (e.g. adrenaline)
hyperbaric solutions contain 50–80 mg/mL glucose [6]. are administered directly into the muscles of the heart.
parenteral solutions administered intravenously are suitable

More routes can be distinguished for rapid onset of action.
Intracostal punction and insertion of a cannula into the
pleural cavity is mostly used to induce pleurodesis and
thereby reduce pleural effusions. Intrapleural adminis-
13.3.2 Prolonged Action
tration of sclerosing agents such as sterile talcum
powder, doxycycline or bleomycin destroy the meso-
Prolonged action of parenteral medicines is achieved by a
thelial cell layer and incite pleuritis, adhesions, and
different route of administration and different formulations.
destruction of the pleural space.
In general for example parenteral suspensions have a later
The arterial route is used to deliver some
onset and prolonged activity compared to parenteral
antineoplastics (e.g. cisplatin) to treat head and neck
solutions.
cancer.
Parenteral administration can also be done
endotracheally. Through the tracheal tube medicine
(containing e.g. atropine or epinephrine) is delivered 13.3.2.1 Intramuscular Administration
directly into the patient’s bronchi. Administration into the muscle results in a delayed onset of
action because the active substance has to be absorbed in the
muscle, passed through capillary walls to be transported via
the bloodstream to reach the site of action. Because most
13.2.5 Administration Methods capillaries are fenestrated, all substances, whether lipid-
soluble or not, cross the capillary wall at rates that are
Parenterals can be administered by: extremely rapid compared with their rates across other
• Direct (bolus) injection body membranes.
• Infusion by gravity In addition the nature of the formulation affects the
• Injection/infusion by pump absorption rate of medicines administrated by intramuscular
• During extracorporeal circulation. route.
Different types of veins can be punctured to be used for
intravenous administration:
• Small venous vessels (e.g. veins in the forearm) Differences Between Muscles
• Middle size venous vessel (e.g. vena brachialis) The absorption rate after intramuscular administration
• Large central veins (e.g. vena jugularis or vena subclavia) differs depending on type of muscle chosen. Studies
An infusion can also be administered subcutaneously. have shown that intramuscular injections result in dif-
However the volume to be administered is limited to ferent plasma concentrations of narcotics and per-
20–30 mL per 24 h (see Sect. 13.10.3). During extracorporeal ceived pain relief depending on the type of muscle
circulation procedures such as haemodialysis a parenteral used for administration. This was also found for the
liquid can be administered via ports in the dialysis devices. response to vaccination and use of antibiotics and
insulin [7]. Absorption of active substances from the
intramuscular site depends on the quantity and com-
13.3 Biopharmaceutics position of the connective tissue and the rate of vascu-
lar perfusion of the area. Blood flow in the muscles
The rate of absorption of the active substance and varies (it is increased in deltoid muscle) and is
subsequent duration of action will be determined by: influenced by the exercise of the muscle and morbid-
• Nature of the vehicle ity. The muscles are covered with the subcutaneous
• Physico-chemical characteristics of the active substance connective tissue, a lipid layer (adipose layer) and the
• Interaction of active substance with vehicles, tissue and skin. The thickness and the lipid content of these
body fluid tissues are different in different body areas. The sub-
cutaneous fat layer at the gluteal intramuscular injec-
tion site is thicker in females (mostly > 3 cm) than in
13.3.1 Rapid Action males. The medication should be administered with a
needle long enough to reach the muscle without
In emergency cases, e.g. cardiac arrest, anaphylactic shock penetrating underlying structures.
or severe asthma, immediate action is required. Aqueous
13 Parenteral 271
therefore extremely important. In any case the proteinaceous

13.4 Side Effects and Toxicity medicine should be stored and handled under optimal
conditions. Freeze-dried particles should be completely
Parenteral administration can be associated with pain and dissolved, the recommended storage conditions should be
additional side effects and toxic reactions. These reactions adhered to, the preparation should not be shaken and should
can be more rapid and intense than with oral or cutaneous be not be administered with a peristaltic pump. The route of
administration and may need fast intervention. Relevant administration can influence the immunogenicity of the pro-
types of adverse reactions are Protein hypersensitivity, tein. Subcutaneous injection is associated with higher poten-
(Thrombo)phlebitis, Pain, Extravasation and Damage by tial of immunogenicity than i.v. administration [8].
foreign particles.
Specific active substances exert their common adverse 13.4.2 (Thrombo)phlebitis

reactions when administered parenterally. Their rapid
onset may lead to severe problems and therefore some Phlebitis is an infection of a blood vessel. Infusion-related
substances require special attention beforehand: phlebitis is characterised by pain, tenderness, erythema,
PRODUCT DESIGN
• Benzylpenicillin (potential allergic reaction). induration, oedema and a local temperature increase. These
• Rituximab and other chimeric antibodies (infusion- circumstances may lead to thrombus formation or venous
related reactions such as hypotension, cardiopul- tissue destruction or both.
monary reactions, angioedema; mild to moderate The incidence and duration of phlebitis seems to be
infusion-related reactions such as fever, chills and dependent on a variety of factors. Physical-chemical factors
rigors occur frequently). such as low pH, hypertonicity, particles and precipitation
• Phenytoin (cardiovascular reactions, slow injection play a role in the cause. Active substances that are poorly
is associated with a high probability of soluble in water may precipitate and can cause acute phlebi-
precipitation). tis. Active substances with adequate aqueous solubility may
tend to cause phlebitis only because of prolonged or chronic
administration. Clinical factors involving injection tech-
nique (infiltration, extravasation, type of needle, duration
of infusion) but also irritating characteristics of the active
13.4.1 Protein Hypersensitivity
substance can contribute to the occurrence of phlebitis [9,
10]. Sometimes (septic) phlebitis is caused by bacterial
With an increasing use of parenterally administered proteins
infection (e.g. cause of inappropriate aseptic technique dur-
there is an increased risk for hypersensitivity reactions.
ing catheter insertion) and is characterised by inflammation
Proteins of any origin might elicit an immune response.
with suppuration of the vein wall. Local responses to the
Antibody formation against the protein may induce different
parenteral challenges can be diminished by dilution of the
results, e.g. no impact on efficacy, decrease of efficacy and
medicine or by central venous instead of peripheral venous
neutralisation of the physiological protein. Reduced activity
administration (see Sect. 13.10.3).
is derived from reduced half-life of the protein molecules in
the circulation and rapid clearance by immune cells. Many
factors influence the immunogenicity of proteins, including
changes in the primary structure (sequence variation and 13.4.3 Pain
glycosylation), storage conditions and changes in the tertiary
structure (denaturation or aggregation) (see Sect. 18.4.1.4), Parenteral administration can be associated with pain at the
contaminants or impurities arising from the production pro- injection site. The so-called injection fear may be dimin-
cess, dose and length of treatment, the route of administra- ished by applying topically anaesthetics prior to injection.
tion, and patient characteristics. Aggregation, which Eutectic mixtures of local anaesthetics (e.g. lidocaine/
includes formation of dimers and high-order aggregates, prilocaine cream or a tetracaine gel) have proven to be
may be mediated by pH, ionic strength, concentration, effective and well-tolerated in the relief of pain associated
counter-ion composition of the formulation, temperature, with intramuscular injections, venepuncture or intravenous
sheer stress. Purification and concentration processes such injection in adults and children.
as ultrafiltration, ion-exchange chromatography, Non-physiological osmolality and pH or increased buffer
lyophilisation, precipitation or ‘salting out’ can induce concentrations in formulations can be responsible for pain at
aggregation (see Sect. 22.2.5). Appropriate formulation of the injection site. Therefore some formulations for intramus-
a protein product and stabilisation of the active substance is cular use contain a local anaesthetic. Needle-free injection
technologies are alternatives to reduce the intensity of injec- Table 13.1 Quinine Hydrochloride 600 mg ¼ 5 mL (120 mg/mL)
tion pain [11]. Solution for Injection [14]
Quinine hydrochloride 12 g
Hydrochloric acid q.s.
13.4.4 Extravasation Water for injections ad 100 mL
Extravasation is the process by which any injection or infu-

sion solution accidentally leaks into the surrounding tissue. example for this principle is a quinine injection (Table 13.1).
The degree of damage due to extravasation depends on the Quinine has low water solubility and a pKa around 4. By
active substance, the concentration, the localisation of the adjusting the pH of the quinine solution to pH 3, about 90 %
extravasation and the length of time an active substance may of the quinine is ionised, resulting in a clear solution in the
develop the damage. According to the type and severity of desired concentration.
damage, active substances are categorised as irritants or
vesicants [12].
13.5.2.2 Salt Formation
Salts of acidic and basic active substances have, in general,
higher solubility than their corresponding acid or base forms.
13.4.5 Damage by Foreign Particles
Haloperidol is almost insoluble in water (< 0.1 mg/mL) but
haloperidol hydrochloride dissolves up to 3 mg/mL. Salt
The presence of visible foreign particles, which cannot be
formation of haloperidol with lactic or tartaric acid results
metabolised, must be avoided in injection solutions (see
in increased water solubility and allows producing haloperi-
Sect. 32.12). However, the release of particulate matter
dol injection solution (Haldol®) with a concentration up to
(such as rubber chips, chemical fibres, glass fragments) is
5 mg/mL.
an intrinsic element of the production process. They origi-
On the other hand decreased solubility of an active sub-
nate from the formulation, processing equipment, primary
stance and the formulation as a suspension may be advanta-
package or the preparation process prior to use. Particles
geous. The duration of action of insulin is enhanced by
larger than 8 μm are generally trapped in the capillaries of
forming salts with protamin and zinc with a lower solubility
the lungs, causing (thrombo) phlebitis and embolism.
and lower rate of dissolution of insulin.
Smaller particles can be trapped in the liver, spleen and
spinal cord [13]. Foreign body granulomas may result from
intramuscular or subcutaneous injection of products 13.5.2.3 Complexation
containing foreign particles. Aqueous solubility of an active substance with low water
solubility may be increased by molecular complexation with
cyclodextrins, polyvidone and macrogols.
13.5 Product Formulation of Injections

13.5.3 Vehicle
The parenteral route is used for the administration of ‘small’
Water for injection is the preferred vehicle for the prepara-
molecules as well as for ‘large’ molecules (proteins, mono-
tion of parenteral solutions (injections and infusions). When
clonal antibodies, vaccines, immunoglobulins).
the active substance is poorly or not soluble in water,
co-solvents or non-aqueous vehicles can be employed, or
dosage forms such as liposomes or microspheres can
13.5.2 Solubility of the Active Substance
be used.
Solubility can be improved by chemical modifications
(change of pH, use of buffer, derivatisation, complexation, 13.5.3.1 Co-solvents
salt formation) and other techniques (use of excipients such Co-solvents lower the surface tension of water resulting in
as surfactants, solubilisers, cyclodextrines and increased solubility of poorly water soluble active
phospholipids). substances. The most often used co-solvents in licensed
injections are ethanol, glycerol, propylene glycol and
13.5.2.1 Buffers and pH Adjustment macrogols (see Sects. 23.3.2, 23.3.3 and 23.3.4). The com-
For active substances that are ionisable, aqueous solubility bination of propylene glycol and ethanol is commonly used
can be raised by pH adjustment (see Sect. 19.1.1). An to dissolve lipophilic active substances [15].
13 Parenteral 273
infrequently in injectable formulations. It is often not able

Diazepam is only slightly water-soluble and has a pKa to achieve the desired concentration of the active sub-
of 3.4, which is not suitable to increase solubility by stance. Ethanol improves the solubility, but is, in
pH adjustment. The brand Diazepam-injection CF® concentrations higher than 10 %, painful when injected.
5 mg/mL contains diazepam solubilised in a Propylene glycol elicits a haemolytic response in vitro
co-solvent mixture of propylene glycol and ethanol. and in vivo, which could be reduced by the addition of
Nimodipine is poorly soluble in water: < 0.1 mg/mL. either saline or macrogol 400. Macrogol 300 and macrogol
The licensed pharmaceutical product Nimotop® infusion 400 are generally considered to be among the safest organic
solution contains 0.2 mg/mL nimodipine and 170 mg/mL co-solvents. Although macrogols are biocompatible, per-
macrogol 400. This high concentration of macrogol is oxide impurities in macrogols can cause the degradation of
needed to dissolve the active substance but causes phlebi- oxidisable active substances [15].
tis when Nimotop® is administered via a peripheral vein.
Therefore in the product information it is recommended
to administer Nimotop® via a central venous catheter.
13.5.3.2 Lipophilic Solvents
Vegetable oils such as cottonseed oil, peanut oil, and soy-
PRODUCT DESIGN
After diluting the infusion or injection concentrate with bean oil can dissolve very lipophilic substances. Oils must
an aqueous solution or with blood the active substance may be free from rancidity. Also semi synthetic lipophilic
precipitate. This is due to the concomitant dilution of the products such as isopropyl myristate and medium chain
co-solvent(s) and oversaturated solutions. Whether or not triglycerides are used in licensed parenteral liquids. They
precipitation occurs in mixtures of water and co-solvents are stable and colourless.
can be calculated in analogy to the calculation of the chance Oily injectable formulations are only administered by
of precipitation in water, see Sect. 18.1.1. intramuscular injection providing a depot for sustained
Supersaturated solid solutions of poorly water-soluble drug delivery. A good example is the oil-based extended
compounds are inherently prone to recrystallisation over release injection product that contains haloperidol esterified
time (see Sect. 18.1.6). If the appropriate formulation to a decanoate dissolved in sesame oil. The volume to be
principles and production processes are utilised, such systems injected is deposited deep into the gluteal muscle and forms
can represent a formulation option for injection of poorly a depot from where it is leached over a 1 month period into
water-soluble active substances. However, crystallisation is the blood stream according to its oil/water partition coeffi-
not predictable. Serious clinical problems have been reported cient. This phenomenon together with the time needed for
when precipitates have caused venous blockages [16]. circulating enzymes to hydrolyse the ester into the active
base is responsible for the prolonged length of action of this
formulation.
Co-trimoxazole is the combination of trimethoprim (sol-
Another example for a long-acting formulation is
ubility 0.1–1 mg/mL; pKa ¼ 7.4) and sulfamethoxazole
the intramuscular injection of fulvestrant, dissolved in
(solubility < 0.1 mg/mL; pKa ¼ 6). The licensed phar-
castor oil and organic solvents. It is administered
maceutical preparation Bactrimel® is a concentrated
once monthly to treat hormone receptor positive breast
co-trimoxazole solution of 16/80 mg/mL in propylene
cancer.
glycol, ethanol and water, with ethanolamine and sodium
For intravenous or intramuscular administration,
hydroxide. The pH of the solution is 9–10.
oil-soluble actives can be formulated as an oil–water-
Before administration, the injection fluid 16/80 mg/
emulsion. When administered intravenously it is essential
mL has to be diluted to the concentration range of
that the droplet size is about the same size as the lipid
0.125/0.625–8/40 mg/mL. The dilution causes reduced
particles that circulate in the blood, the chylomicrons
concentrations of organic solvents and a decreased pH
(0.2–3 μm). A typical emulsion contains 10–20 % soybean
value. Since the active substance precipitates slowly,
oil, 2 % glycerol and 1 % egg lecithin. These emulsions
the diluted preparation can be administered safely.
cannot be autoclaved. Coalescence of the droplets of the
internal phase is a typical sign of instability. All-in-one
For an overview of the toxicity of co-solvents, when total parenteral nutrition admixtures are a typical example
used parenterally, reference is made to the literature for parenterally administered emulsion (compare
[17]. Glycerol is a safe co-solvent, but it is used Sect. 13.9).
Diprivan® or Disoprivan® is an example of a licensed Several injectable prolonged release biodegradable

medicinal product formulated as an emulsion. The microspheres are available as licensed products,
active substance propofol (di-isopropyl phenol) is e.g. Lupron Depot® and Risperdal® Consta [18, 19].
solubilised in an emulsion composed of 10 % soybean The injectable ultrasound contrast agent (Optison®)
oil with egg phosphatide. consists of heat-denaturated albumin microspheres
filled with the gas octafluoropropane. In a similar
manner sulphur hexafluoride containing microspheres
(SonoVue®) are used as injectable contrast agent in
13.5.3.3 Microspheres and Liposomes echocardiography.
Microspheres and liposomes are described in Sect. 13.2.2
Some examples, described below, illustrate how these
techniques are used to process substances with poor solubil-
ity into an injectable liquid. 13.5.3.4 Surfactants
Surfactants reduce surface tension and increase the solubility of
DaunoXome®, used in treatment of Kaposi’s sarcoma, lipophilic active substances in aqueous medium; solubilisates
is an example of a liposomal antineoplastic medicine. are formed (see Sect. 18.3.3). Lecithin, various phospholipids,
Daunorubicin hydrochloride (1 mg/mL) is encap- polysorbate (Tween®) and polyoxyethylene castor oils such as
sulated in small liposomes. Amphotericin B, which is Cremophor® EL can be used in injections [15].
used in the treatment of systemic fungal infection, is
also formulated as a stable colloidal particle. Phytomenadione (Vitamin K1) appears as a non-
The Swiss Serum Institute developed liposomal- ionisable, water-insoluble viscous liquid. In Konakion®
based vaccines against hepatitis A and B, influenza, MM injection fluid 10 mg/mL it is solubilised with
diphtheria and tetanus [18]. lecithin and glycocholic acid creating micelles.
A liposomal injection solution of verteporin
(Visudyne®) is formulated with egg phosphatidyl-
glycerol and dimyristoylphosphatidyl choline. The
freeze-dried powder, contains apart from the Amiodarone hydrochloride, which has a poor water solu-
liposomes, verteporin, lactose as lyoprotector, and bility of 0.7 mg/mL, is solubilised in licensed pharmaceu-
osmolality adjusting excipients. By reconstitution tical preparations thereby achieving a concentration of
with water an opaque dark green injectable solution 50 mg/mL. Infusion solutions prepared with 5 % glucose
is generated, which is injected intravenously within as a vehicle still have amiodarone concentrations
the scope of photodynamic therapy. (6–15 mg/mL) exceeding by far the maximum concen-
tration of water solubility. The resulting infusion solution
contains the active substance still solubilised.
Microsphere sizes range from 10 to 200 μm. The
smaller the microspheres are, the better is their
syringeability and the smaller are the needle diameters Polysorbate (Tween® 20 and 80) and Cremophor RH40®
required for injection, which results in reduced patient (macrogol glycerol hydroxyl stearate) or Cremophor EL®
discomfort. The larger the microspheres, the lower is the (polyoxylated 35 castor oil) can cause serious hypersensitiv-
risk that the particles will be cleared from the injection ity reactions when administered parenterally [15]. They may
site by macrophages. 10 μm is generally considered to be a cause incompatibilities by leaching plasticisers (such as
safe lower size limit to avoid particle uptake by phthalates) from polyvinyl chloride infusion devices.
macrophages. The common microsphere size is about
30 μm. Microspheres can be administered at the site of The combination of 200 mg/mL polyoxyethylene
action and guarantee prolonged activity by slow release of hydrogenated castor oil and ethanol is used to solubi-
the active substance. Furthermore, sensitive active lise the active substance tacrolimus (water solubility
substances such as peptides and proteins may be protected < 0.1 mg/mL) up to 5 mg/mL in Prograf® injection
from chemical and enzymatic degradation when entrapped concentrate. The product is administered intravenously
in microspheres. after dilution to concentrations of 0.004–0.1 mg/mL.
13 Parenteral 275
13.5.4 pH and Buffer Capacity

(dipyridamol 5 mg/mL). The solubility of dipyridamol
Solubility and stability of the active substances are to be is < 0.1 mg/mL, but higher at a pH 3.3
considered when evaluating the optimal pH of parenteral [21]. Experiments showed that even after dilution
solutions. Moreover the pH of the solution has an impact with 0.9 % NaCl or glucose 5 % solution (1:2 ratio),
on the infusion tolerance, which is also depending on the the pH still amounts to pH 3. Information about the pH
volume and rate of administration and the buffer capacity of of the diluted parenterals is not to be found in the
the formulation. To prevent possible adverse effects the pH literature for all licensed products [20].
should preferably be in the physiological range. The pH of
the blood varies between 7.35 and 7.45 and has a large buffer
capacity and, theoretically, a deviant pH of an intravenous
injection will be corrected fast. The mixing, and thus the
neutralisation process, however takes rather long as blood 13.5.5 Osmotic Value
flows are laminar. Fast infusion will disturb this laminar flow
and with irritating solutions might be preferred above slow As a measure of the tonicity of blood one can calculate
PRODUCT DESIGN
infusion. This effect is confirmed in animal tests [20]. Intra- with the osmotic value because active substances and
venous injections have a higher chance of causing phlebitis additives cannot pass the membrane of the erythrocyte (see
in smaller vessels than in larger vessels where the blood Sect. 18.5.2). The osmotic value of blood is around
flows faster. If the injection remains for too long at the 290 mOsm/kg. Some parenteral fluids however contain
place of injection such as with subcutaneous and intramus- substances that can pass the membrane fast: ethanol, glyc-
cular administration there is more chance of irritation than erol, urea. Hyperosmotic solutions of these substances may
with intravenous administration. cause haemolysis; so they are hypotonic. The iso-osmotic
If a larger volume is given intravenously, the tolerated pH concentration of ethanol is for example 1.39 % m/m.
range is 3–11 [1]. The more the pH of the formulation Ethanol 5 % v/v infusion fluid is therefore hyperosmotic
approximates to the lower and upper limit of this pH range but appears to be practically isotonic.
the higher is the probability of discomfort and irritation at Parenteral products with osmotic values differing from
the injection site. Non-toxic acids and bases are used to set the physiological value may cause phlebitis and irritation.
the pH of parenterals. Lactic, maleic and hydrochloric acid This is especially applicable when the injection remains
and sodium hydroxide are used most often. They have some relatively long at the site of injection such as after subcuta-
buffering capacity in the acid area. Whether the resulting neous, intramuscular, epidural and intrathecal administra-
solution has sufficient buffering capacity depends on the pKa tion. There is a higher chance of phlebitis in small vessels
of the used base or acid and the pH of the solution (see Sect. after intravenous administration. However, it is not known
18.1.1). which limits should be considered to prevent phlebitis and
Buffers, mostly phosphate buffer solution, are included in irritation. According to some sources [22] the osmolarity of
the formulations to ensure the pH of the solution being an intravenous injection should not be higher than
maintained throughout the shelf life of the product. The 500 mOsm/kg. For subcutaneous and intramuscular admin-
buffer prevents pH changes caused by degradation products istration the range is smaller.
or leaching of ions from glass containers (see Sect. 24.2.1). As is the case for the pH level and buffer capacity,
Buffers may increase the hydrolysis rate of the active adjustment of osmotic value to physiological conditions is
substances (see Sect. 22.2.1) and may decrease solubility advisable. Sodium chloride or glucose are mostly used to
(Sect. 18.1.1). High buffer capacity should be avoided in adjust tonicity of parenterals. Sometimes deviating medical
order to minimise irritation and pain at the injection site and requirements are to be met. For example, hyperbaric
disturbance of the physiological pH. solutions of local anaesthetics are used in spinal anaesthesia
(see Sect. 13.2.4). Hyperbaricity in comparison to the cere-
brospinal fluid is achieved by a high glucose concentration
However, due to active substance stability, it is still
(7.5 %) which is also a hyperosmolar.
necessary to develop injections with extreme pH
Baricity and dose of the local anaesthetic along with the
values. A currently licensed intravenous product in
patient position determine the anaesthetic block height.
UK with a very low pH of 2.8 is Persantin®
(continued)
butylated hydroxytoluene) or have a lower redox potential

Nitroglycerin, Concentrate for Infusion 1 mg/ml than the active substance to be protected (i.e. sodium
The alcoholic nitroglycerin solution 10 mg/g contains metabisulfite, sodium formaldehydesulfoxylate). Edetate
90 % v/v ethanol (¼ 86.5 % m/m). The nitroglycerin increases the activity of antioxidants by chelating polyvalent
infusion concentrate thus contains 86.5 mg ethanol per cations, which may generate free radicals or be involved in
ml. It has an osmotic value of 1,800 mosmol/l and is electron transfer reactions (see also Sects. 23.10 and 22.2.2.2).
thus hyper osmotic, but at the same time hypotonic Another strategy to diminish oxidation is to remove oxygen
because ethanol can pass the erythrocyte membrane by flushing the injection solution with nitrogen prior to
freely. This solution can only be administered when it closure (see Sect. 13.7.4).
is mixed with NaCl 0,9 % or glucose 5 %.
Physostigmine salicylate can degrade successively by
hydrolysis and oxidation by oxygen. To prevent oxi-
dation during preparation, storage and administration
13.5.6 Viscosity
to the patient physostigmine salicylate injection fluid
(see Table 13.2) is stabilised with 0.1 mg/mL sodium
Parenteral formulations should not be more viscous than
metabisulfite. In general, to prevent oxidation sodium
water because as the viscosity of the formulation increases,
metabisulfite is used in higher concentrations
the ease of administration decreases and the likelihood of
i.e. 1 mg/mL. Because of the potential allergic
pain caused by injection increases. Polymers that modify
reactions to sodium metabisulfite and the ability of
viscosity of the formulation are more frequently used in
metabisulfite to form adducts with physostigmine,
parenteral suspensions than in parenteral solutions. By addi-
the concentration is limited and arbitrarily set at
tion of hydrophilic or lipophilic polymers parenteral
0.1 mg/mL. This concentration is adequate to protect
suspensions are stabilised.
the solution from discolouration.
Table 13.2 Physostigmine Salicylate 2 mg ¼ 2 mL (1 mg/mL)
13.5.7 Excipients for Suspensions Solution for Injection [23]
and Emulsions
Physostigmine salicylate 0.1 g
Hydrochloric acid q.s.
Typical excipients used in parenteral suspensions include
Sodium metabisulfite 0.01 g
surfactants that are used to stabilise emulsions and
Water for injections ad 100 mL
suspensions as wetting agents (polysorbate 80, poloxamer),
as micelle makers for the preparation of solubilisations and
to influence the flocculation and deflocculation behaviour of
a dispersed system (carmellose sodium, polyvidone). Paren-
terally used surfactants in high concentrations are toxic and
13.5.9 Preservatives
may cause venous irritation and occasional thrombophlebi-
tis. However, these high concentrations are not necessary to
Single dose vials should be used as much as possible to avoid
formulate stable parenteral suspensions.
microbial contamination entering the vial as in the case of
Only a limited number of emulsifiers are commonly
multidose vials. However, for economic reasons parenteral
regarded as safe to use in emulsions for parenteral adminis-
solutions are still packaged in multidose vials and
tration. Most important are lecithin, poloxamer and
preservatives are incorporated in them. According to the
macrogolglycerol ricinoleate (Cremophor EL®). This latter
Ph.Eur. multidose vials must contain a preservative. How-
excipient is linked to anaphylactic reactions and temporary
ever, the single dose may not exceed 15 mL. Parenteral
haematological disorders.
solutions which contain high concentrations of co-solvents
such as propylene glycol or glycerol, or oil-based products,
13.5.8 Antioxidants mostly do not require the addition of preservatives, although
it has been established that micro-organisms may survive
Antioxidants are used to reduce or inhibit the oxidation of in non-aqueous solutions [24]. The activity of preser-
active substances or excipients. Active substances in vatives can be affected by the pH, the concentration,
parenterals which may undergo oxidative degradation are the presence of binding or complexing excipients, and
e.g. phenothiazines, catecholamines, polyene antifungal incompatibility reactions with proteins and rubber as con-
agents, steroids, morphine. Antioxidants either prevent the tainer closure material. Commonly used preservatives and
formation of free radicals (i.e. butylated hydroxyanisole, typical concentrations used are: benzyl alcohol (1.0 %),
13 Parenteral 277
chlorobutanol (0.5 %), phenol (0.5 %), and metacresol Labelling of parenterals is discussed in Sect. 37.3.2. For
(0.1 %). Some preservatives, such as the parabens, cause injections usually both the total amount of active substance
irritation or adverse reactions and are hardly used anymore and the concentration should be indicated.
in parenterals. If a formulation is intended for paediatric
administration, restrictions for certain preservatives must
be considered. European Medicines Agency (EMA)
recommended that parenteral solutions containing benzyl 13.5.12 Stability
alcohol should not be used in pre-term and full-term
neonates, due to neurotoxicity, cardiovascular failure, intra- Details of chemical and physical degradation reactions of
ventricular haemorrhage, gasping respirations and metabolic medicines (including proteins), and stability investigation
acidosis (‘gasping syndrome’). Due to the risk of fatal toxic are given in Chap. 22.
reactions arising from exposure to benzyl alcohol in excess Injection solutions containing ‘small’ molecules may
of 90 mg/kg/day, this preservative should also not be used in degrade by hydrolysis, oxidation and epimerisation
children up to 3 years old [25]. reactions. The reaction rate determines whether sterilisation
Due to their toxicity preservatives are not allowed in by heat can take place or not. Injection fluids that tolerate
PRODUCT DESIGN
injections for epidural, intrathecal, intracisternal or intraoc- autoclaving usually have a shelf life of several years at room
ular use [26]. temperature. Active substances that are not stable in solution
are usually prepared as powder – commonly by freeze drying
the solution – and have to be reconstituted immediately
13.5.10 Excipients Used in Freeze-Drying before administration by the caregiver or the patient. Physi-
cal instability regards mainly suspensions (resuspendability)
Proteinaceous active substances are usually formulated in an and protein solutions (precipitation and aggregation).
elaborated excipient system prior to the freeze-drying pro- Incompatibilities (precipitation) have to be checked for
cedure. Bulking agents, such as mannitol or glycine, are used when solutions of poor water-soluble substances in
to increase the bulk volume and provide a suitable matrix in co-solvents are diluted or when parenteral solutions are
which a small quantity of protein is dispersed [27]. Further combined.
details regarding use of cryoprotective excipients are Protein products are especially prone to changes of the
described in Sect. 22.2.5. tertiary and quaternary structure of the molecules and
thereby loss of activity. Degradation is induced by heat and
shear stress. Rigorous shaking and administration by peri-
13.5.11 Packaging and Labelling staltic pumps should be avoided.
Injection fluids are packaged in ampoules, vials or bottles

(container size 100 mL), syringes, and cartridges
manufactured from glass or plastic. The containers must be
13.5.13 Storage Temperature and Shelf Life
transparent to allow visual inspection of the content. Light
sensitive active substances should be preferably protected by
See Sect. 22.6.1 for a general discussion of shelf life. As
light-tight secondary packaging; amber glass is an option as
long as the container of injection fluids remains closed, the
well but it hinders checking for clarity.
storage temperature and shelf life are determined by the
Containers for injections are discussed in Sects. 24.2.1
rate of the degradation reaction. Most parenterals can be
(glass quality), 24.2.4 (rubber), 24.3 (closures), 24.4.14
stored at room temperature, exceptions are vaccines and
(ampoules) and 24.4.17 (syringes). Although glass is a pre-
protein medicines. Parenterals that are not sterilised in the
ferred material, care should be taken to avoid possible
final container are to be stored in the fridge or freezer with
incompatibilities. In particular, for instance, adsorption and
regard to maintaining their sterility. Storage temperature
aggregation of proteins touching glass surfaces, release of
and in-use stability after first opening of ampoules and
glass particles in solutions with pH > 7 and specific ions or
bottles are also determined by the chance of
both, release of aluminium from class I glass, etcetera. Class
microbiological contamination.
I glass is generally to be preferred but its suitability is not a
matter of course and has to be tested. Rubber closures need
attention as well because of release of rubber particles dur- The EMA Note for Guidance on Unpreserved Sterile
ing autoclaving, Products requires licensed parenteral medicines to be
Because of the high price, type II glass is to be consid- labelled as follows:
ered, and when tested might be found to be appropriate.
(continued)
13.5.15.2 Gels
Chemical and physical in use stability has been Biodegradable in situ gel forming implant systems secure
demonstrated for x hours/days at y C. From a prolonged activity. They are formulated by dissolving biode-
microbiological point of view, the product should be gradable polymers (such as poly (dl-lactide), lactide/glycolide
used immediately. If not used immediately, in-use copolymers, lactide/caprolactone copolymers) in a biocom-
storage times and conditions prior to use are the patible organic solvent (e.g. N-methyl-2-pyrrolidone (NMP)).
responsibility of the user and would normally not be Active substances are either dissolved or dispersed in the
longer than 24 h at 2–8 C, unless reconstitution/dilu- polylactic-co-glycolic acid (PLGA) solution. When the liquid
tion (etc.) has taken place in controlled and validated formulation is injected intramuscularly or subcutaneously, the
aseptic conditions. organic solvent diffuses into body fluid and water penetrates
into the solution. This leads to precipitation of the polymer
forming a solid polymeric implant at the injection site. The
The shelf life of reconstituted parenterals prepared in the
active substance is released over a prolonged period when the
hospital pharmacy is to be determined by the responsible
polymer is biodegraded [29].
pharmacist (see Sect. 22.6). When licensed injection fluids
are reconstituted and prepared for individual patients the
shelf life is determined by evaluation of the physico-chemical An advanced injectable gel product is Eligard®
stability and risk of microbiological contamination. Shelf containing leuprolide acetate and PLGA 75/25
life depends from a microbiological viewpoint on the risks dissolved in NMP in a 45:55 (w/w) ratio. The 1, 3
associated with aseptic preparation and the results of valida- and 4 months Eligard® formulations are supplied in
tion studies performed under the pharmacy’s specified asep- two separate syringes. One syringe contains the
tic preparation conditions (see Sect. 31.3.6). PLGA/NMP solution and the second syringe
In-use stability of preserved injection fluids in multiple leuprolide acetate. Prior to administration the content
dose vials is limited to a maximum of 28 days. Typical of two syringes is mixed until it is homogeneous.
examples are multidose vials of insulin preserved with
methyl hydroxyl benzoate and multidose vials of low molec-
ular heparin preserved with benzyl alcohol.
13.5.15.3 Implants
Implants are solid polymers loaded with an active substance.
13.5.14 Quality Requirements The active substance is delivered at a constant rate as long as
the implant stays at the administration site. Local or sys-
Parenteral solutions are to be tested for absence of visible and temic activity can be achieved. The duration of activity
non-visible particles and sterility as specified in the Ph. Eur. varies from days to years. Insertion and removal (if not
Furthermore, freedom from pyrogens or endotoxins and the biodegradable) requires medical assistance [30].
uniformity of dosage units and content are stipulated (see In order to achieve high local concentrations of
Sect. 32.8). Suspensions should be easily resuspendable to antibiotics in infected bone or joint, methyl methacrylate/
ensure precise dosing and uniformity of the dose during methyl acrylate copolymer (PMMA) bead chains or mini-
administration. Parenteral emulsions should be homogeneous. chains loaded with an antibiotic (mostly gentamicin sulfate)
are inserted.
13.5.15 Special Parenteral Preparations Gentamicin sulfate is heat resistant and highly soluble
in water. A bead chain consists of 10, 30 or 60 beads
In practice the pharmacist may dispense special injections. (diameter 7 mm) threaded on a flexible steel thread. A
This section briefly describes their formulation and mini-chain contains 10 or 20 oval mini beads threaded
biopharmaceutic characteristics, but not their way of prepa- over a length of 10 or 20 cm. The beads are sterilised
ration and quality requirements. with ethylene oxide. The chain should be removed
after a period of 7–10 days.
13.5.15.1 Suspensions Another typical implantable product is the horse
Parenteral suspensions are injected subcutaneously or intra- collagen sponge loaded with gentamicin. The implant
muscularly and are usually meant for an extended action is absorbable. High antibiotic concentrations are
[28]. Examples of parenteral suspensions licensed in Europe achieved at the site of implantation over several days.
are penicillin G procaine suspension and medroxypro-
gesterone acetate suspension.
13 Parenteral 279
13.5.15.4 Derivatives infusion solutions. Metabolic alkalosis is treated with

Protein and peptide pegylation (conjugation to polymers of hydrochloric acid containing infusion solutions.
long-chain macrogol – or polyethylene glycol) improves the Sodium chloride 0.9 % solution and 5 % glucose
biopharmaceutical properties of active substances. The solutions are most suitable to be used as vehicle solutions
improvement encompasses increased stability, resistance to for parenterally administered injections or infusions.
proteolytic inactivation and extension of the half-lives. By Blood volume expanders can be crystalloid or colloidal.
this the delivery and efficacy of proteins is improved [31]. The most often used crystalloid solutions are 0.9 % sodium
chloride solution, 5 % glucose solutions and their
combinations, e.g. 0.45 % sodium chloride/2.5 % glucose
The application of filgrastim pegylation technology
solution. In addition infusion solutions containing multiple
resulted in a second generation molecule named
electrolytes such as Ringer’s solution or Lactated Ringer’s
pegfilgrastim, with significantly altered pharmacoki-
are administered. These solutions contain also potassium,
netic properties in comparison to filgrastim.
magnesium, calcium, and phosphate [34].
Pegfilgrastim has the same mechanism of action as
Blood volume expanders used to compensate loss of
filgrastrim but the pegylation markedly reduces renal
plasma are formulated as electrolyte solutions with macro-
clearance, leaving neutrophil-mediated clearance as
PRODUCT DESIGN
molecular substances such as gelatine, polygeline,
the major route of elimination. As a result, clearance
hydroxyethyl starch (HES), and albumin. Hydroxyethyl
of pegfilgrastim is decreased and serum concentrations
starch is similar to albumin but cheaper. However there are
are sustained throughout the duration of neutropenia.
restrictions in its use. European Medicine Agency (EMA)
In clinical studies with standard, multicycle chemo-
has decided that HES solutions should not be used in criti-
therapy, a single subcutaneous dose of pegfilgrastim
cally ill adult patients, including patients with sepsis or burn
has been shown to have similar efficacy and safety as
injuries and excess bleeding particularly in patients
daily subcutaneous injections doses of filgrastim in
undergoing open heart surgery in association with cardiopul-
patients with solid tumours [32].
monary bypass, because an increased risk of mortality and
Further examples of pegylated protein active
renal injury requiring renal replacement therapy [35].
substances are peginterferon and pegvisomant.
Osmotic diuretics are rapidly filtered in the glomerulus
and not reabsorbed in the tubules. As a result of the osmotic
Polysialylation (the process whereby PSA-polysialic acid gradients thereby achieved in the renal tubules, the reabsorp-
is conjugated with proteins) is an alternative to pegylation tion of water is inhibited, and urine excretion increased (see
limiting potential toxic accumulation and immunogenic also Sect. 13.6.3).
potential of macrogol [33]. Parenteral nutrition solutions are discussed separately in
Sect. 13.9.
13.6 Product Formulation of Infusions

13.6.2 Buffer Capacity
Many formulation characteristics and quality requirements
for infusions are the same as for injections. Large volume infusions should have a physiological pH,
e.g. pH 7.4 and little or no buffer capacity. In general
infusions with pH 5–9 are tolerated by peripheral veins.
13.6.1 Types of Infusions The pH values of commonly used infusion solutions vary
between 4 and 8 depending on the type of formulation.
Infusions are sterile solutions or emulsions that are A lower pH is acceptable if solutions are not buffered.
administered intravenously, subcutaneously or intrathe- The pH of 5 % glucose solutions amounts from 4.0 to 5.0.
cally/epidurally. Infusions are used as: This is necessary to prevent degradation of glucose (see
• Solutions regulating the acid–base balance Sect. 13.6.4). Infusion fluids that are used to correct the pH
• Vehicle solutions for continuous infusion of the blood have a deviant pH value (e.g. pH 8.0 for sodium
• Blood volume expanders hydrogen carbonate infusion).
• Osmotic diuretics
• Partial and total parenteral nutrition
Shifts of the physiological pH may require administration 13.6.3 Osmolarity
of acid or base containing infusions. Metabolic acidosis is
treated by infusion of sodium bicarbonate containing See Sect. 18.5 about osmosis and tonicity.
Infusion solutions have to be isotonic with blood because per mL or L. This differs from country to country and even
of the large volume administered. Typically used isotonic within countries hospitals might have different policies
infusion solutions are 0.9 % NaCl solution and 5 % glucose depending the preference of the prescribers. This may lead
solution. to confusion about the type of unit. The material and adhe-
Hyperosmotic mannitol 20 % infusion is used as osmotic sive of the labels are discussed in Sect. 24.2.6.
diuretic. Hypotonic solutions such as 0.65 % sodium chlo-
ride are used in elderly patients to keep the salt load low, or
in children to prevent dehydration. 13.6.6 Quality Requirements
Infusion fluids for neonates are often hyperosmotic, hav-
ing no choice since only small volumes can be administered. According to the Ph. Eur. parenteral preparations should be
According to some recommendations [36] if osmolarity sterile, free from visible and non-visible particles and free
of the infusion is higher than 500 mOsmol/l, administration from endotoxins/pyrogens (see Sect. 12.8).
should occur via a central venous catheter that is inserted in a
vessel with high blood flow such as the vena subclavia,
proximal axillary vein or superior vena cava.
The preparation of parenteral solutions encompasses the

13.6.4 Stability following steps:
• Starting material and equipment (provision and quality
In addition to what has been said about the stability of control of active substances, excipients and packaging
injections (Sect. 13.5.12) some specific comments can be material according to specifications, cleaning and disin-
given regarding infusions. In practice most concern is about fection or sterilisation of equipment and primary packag-
the chemical and physical (precipitation!) stability of active ing material e.g. vials, elastomeric closures)
substances when mixing injections with the infusion vehicle. • Preparation of the bulk solution
As a consequence of incompatibilities some active • Control of bioburden
substances are only compatible with 0.9 % NaCl vehicle • Purging with inert gas
(e.g. furosemide-Na injection concentrate) and others are • Filling and closing
only compatible with 5 % glucose solution. As the mixtures • Sterilisation (in final containers)
often have to be kept after mixing also the chemical stability • Visual inspection
is an issue as well as minimising the chance of micro- • Labelling
biological contamination by proper aseptic handling and
administration.
Regarding the stability of infusion vehicles only glucose 13.7.1 Starting Material and Equipment
5 % has to be mentioned. Glucose 5 % infusion solutions
should have a pH lower than 5.5 before sterilisation. Higher Pyrogen-free starting materials, packaging materials and
pH values cause yellow or brown discolouration and formation equipment is to be used. Water (see Sect. 23.3.1) and packag-
of cytotoxic degradation products such as 3-desoxyglucosone, ing material bear the highest chance for endotoxin contamina-
3,4-dideoxyglucosone-3-ene, formic acid, 5-hydroxymethyl- tion. A typical procedure for depyrogenation of glassware and
2-furfural, acetaldehyde [37]. equipment is by dry heating at 250 C during 30 min. Adsorp-
tion on adsorptive agents is also an option, however difficult to
perform and not too reliable that it can be used for the removal
13.6.5 Container and Labelling pyrogens from the solution. Selective adsorption of the chem-
ical substances from solution to the filter may occur.
Infusion fluids are usually packaged in glass bottles or plas- Water must meet the standards for Water for injections
tic containers (see Sects. 24.4.5 and 24.4.13). The adsorption (Ph.Eur.) (see Sect. 20.3.1). The water should be prepared
of lipophilic substances to plastic infusion bags requires freshly or kept at a high temperature (80 C) to remain
attention. sterile and pyrogen free.
For the labelling of injections and infusion see Sect. Microbiological contamination of the starting material
37.3.2. For infusions the concentration and the total volume should be minimal to make sterilisation as effective as pos-
would be enough. Electrolytes might be labelled as sible. Premises for preparation of parenteral products are
milliequivalents or millimoles or as milligrams or grams classified as described in Sect. 27.4.1.
13 Parenteral 281
13.7.2 Preparation of the Bulk Solution process should be validated to ensure adequate displacement
of air by the gas in each container. Research data [40], using
The active substance and the excipients are dissolved in an nitrogen, showed that the best results are obtained by the
adequate volume of water for injections in glass or stainless following inert-gas purging method:
steel vessels and stirred to obtain a homogeneous solution. • Before and during the preparation purge nitrogen through
To prevent particle contamination, starting materials with a water for injection.
low particulate burden should be used and materials liable to • Purge nitrogen through an air dispersion device from the
generate fibres should be kept to a minimum in clean areas. bottom of the vessel.
Particles that come from the starting materials or the prepa- • Keep the contact surface between the solution and the air
ration environment can be removed by filtration (see Sect. above the surface as small as possible, preferably by not
30.6). Good preparation practice (clean rooms, clothing, using cylindrical but conical vessels.
cleaning, etc.) is to be followed to minimise particle and • Keep the preparation vessel closed as much as possible.
microbiological contamination during all processing stages • Seal the container immediately after filling.
(see Sect. 27.4.4 and Chap. 31). However, validation possibilities of specific preparations are
limited because it is still impossible to measure the oxygen
PRODUCT DESIGN
concentration in the solution in ampoules for instance.
13.7.3 Control of Bioburden Once the need for inert-gas purging has been established,
various strategies to reduce the loss of inert gas during shelf
Components of parenteral solutions (active substances, life should be evaluated. These approaches include selecting
excipients, intermediates and packaging material) should the proper closure (type and size) and optimizing vial head-
be routinely tested for bioburden and bacterial endotoxin space. Oxygen concentration in the headspace of the vials is
level to ensure they are not adding an excessive microbial monitored during the filling process and storage of the prod-
load. Bioburden is usually determined on the unfiltered bulk uct by electrochemical methods, gas chromatography or
solution. Testing of filtered bulk parenteral solution either Frequency Modulation Spectroscopy (FMS). With FMS
before or after filling into the final container may be done by it is possible to measure headspace oxygen concentrations
comparison to the previously tested unfiltered bulk solution. in sealed containers in a rapid and non-destructive
Initial bioburden and endotoxin monitoring should be manner [41].
conducted to establish appropriately designed and sized
terminal sterilisation methods such as filtration/aseptic fill-
ing or terminal heat treatment (see Sects. 30.5 and 30.6). 13.7.5 Filling and Closing
Bioburden is also used as a parameter to evaluate process
control. The Ph.Eur. states that each container should be filled with a
In industrial production quantitative analysis of the sufficient overfill to ensure withdrawal of the declared vol-
microbiological burden of the product is carried out ume. The required overfill is not described in Ph. Eur.
before and after every micro-organism reducing step. Table 13.3 presents the recommended fill volumes permitted
Rapid microbiological methods (RMM), such as by USP to allow withdrawal and administration of the
ATP-bioluminescence are capable of producing results in declared volumes [42].
real time, since traditional culture-based microbiological Filled containers should be sealed as soon as possible, to
analysis techniques take at least several days to get a result prevent the contents from being contaminated. Container
[38, 39], see also Sect. 19.6.5 closure integrity may be evaluated by different methods:
dye penetration pressure/vacuum decay, electrical conduc-
tivity and laser-based headspace detection [43], see also
13.7.4 Purging with Inert Gas Sect. 24.3.1 for small scale methods. Validation studies of
the “old fashioned” dye penetration method showed lack of
Solutions containing active substances which are degraded sensitivity and reliability [44].
by oxidation are preferably protected by introducing inert It is also possible to identify ampoules which are not
gas during and after filling. Helium, argon, carbon dioxide closed tightly by applying a vacuum during the sterilisation
and nitrogen are the most commonly used gases for purging. program. Ampoules, which are not completely closed, will
Efficacy of purging depends on the purging method, gas be empty afterwards.
pressure, the shape and volume of the container. This
Table 13.3 Recommended excess with filling injection fluids [after Each final container should be checked for visible defects
42] (cracks, presence of visible particles, etc.). Products in
Recommended excess volume which particles are detected should be discarded.
Labelled volume For mobile fluids For viscous fluids The container must be transparent to permit inspection of
(mL) (mL) (mL) the content. If this is not the case (opaque container) an
0.5 0.10 0.12 alternative particle counting method has to be applied (see
1.0 0.10 0.15
Sect. 32.12).
2.0 0.15 0.25
Inspection of the parenteral preparations may be done by
5.0 0.30 0.50
operators or semi-automated and automated.
10.0 0.50 0.70
A number of factors affect the accuracy and reliabil-
20.0 0.60 0.90
30.0 0.80 1.20
ity of the visual inspection by operators, so individual
50.0 or more 2% 3%
performance is the determinant. Inspection is best
performed under recommended light conditions
(250–375 foot-candles (Fc)) and against a black and
13.7.6 Sterilisation white background. Recent studies showed that a single
18 % grey backdrop may be as effective as the black/
Products should always be sterilised as soon as possible after white backdrop and has the advantage of reducing
filling and closing. Important factors in determining the inspection dwell [46].
suitable sterilisation method are the type and the stability The operator gently swirls or inverts each individual
of the product. When stability of the formulation and container, making sure that no air bubbles are introduced
containers allows autoclaving (15 min at 121 C), this is and observes for about 5 s in front of the white and dark
the preferred method. It is rapid and inexpensive. However, panel. Particles present in the product are seen as
stability of many pharmaceutical products will be affected illuminated dots.
by elevated temperatures. Heat-labile products can only be Semi-automated systems provide container handling
sterilised by a non-thermal method usually by filtration for the operator, but the inspection process is still a
through bacteria-remaining filters or, with defined manual inspection. The advantage of the semi-automated
circumstances, with a method using less heat in combination systems is that the lighting and container rotation reduce
with other measures. The starting materials and the equip- inspection time and a group of several containers is
ment should be sterilised before preparation and the product constantly being passed in front of the inspector. The
should be prepared under aseptic conditions. For further time interval must be long enough to guarantee reliable
details see Chaps. 30 and 31. inspection but short enough not to tire the eye of the
operator.
Automated inspection is performed by light transmission
Adapting the formulation may allow the application of
and camera-based systems. This process decreases human
a more reliable sterilisation method. An example is
contact with the packaging component. Compared with
talc powder used in pleurodesis. The easiest and
manual inspection, an automated vial inspection process is
cheapest sterilisation method for talc powder is
more consistent and can be more cost-effective over a longer
prolonged dry heat exposure. But this sterilisation
time period of use.
method is more difficult to validate than autoclaving.
Instead of pure talc powder, a talc suspension in 0.9 %
NaCl solution was prepared and autoclaved [45].
Visual inspection is a process that requires high con-
centration of the inspector. In hospital pharmacies the
inspection period is limited, e.g. to 30 min followed by
a minimum 15 min break between two periods. Inspec-
13.7.7 Visual Inspection tion personnel should be appropriately trained and
have their competency assessed. Candidates are
Parenteral solutions should be free from visible particles and given a set of characterised containers bearing con-
may only contain a limited amount of particles that are not tainer closure defects and particulate matter and must
detectable by visual inspection (see Sects. 13.5.12 be able to identify the contaminated products.
and 13.6.6).
13 Parenteral 283
13.7.8 Labelling Administer medicines (RTAs). Reconstitution of parenterals

is not always described in the Summary of Product
Labelling is the last step of the production process (see Sect. Characteristics (SmPC) and Package Information Leaflet
37.3). The labelling process should be preferably performed (PIL). If so this process may be called ‘reconstitution in
in the preparation area, where no additional unlabelled excess of the SmPC’ (see Fig. 1.2). If this is considered to
products are present. Identity of the labels should be checked be a variance from the SPmC, it results legally in off-label
and reconciliation performed: number of applied labels use and should be supported by evidence, e.g. an appropriate
should to be equal to the number of produced containers. risk assessment including the benefits and evidence about
Labelling and final packaging operations in the hospital compatibility and a possible longer shelf life (see Sect. 22.6).
pharmacies is becoming increasingly automated. Preparing RTAs is usually aimed at reduction of the risk
on faulty composition and microbiological contamination
during handling of parenteral medicines on the wards, see
13.7.9 In-process Controls also Sect. 21.5.3. This is usually achieved by pre-filling of
syringes, pre-diluting injections or mixing injections with
The following in-process controls are recommended as a infusion solutions. The concept of standard concentrations in
PRODUCT DESIGN
minimum: pre-filled syringes supplied by the central pharmacy to the
• Visual inspection of the solution after each process step wards (for instance the intensive care department) is now the
• Filling volume practice in several European countries. Patient specific dos-
• Integrity of the filter device by a bubble point test or ing can subsequently be achieved by adapting the rate of
forward-flow-test (see Sect. 30.6.5) infusion.
• pH of aqueous solutions
• Time, temperature and pressure during the sterilisation
process 13.8.2 Product Formulation
• Container-closure integrity test
• Yield The formulation of a RTA product should be based on
In-process controls may be performed in regular intervals currently available information on active substance stability
during a process step or at the end of a process step. The and compatibility (see Sect. 22.6). Definition of specific
objectives of in-process controls are both quality control and characteristics is relevant for the design and description of
process control. a RTA product. In several European countries this informa-
tion is included a locally, regionally or nationally
standardised document: Parenteral Manual
13.7.10 Release Control
13.8.2.1 The Definition of a RTA Product
Finished products are the subject of release controls. As a The definition of a RTA product may contain the listed items
minimum: and follow the examples given:
• The correctness of container type and labelling used. • Amount of the active substance
• Each vial is checked for visible particles. The finished • Primary packaging
product is also controlled on particulate matter (see • Administration route
Sect. 32.12). • Administration method
• Sterility: samples withdrawn are tested for sterility and The combination of the active substance, the amount and
freedom from endotoxins (see Sect. 19.6.1). the packaging determines the composition. The combination
• Assay of identity, purity, content and withdrawable vol- of the administration route and administration method
ume (see Chap. 32). describes the administration of the product. Sometimes com-
parable licensed medicines differ to such an extent that apart
from the generic name also the brand name has to be part of
13.8 Reconstitution the definition (see examples).
Several examples of RTA products are presented, derived
13.8.1 Definition and modified from a Dutch Parenteral Manual:
Most parenteral medicines need at least a minimal manipu- Example 1: Adalimumab Adalimumab is only available as
lation e.g. withdrawing the product from a vial or an Humira® 40 mg/0.8 mL solution for injection in a single-use
ampoule in a syringe) in order to be administered. This pre-filled syringe. So for the description of the corresponding
process is called reconstitution and it leads to Ready To ready to administer product only the route of injection has to
be added, which results in: Adalimumab 40 mg in pre-filled When diluting a parenteral product the presence of
syringe administered by subcutaneous injection. co-solvents, antioxidants, the pH, the solubility, etc. has to
be taken into account:
Example 2: Parecoxib Parecoxib, can be administered in • Dilution of a partly or complete non-aqueous injection
three ways: vehicle with water or sodium chloride solution may
• Intramuscularly decrease solubility causing the active substance to precip-
• Intravenously as a bolus itate (see Sect. 18.1.3).
• Intravenously as an infusion • Precipitation of active substances can occur due to pH
The commercially available product Dynastat® powder change upon diluting (see Sect. 18.1.2): dilution of furo-
for solution for injection 20 mg and 40 mg must be semide injection solution (pH of 8.0–9.3) with 5 % glu-
reconstituted before use. The following ready to administer cose (pH of 4.3–4.5) lowers its pH and therefore
parecoxib preparations are possible: decreases its solubility resulting in precipitation.
• Parecoxib sodium in a syringe administered • Diluting a solution containing an antioxidant may lead to
intramusculary or intravenously as a bolus an amount of antioxidant being insufficient for taking
• Parecoxib sodium, reconstituted with the solvent away all the oxygen dissolved in the diluting solution,
indicated in the SmPC, diluted in an infusion bag/bottle and may lead thus to oxidation of the active substance in
100 mL, administered intravenously the reconstituted product.
• Suspension or emulsion can only be diluted according to
Example 3: Amphotericin B Various amphotericin B the package leaflet otherwise the physico-chemical sta-
formulations have been developed and commercialised: bility may be endangered (e.g. breaking of the lipid
Fungizone®, Ambisome®, Abelcet® and Amphocil®. emulsion).
These differ by the physico-chemical principle that has
been used to create a colloidal systems (see Sect. 18.4.1). 13.8.2.3 pH and Osmotic Value
As a result they differ in their serum pharmacokinetics as Registration authorities invite the manufacturer to include
well as their tissue localisation, tissue retention and toxicity. pH and osmotic value of the product in the packaging leaflet.
These products should not be substituted by each other and The pH and the osmotic value of the undiluted as well as the
therefore the brand name has to be part of the definition. ready to administer product are important in order to esti-
The following RTA product descriptions of amphotericin mate the chance of phlebitis. The information about pH is
B may be necessary: also useful for investigating the possibility of mixing
• Fungizone®: Amphotericin B colloidal dispersion reconstituted products.
10–50 mg in an infusion bag/bottle 500 mL
• Ambisome®:Amphotericin B liposomal 40–120 mg in an 13.8.2.4 Packaging
infusion bag/bottle 100 mL Ready to administer products may be packaged in the fol-
• Abelcet® Amphotericin B lipid complex 120–500 mg in lowing primary containers:
an infusion bag/bottle 500 mL • Injection syringe (see Sect. 24.4.17) closed with a cap
• Amphocil®:Amphotericin B colloidal dispersion when the product is not administered immediately
40–400 mg in an infusion bag/bottle X mL • Infusion bag or bottle (see Sects. 24.4.5 and 24.4.13)
• Vial
• Portable infusion system
13.8.2.2 Solvent and Diluting Batch wise reconstitution of ready to administer parenteral
Many parenteral medicines, particularly protein derivatives, are products and keeping them in stock is only possible if com-
available as dry powder in order to achieve long term stability. patibility of active substance with packaging system and the
This powder has to be dissolved and diluted prior to use. stability are known.
Solvents for reconstitution or for diluting sterile concentrated
solution include sterile water for injection and various sterile 13.8.2.5 Storage and Shelf Life
aqueous solutions of electrolytes or glucose or both. Shelf life is particularly important when the reconstituted
To prevent aggregation of therapeutic proteins, the nature product is not used immediately. For obtaining and
of the solutions used for reconstitution and for diluting them interpreting chemical and physico-chemical data on shelf
must be carefully chosen; 5 % glucose solutions are not life, stability and incompatibilities of reconstituted
indicated. Sodium chloride solution has a limited use due medicines see Sect. 22.6.3.
to incompatibility with several active substances. For exam- Reconstituted parenteral medicines often have a short
ple, amphotericin B injection fluids cannot be diluted with shelf life and have to be administered immediately. The
sodium chloride and other electrolyte solutions because of shelf life of some sensitive infusion solutions can be
the destabilisation of the colloidal systems. prolonged when they are stored under cool conditions and
13 Parenteral 285
protected from light. If appropriate light protection during Section 13.8.2.2 describes the (im)possibility of diluting
administration should be obtained by wrapping it up in the active substance with solvent as an (in)compatibility. It is
aluminium foil or using opaque syringes. important to be vigilant for incompatibilities associated with
Shelf life may be shortened due to reaching body temper- multiple infusions co-administered to a patient. Mixing paren-
ature if the infusion bags are carried on the body of the teral solutions of active substances occurs in the infusion bag
patient. or syringe, but also at an Y-site junction (see Sect. 13.10.4)
Preferable storage is at room temperature. But storage where two or more intravenous lines meet. The mixture
in the fridge or freezer may be possible and may lengthen should be inspected visually for precipitation, turbidity or
the shelf life. If the reconstituted products are stored in colour change, but the absence of any visible change to a
the fridge or in the freezer, they should be brought to solution upon mixing does not automatically exclude degra-
room temperature prior to administration. Otherwise infu- dation or precipitation of either or both components.
sion can disturb the blood- and body temperature of the Numerous references are available for data on parenteral
patients [47]. incompatibilities. Only current edition of these references
Further disadvantages of storing in the freezer are: should be used, therefore databases are to be preferred, such
• Unknown stability of the product (pH shift, precipitation) as Stabilis® (see Sect. 39.2.6). Pharmacists could also create
PRODUCT DESIGN
or primary package. their own compatibility charts resulting from literature data,
• While freezing, the contents expand in the administration experience and own testing.
system; therefore the administration system should not be
filled to the maximal capacity.
• Defrosting takes a long time at room temperature; induc- 13.8.3 Method of Preparation
ing it by heating in the microwave is not useful due to the
fact of local overheating. Reconstitution of parenterals is commonly performed on hos-
As to the shelf life from a microbiological viewpoint refer- pital wards by physicians or nurses. The risk of erroneous
ence is made to chapter Aseptic handling (Sect. 31.3.6). preparation and microbiological contamination during
A system is given for determination of microbiological handling, can be reduced if the hospital pharmacy performs
shelf life in relation to the risk of microbiological contami- reconstitution under specific precautions (see also Sect. 31.3
nation at aseptic handling. Aseptic handling). These reconstituted medicines are supplied
to the wards either labelled for individual patients or as a batch
as ward stock. Common products that are reconstituted in the
13.8.2.6 Compatibilities and Incompatibilities
pharmacy instead of on the wards (see also Sect. 31.3.2):
Mixing parenteral solutions of active substances or diluting a
• Antineoplastics (high-risk medication as well as protec-
concentrate with certain solvents can lead to incompatibility
tion of the personnel from the product)
and consequent precipitation and loss of activity of one or
• Parenteral nutrition (a microbiologically vulnerable prod-
both active substances. There may be reasons for mixing two
uct to be protected from personnel, needing several com-
or more parenteral solutions in the same infusion bag or in
plex process steps)
the same syringe:
• Blinded clinical trial medication
• Difficulties with venous access limiting the number of
• Some emergency medication (to be placed as a depot on
intravenous lines available for continuous administration
the ward)
of multiple medicines.
Some European countries have developed national guidelines
• Patient has restrictions to the volume that can be paren-
for the preparation of ready to administer products in hospital
terally administered.
pharmacy (German Society of Hospital Pharmacists: Guide-
• Therapeutic necessity of combining active substances.
line for the aseptic preparation of ready to use-/administer
• Multiple active substances are required by parenteral
parenterals) or at the hospital ward (Dutch Society of Hospital
administration within a short time frame.
Pharmacist: Guideline for the preparation prior to use on the
ward) [49, 50]. For further information on aseptic handling
During palliative care, patients at home require many see Chap. 31.
active substances that are delivered from the same The reconstitution of ready to administer products on the
syringe in a syringe driver over 24 h. This method is ward includes the following steps:
only possible when the patient is stabilised; otherwise • Selection of the starting material and utensils according
the ability to control the dose is lost. Regional to standard procedures
guidelines and protocols are also developed for con- • Preparation of the label for administration of the product
tinuous subcutaneous home infusion [48]. • Reconstitution of the product
• Quality control (see Sect. 13.8.4)
Basic steps of reconstitution may be: dissolving, volume for the disinfection of the surface, the rubber of the
measuring and mixing. They are conducted under a certain injection bottles, neck of the glass ampoules, and injec-
level of aseptic conditions. In order to obtain an accurate tion point of infusion bag.
content the following instructions are given: • Reconstitution of the product following the SmPC or
• Infusion bags are quite flexible and allow fairly large preparation according to local guidance.
volumes to be added without difficulty (maximal 30 % • Labelling the product with the administration label
of the volume); when a larger volume than the maximum immediately after preparation.
has to be added, a larger infusion bag should be chosen. • Use of a waste container for the needles.
• The smallest possible syringe should be used in which the
dosage will fit, because the smaller the syringe, the more
accurately the volume can be measured; syringes should 13.8.4 Control and Quality Requirements
be filled to a maximum of 75 % of the nominal volume.
• For accuracy of small volume solutions (less than 5 ml), 13.8.4.1 Control
small-sized syringes should be used and then the solution The following passage describes how the control on a ward
should be transferred into a larger syringe with help of the of a healthcare establishment can be done. A second person
diluent. checks whether the preparation has been done following the
• After reconstitution of a lyophilised powder, a new agreed method on the workplace:
syringe and needle should be used to withdraw the correct
volume of the reconstituted solution into the syringe, Materials:
because of the dead volume of solvent used for • Right medication order
reconstitution. • Right medicine (by means of empty ampoules or bottles)
• Right strength (by means of empty ampoules or bottles)
• Shelf life/expiry date
As an example this reconstitution in excess of the • Right calculation
SmPC may be given: • Right solvents if applicable
• Right amount of diluting fluid if applicable
To be prepared: Dobutamine HCl 250 mg in injection • Right method of preparation
syringe 50 mL
Licenced Dobutamin HCl 250 mg powder in
pharmaceutical infusion bottle. Reconstituted medicine:
product: • Right administration label
Instruction for Add 10 mL sterile water for injection to • Appearance: check on discolouration/turbidity/
preparation: the bottle; gently rotate the bottle until
crystallisation
the solution is clear (concentration of
25 mg/mL). • Storage: room temperature or 2–8 C, under light-
Fill a 50 mL perfusor syringe with protecting conditions (if necessary)
40 mL 0.9 % NaCl solution and When injection solutions are prepared by the pharmacy
withdraw the air to the volume of 55 mL.
further checks are implemented. The used preparation record
Use a small-size syringe to withdraw
10 mL solution from the bottle and add as well as the batch number and the labelling are also
the solution via a connector to the controlled by a second person.
diluting solution.
Mix and expel excess air from the
syringe.
13.9 Parenteral Nutrition
When the reconstitution takes place on the hospital wards 13.9.1 Orientation
recommendations for safe handling include:
• Area in which the product is to be prepared should be Parenteral nutrition formulations provide nutritive support
clean, tidy and quiet (use of laminar airflow workbench for patients who are not able, not allowed or not willing to
when possible) eat for a critical period of time. Indications for parenteral
• Cleaning the hands according to local policy. nutrition include pre- and postoperative periods of major
• Wearing clean working clothes that must be replaced surgery or trauma, severe obstruction of the gut (e.g. by
once daily and disposable protective gloves. tumours), severe motility disorders (e.g. ileus), severely
• Use a 70 % V/V alcohol (see Sect. 26.7.2 about the occu- impaired absorption capacity (e.g. short bowel syndrome,
pational safety and health aspects) or other disinfectant mucositis in stem cell transplantation patients). Parenteral
13 Parenteral 287
nutrition can be used supplemental to enteral nutrition (given chambers are mixed just prior to infusion, by breaking the
by oral route or feeding tubes) or exclusively. The latter type separation seals between the bag chambers. Vitamins and
of nutritional support is called total parenteral nutrition trace elements are added to the infusion bag prior to the
(TPN). The intravenous route should only be used when administration or administered as a separate infusion solu-
oral, (naso)gastric or intestinal routes are not readily avail- tion. AIO admixtures reduce manipulations, save materials
able and for a period as short as possible. Enteral nutrition is and personnel workload. They require only one intravenous
advantageous because it provides the uptake of the nutritive line and the risk of infection is lowered by reduced manipu-
substances in a physiological manner and promotes the lation. AIO mixtures offer a convenient system for patients,
integrity of the gastrointestinal mucosa. Standard enteral clinicians and nursing staff. Table 13.4 shows an example of
preparations have been modified by the addition of a standard adult parenteral nutrition admixture. The pH of
immunonutrients, such as arginine, glutamine, omega-3 such an admixture is 5.0–5.6 and the osmolarity comes to
fatty acids, nucleotides and others. These components 1,000–1,200 mOsmol/L.
should stimulate the immune system, control inflammatory The calculation of the energy, substrate and volume needs
responses and improve the nitrogen balance and protein in parenteral nutrition is given in textbooks and guidelines
synthesis after injury [51]. [52]. The needs depend on the patient’s disease and
PRODUCT DESIGN
nutritional status. The first step is the specification and
calculation of the necessary amounts of fluid, glucose, and
13.9.2 Product Formulation amino acids (macro-nutrients). The second step includes the
calculation of the electrolytes. Vitamins and trace elements
13.9.2.1 Components are commonly added in standard amounts according to pro-
Components used in parenteral nutrition formulations fessional guidelines.
include amino acids, carbohydrates, and lipids, as well as Standard AIO admixtures are used in most adults
electrolytes, vitamins and trace elements. The amounts of patients. However, the patients’ requirements regarding
the components are to be calculated according to the needs calories and electrolytes may vary. Dialysis patients
of the individual patient with regard to the caloric require restricted administration of electrolytes, however
requirements, metabolic status, fluid and electrolyte balance, patients with severe diarrhoea need a higher amount of
acid–base status, and other specific goals of parenteral nutri- electrolytes. Standard parenteral nutrition admixtures cannot
tion. The components are dissolved in either water or a lipid be used in severely ill paediatric patients, neonates and
phase. Both phases have to be combined in the right ratios premature newborns. These patients need individualised
into an emulsion. The compatibility and stability of all admixtures. In premature infants and newborns the all-in-
components and the physical stability of the resulting emul- two system is preferred [53]. The lipid emulsion is mixed
sion is to be taken into account. The design of parenteral with the vitamin combination in a separate container and
nutrition mixtures therefore requires a high level of formu- either administered with the amino acid/glucose/electrolyte
lation knowledge. Individualisation of the nutrient products admixture in parallel (Y-site) or via a separate venous
may be limited by these formulation constraints. access.
Parenteral nutrition is administered by different
approaches:
• ‘All-in-one’ admixture – all components are admixed in a
Table 13.4 Example of Standard Adult Parenteral Nutrition
single container and administered simultaneously Admixture
through an intravenous line
Fat (soja oil or olive oil) 100 g
• ‘All-in-two’ system – combination of two containers, Glucose 250 g
where the lipid emulsion is provided in a separate L-amino acids (mixture of essential and 90 g
container non-essential)
• ‘All-in-three’ system (or multi-bottle system, modular Sodium 80 mmol
system) – combination of three containers, where the Potassium 60 mmol
carbohydrate solution, amino acid solution, and lipid Calcium 5 mmol
emulsion is provided in a separate container each Magnesium 10 mmol
‘All-in-one’ (AIO) admixtures can be industrially Phosphorus 25 mmol
manufactured standard AIOs or individually compounded Trace elements (Cr, Cu, F, Fe, I, Mo, Mn, Se, Zn)
AIO admixtures. The commercially available standard AIO Water-soluble vitamins (vit. B1, B2, B3, B5, B6, B11, B12, C)
is provided in three-chamber infusion bags which contain Fat-Soluble vitamins (vit.A, D2, E, K1)
the amino acids, carbohydrates, lipids, and electrolytes in Excipients
Water for injection ad 2,000–2,500 mL
three separate compartments. The contents of the three
The fluid, energy, and substrate requirements and the com- Admixture of calcium and phosphate ions in the same
position of the admixtures is stated in different guidelines nutrition solution may lead to precipitation of calcium phos-
[52]. Fusch et al. presented a standardised questionnaire, phate. These precipitates are hardly detectable in the nutri-
which takes into account partial parenteral nutrition and tion admixtures by visible inspection and are not detectable
enteral nutrition and should be used for prescribing parenteral in lipid containing AIO admixtures.
nutrition to neonates [53, 54]. Examples for the composition of The solubility of calcium phosphate depends on the type
a neonatal AIO admixture can be found in the literature [53]. of amino acid product used, the type of calcium and phos-
phate salts used, temperature, magnesium concentration,
13.9.2.2 pH and the final volume of the admixture. The pH of the
The pH of different amino acid infusion solutions parenteral nutrition admixture influences the equilibrium
manufactured by different companies varies from between the trivalent phosphate ion and its monobasic
pH 5.0–7.4. Glucose infusion solutions have a pH 4–5. (H2PO4) and dibasic (HPO42) forms. The aqueous solu-
When mixed, amino-acids will function as buffers and pre- bility of the monobasic and dibasic calcium phosphate
vent the decline of pH below 5. In an all-in-one-mixture the amounts to 18 g/L and 0.3 g/L, respectively. At the physio-
amino acids also prevent the enlargement and merging of the logical pH of 7.4 about 60 % of the phosphate exists in the
lipid globules. Paediatric amino acid solutions are more poorly soluble dibasic form. If the pH of the nutrition admix-
acidic than those used in adults and cause a lower pH of ture is lower than pH 6.4, the monobasic form is the predomi-
the combined admixtures. nant one and the chance of precipitation is diminished (see
Sect. 18.1.1).
13.9.2.3 Osmotic Value and Fluid Supplement
Parenteral nutrition admixtures are hypertonic. Glucose, FDA Safety Alert: “Hazards of Precipitation
amino acids and electrolytes induce a hyperosmolar Associated With Parenteral Nutrition” The Food and
(1,300–1,800 mOsm/L) infusion solution. Drug Administration warned against the risk of
Fluid supplementation has to be considered carefully precipitations in parenteral nutrition mixtures in 1994
because the relative body water-content is age-related and [55]. This warning occurred after two deaths and at
highest in premature infants. The amount of water provided least two patients with dyspnoea after infusion of all-
by the nutrition solution and the water used for the dissolu- in-one nutrition admixtures. The FDA suspected that
tion of medicines should not exceed the total need for water. these admixtures contained calcium phosphate
Thereby, often highly concentrated nutrition admixtures precipitates.
with low final volume are to be administered.
Temperature has a large influence on the calcium phos-
13.9.2.4 Compatibility phate solubility. Increased temperature shifts the phosphate
Monovalent cations do not cause physical incompatibility equilibrium from the monobasic to the dibasic form thereby
of parenteral nutrition admixtures, unless they are present in raising the chance of precipitation. Elevated temperatures
high concentrations. The positive charged divalent ions (Ca2+, also increase the dissociation of calcium gluconate thereby
Mg2+) and even more crucial trivalent ions (Fe 3+) neutralise generating free calcium ions that precipitate with the
the zeta potential (see Sect. 18.4.1) of the lipid droplets and can phosphate ions.
cause aggregation, coalescence and phase separation. In order to avoid high phosphate concentrations, organic
phosphates, such as sodium glycerophosphate solutions,
The Critical Aggregation Number (CAN) corresponds should be utilised in the formulation of nutrition solutions.
to the cationic concentrations at which lipid particles The phosphate moiety is covalently bound and rarely
aggregate. The result amounts to the cations expressed hydrolysed.
as monovalent cations and should not exceed If trace elements are added to the lipid-containing nutri-
600 mmol/L. tion admixtures they can cause disintegration of the emul-
CAN is calculated by the following equation: sion even in low concentrations, they catalyse chemical
decomposition (e.g. of vitamins) and increase (lipid) peroxi-
CAN ðmmol=LÞ ¼ a þ 64b þ 729c ð13:1Þ dation. Trace element solutions show a strong acidic pH,
which also may reduce the stability of the emulsions. It is
a ¼ concentration of monovalent cations unknown why the concentrations of trace elements decrease
b ¼ concentration of divalent cations during storage of the admixtures. It might be caused
c ¼ concentration of trivalent cations by adsorption to the packaging materials or precipitation
of insoluble complexes [56]. In order to minimise lipid
13 Parenteral 289
peroxidation, lipid emulsions should be stored light- oxygen. The products should be stored light-protected in the
protected and refrigerated. Trace elements should be added refrigerator. Degradation of ascorbic acid produces oxalic
immediately before administration or preferably acid which may form the insoluble calcium oxalate. The
administered as separate infusion [57]. Simultaneous admin- oxidation rate of ascorbic acid depends on the amount of
istration of trace elements and multivitamins in AIO oxygen present. Stability is maintained by optimising both
admixtures is problematic due to the physico-chemical the formulation and packaging of the products (e.g. use of
reactions. If trace elements and vitamins are included in multilayer bags). Removal of oxygen during preparation and
the same nutrient admixtures, compatibility of these storage reduces the degradation rate significantly [60].
elements and compatibility with the other components
have to be studied. 13.9.2.7 Packaging
Parenteral nutrition fluids can be packaged in plastic bags,
13.9.2.5 Excipients preferably ethylene-vinyl-acetate (EVA) bags or syringes
The most important excipients in parenteral nutrition depending on the total volume of the admixtures. Neonatal
solutions are emulsifying agents. Lecithin and phosphatides nutrition admixtures can be administered by syringe pumps.
are mostly used. The emulsifying capacity of phosphatides If the volume to be administered per day exceeds 50 mL,
PRODUCT DESIGN
correlates with their ionisation rate and thereby the pH of the repeated filling of the syringe can be performed with a
emulsion. The pH also influences the stability of the lipid specific closed syringe-filling system (see Fig. 13.3). Pre-
droplets [58]. If the pH decreases below 3, the droplet filled infusion lines further enhance patient-safety.
surfaces are no longer negatively charged and the droplets Interactions of lipophilic nutrition components with the
coalesce (see Sect. 18.4.1). If necessary, the pH is adjusted surfaces of the containers and administration devices may
with an aqueous solution of sodium hydroxide or occur. Nutrition components can be adsorbed or absorbed by
hydrochloric acid. plastic materials and components of the plastic materials can
Although lipids, oils and fat-soluble vitamins, such as be leached. Vitamin A is absorbed by polyvinyl chloride
tocopherol, undergo oxidation reactions, antioxidants are containing infusion bags and intravenous tubing [61].
usually not added to the nutrition admixtures because of It is still a matter of discussion whether parenteral nutri-
toxicity. Maximum recommended amounts of antioxidants, tion admixtures should be protected from light [58]. The
e.g. metabisulfite, are readily exceeded in the target patient light-sensitive vitamins should be added to the lipid-
population. containing admixtures because lipid emulsion provides
light-protection and reduces the degradation rate. When
13.9.2.6 Stability exposed to light those lipids however alter and may deliver
The large number of components (sometimes > 50 different a high load of exogenous toxic hydroperoxides to the patient
components) and the underlying meta-stabile emulsion sys- [62]. Admixtures from the all-in-two or all-in-three type
tem are obvious reasons for incompatibility (as described should be packaged in an additional light-protective second-
above) and instability. The occurrence of incompatibility ary bag in order to achieve a longer shelf life.
and instability is often invisible. Physico-chemical reactions
with negative effects on the stability are [58]:
• Aggregation of lipid droplets, lipid coalescence, and even
phase separation of the emulsion
• Precipitation of calcium phosphate
• Complexation of trace elements
• Oxidation of oxygen-sensitive vitamins
• Chemical degradation of amino acids such as glutamin,
cysteine; reaction of amino-acids with glucose (Maillard
reaction)
• Oxidation of lipids catalysed by trace elements
Administration of aggregated lipid droplets with a size of
5 μm or larger may cause fat embolism, by obstructing small
capillaries in the lungs (internal diameter 4–9 μm) [59]. The
reticuloendothelial system located in the liver eliminates the
enlarged lipid globules from plasma, but this can result in
increased oxidative stress and organ injury. Fig. 13.3 Parenteral nutrition with closed syringe-filling system
Vitamins such as retinol, riboflavin and tocopherol are (Photo: R.Lange, Source: Recepteerkunde 2009, reprinted by permis-
known to be degraded by light (especially UV-light) and sion of the copyrights holder)
13.9.2.8 Shelf Life As in process control (IPC) the components of a paren-

Industrially-manufactured standard multichamber bags teral nutrition admixture are to be inspected visually with
usually have a shelf life of more than 12 months before regard to irregularities in the appearance (homogeneity,
mixing. Admixtures for the individual needs of a patient clarity, particulates, and colour changes).
must be prepared in accordance with aseptic handling (see
Sect. 31.3). The admixtures are prepared in general on a 13.9.3.1 Automated Compounding Devices
daily or weekly basis. The shelf life of standard admixtures Individualised TPN admixtures for paediatric patients are
is maximum 7 days when stored under refrigerated often prepared with automated compounding devices
conditions at 2–8 C, provided that physico-chemical sta- (ACD). A large number of different single source containers
bility is sufficient. can be attached to an ACD using specific compounding
tubing. The tubing device is a single use system and has to
be changed on a daily basis. With a bar code reader the
13.9.3 Method of Preparation identity of the source components can be identified. ACD
utilises fluid pump technology and software that controls the
The industrially manufactured two and three chambers are compounder pump. The fluids are pumped from the source
mixed just prior to infusion, by breaking the separation seals container to the final container by a volumetric (rotary peri-
between the bag chambers. The content is mixed in the staltic pump) or a gravimetric pump system. The volumetric
closed system and vitamins and trace elements can be pump systems also checks the actual total bag weight (to the
added via an injection port prior to administration or expected weight). The systems incorporate an audit record
administered as separate infusion solutions. Nutrition for quality assurance and accuracy.
admixtures (all-in-one, all-in-two system) for the specific The advantages of automated preparation compared to
need of patients are prepared using industrially manual technique are reduction in expenditure of time and
manufactured lipid emulsions and aqueous solutions labour and thereby higher efficiency, higher accuracy, lower
containing amino acids, carbohydrates, electrolytes, probability of microbial contamination, and a lower chance
vitamins and eventually trace elements. All components of work related musculoskeletal disorders. The implementa-
are admixed in sterile empty infusion bags under conditions tion of an ACD however is labour- and cost-intensive. Pro-
of aseptic handling (see Sect. 31.3). cesses have to be defined, described and validated [63] and
AIO parenteral nutrition admixtures are commonly the designated personnel must be well educated and trained.
prepared by the following two methods: Accuracy checks must be done on a regular basis, e.g. by
• All components are admixed in the same infusion bag; daily pumping sterile water and comparing the actually
the components are added in a predefined order one pumped volume and weight with the expected one. Another
after the other and thoroughly mixed after each admixture option is the preparation of a standard admixture and the
step. quantitative analysis of one easy to analyse component such
• Electrolytes and trace elements are if necessary diluted as potassium. Media fill simulation tests are to be designed
with water for injection and added to the premix of and regularly performed by the operators.
glucose and amino-acid solutions; water- and fat-soluble
vitamins are admixed to the lipid emulsion; both
premixes are combined and mixed. 13.9.4 Release Control and Quality
The order in which the components are added is very Requirements
important because specific components may cause
incompatibilities if added too close after each other. Cal- The operators should monitor the appearance of the PN
cium gluconate and sodium/potassium phosphate should admixtures during and after the preparation procedure. The
always be diluted before addition in order to avoid the infusion containers of the preparations are to be checked for
precipitation of calcium phosphate due to high local leakages by visual inspection and imposing pressure on the
concentrations. This is less relevant when organic infusion bag.
phosphates are used. For release control the responsible pharmacist should
Water soluble vitamins should be dissolved in water for review the preparation records and check the recordings of
injection and then added to the parenteral lipid emulsion the weighing of the fluids. Furthermore the correctness of the
containing the lipid soluble vitamins. In this way the emul- labelling is to be checked and the data on the label have to be
sion will contain smaller lipid globules than if the vitamins compared with the original data of the prescription and the
are directly added to the emulsion. This may be relevant for preparation records.
the preparation of total parenteral nutrition for neonates and According to the Ph. Eur. emulsions for infusion should
children. not show any evidence of phase separation, which is
13 Parenteral 291
detectable by visual inspection. The most critical parameter

is the diameter of lipid droplets and its distribution. There is 13.10 Administration
no unique, reliable, method for measuring the size of the
lipid droplets over the whole size distribution range (starting 13.10.1 Terminology
from a few nanometres to many micrometres). Details about
different analysis methods of lipid emulsions can be found in The term ‘injection’ stands, in practice, for the parenteral
the literature [64–67]. administration of a limited volume of injection fluid usually
The United States Pharmacopeia [59] suggests two from a syringe with nominal volumes varying from 1 mL to
methods to measure the lipid globule size distribution and 50 mL into different sites of the body. Injections are
the percentage of fat globules (PFAT): light scattering executed direct or up to a couple of minutes, e.g. slow
method and light obscuration (LO) or light extinction (LE). injection means 10 min or more. Slow injection is appropri-
To be considered stable and safe, a TPN must meet the USP ate when the injection is performed subcutaneously or intra-
requirements where mean lipid droplet size cannot exceed muscularly or during intravenous injection when rapid
500 nm and PFAT must be less than 0.05 % for PFAT of dilution of the injection fluid by the bloodstream is necessary
5 μm (PFAT5). to avoid high local concentrations that may lead to phlebitis
or to precipitation.
PRODUCT DESIGN
Peroxide levels, pH and zeta potential represent further
physico-chemical parameters which are useful to character- The term ‘infusion’ stands for the parenteral administra-
ise the quality and stability of PN admixtures. tion of a larger volume of infusion fluid over a period of
During batch preparation sterility testing can be time. Infusions are administered over short periods such as
performed on randomly selected preparations either by 15 to 30 min, over prolonged periods such as 2 to 3 h or
direct inoculation or by the filtration method. During extem- continuously over 12 h, 24 h or even several days.
poraneous preparation dummy solutions should be prepared
and sterility tests performed with rapid detection methods
such as the bioluminescence test (see Sect. 19.6.5) or the 13.10.2 Injections
colorimetric detection of CO2 production in culture bottles;
although commonly used for blood cultures this last method Disposable plastic (mostly polypropylene, PP) syringes are
was shown to be adequate for sterility testing of multicom- used as containers for the injection of fluids. Prior to admin-
ponent admixtures [68]. istration they are connected to the needle, catheter or port
system which is used to access the injection site.
Syringes are available as 2- or 3-piece syringes. Two
piece syringes consist of a barrel and a plunger with the
13.9.5 Administration of Parenteral Nutrition finger grip, both made of polypropylene. A gasket is not
Admixtures necessary in the 2-piece syringes to achieve a smooth and
steady operation. Three piece syringes consist of a barrel,
Osmolarity of the nutrient admixtures and thereby the infu- plunger made of polypropylene and a polyisoprene gasket.
sion route is determined by the type and amount of the The inner site of the barrel is siliconised in order to ensure
components mixed. In general the admixtures are slippage of the plunger in the 3-piece syringes. The
hyperosmolar and to be administered via a central venous plunger may be coloured for easy recognition of the filling
catheter in a big vein (vena cava superior or vena subclavia). volume and may have a special plunger tip in order to
Only admixtures with a maximum osmolarity of 900 mOsm/ reduce the dead volume of the syringe. This is especially
L can be administered via a peripheral vein and only for a helpful when 1 mL syringes are used to inject small
limited period of time [69]. Long term parenteral nutrition volumes of highly effective and costly medicines. In gen-
can be also administered via a port (see Sect. 13.10.3) espe- eral disposable syringes are free from di-2-ethylhexyl
cially when patients are treated at home. Because of the high phthalate (DEHP) and latex. A backstop of the plunger
probability of incompatibilities nutrition admixtures should prevents it from accidental plunger withdrawal. Injection
always be administered via a separate line and Y-site infu- syringes have a tip in a standard design called Luer® Slip
sion should be avoided. tip (centric or eccentric) as opposed to a Luer-Lo(c)k, see
Patients with end-stage renal failure are maintained Fig. 13.4.
very fluid-restricted which limits the amount of calories This ‘male’ tip fits into the female part of the needle,
that can be delivered intravenously. Intradialytic parenteral stopcocks or other administration devices for making leak-
nutrition (via the dialysis solution, see Sect. 14.4.2) enables free connections between a male taper fitting and its mating
the provision of additional calories and nutritive female part. Key features of Luer taper connectors are
substances [70]. defined in the ISO 594 standards [71] and in the DIN and
some anaesthetists prefer spinal needles that are 12.7 cm

long (5 in.).
For safety reasons needles should not be recapped after
usage and needles should not be disconnected from syringes
before depositing them. There are special waste containers
to prevent re-use and puncture during storage, transport, and
disposal of the waste (see Sect. 26.10).
There are different devices commercially available for
needle-free injection. Commonly jet injectors produce a
Fig. 13.4 Syringe tips, from left to right: Luer Slip centric, Luer Slip
eccentric, Luer-Lo(c)k high-velocity jet of medicine that penetrate the skin.
Medicines and vaccines can be administered either intra-
EN standard 1707:1996 [72]. Luer-Slip fittings simply con- muscularly or subcutaneously by means of a narrow, high
form to Luer taper dimensions and are pressed together and velocity fluid jet that penetrates the skin. The gas-forced
held by friction (they have no threads). A Luer-Lok tip is a needle-free injection systems are typically made up of
variety of the Luer tip were the fittings are securely joined by three components including an injection device, a disposable
means of a hub on the female fitting which screws into needle free syringe and a gas cartridge.
threads in a sleeve on the male fitting. ‘Luer-Lok’ and
‘Luer-Slip’ are registered trademarks of Becton Dickinson.
‘Luer-Lok’ style connectors are often generically referred to
as ‘Luer lock’. Luer-lock tips are always placed centrally. 13.10.3 Infusions
Syringes for oral administration have a differently shaped
tip that does not match with female part of the injection Several ways exist for the access of the circulation with
devices. By this measure inadvertent parenteral injection of infusion devices:
oral liquids can be avoided. • Peripheral access devices
Commonly used volumes of syringes are 1 mL, 2 mL, • Midline and Peripherally inserted central catheters
5 mL, 10 mL, 20 mL, 30 mL and 50 mL. Transparent barrels • Central venous catheters
enable the visual inspection and bold graduations enable • Port systems
accurate measurement of the volume. In order to measure The following factors are relevant for the selection of a
the injection volume precisely, always use syringes with the venous access device:
smallest volume suitable for the volume to be injected. • Subcutaneous infusion is less wearisome for the patient
Filling to more than 50 % of its capacity will result in an than intravenous infusion.
inaccuracy not exceeding 5 %. If the filling degree is around • The effort of insertion increases from the butterfly can-
20 % the inaccuracy will rise to 10 % and filling to not more nula to the port system, which is to be implanted surgi-
than 10 % may lead to an inaccuracy of about 20 %. Impre- cally. The latter procedure is connected with a higher
cision depends very much on individual handling, but will be infection risk.
smallest when the capacity is nearest to the quantity to be • Administration is not possible via a peripheral cannula
measured (see further Sect. 29.1.7). because of hyperosmolality, irritating potential or large
Hypodermic needles are made of stainless steel and are volumes of infusion solutions.
available in a wide range of lengths and diameters (18–30 • Higher chance of thrombophlebitis when irritating infu-
gauge, G, (18 G ¼ 1.3 mm, 24 G ¼ 0.7 mm). Disposable sion solutions are infused in a peripheral vein.
needles are embedded in a plastic or aluminium hub that • Irritation when the infusion is administered
attaches to the syringe barrel by means of a slip or twist-on subcutaneously.
fitting. Coloured hubs reveal easy identification of diameter. • Duration of infusion (the longer, the higher the probabil-
A smooth surface and silicone coating of the needles ity of damaging the blood vessel).
enhances comfort for the patient during injection. The thin- • Frequency of infusion (the more often, the higher the
ner the needle the less painful is the injection. Thicker probability of damaging the blood vessel).
needles are necessary for the injection of viscous fluids. A • The larger the vein, the lower is the probability of dam-
longer needle is necessary to inject deeply into tissues and to aging, but more care is needed to prevent infection and
inject into the epidural space, requiring more thickness to be occlusion.
robust enough. Intrathecal injection is generally performed • A central venous access gives more arm mobility than a
through a 9 cm long (3.5 in.) needle. For obese patients, peripheral venous access.
13 Parenteral 293
VASCULATURE IDENTIFICATION
UPPER EXTREMITY VEIN
ANTHROPOMETRIC MEASUREMENTS
Vein Length Actual diameter
Superior 7 cm 20 mm
Vena Cava
R Innominate 2,5 cm 19 mm
Subclavian 6 cm 19 mm
Axillary 13 cm 16 mm
PRODUCT DESIGN
Basilic 24 cm 8 mm
Cephalic 38 cm 6 mm
Fig. 13.5 Diameters of different large vessels, adapted from Recepteerkunde 2009, #KNMP
Vascular access devices are classified in peripheral and

central venous access devices. Central veins are located in needle
Luer
the trunk and neck and are larger in the diameter than closure
27G
connection
peripheral veins. Figure 13.5 shows the diameter of different
large vessels. flexible plastic
Peripheral veins are located in the arms, hands, legs and A wings
feet. These veins are most commonly used for intravenous
Fig. 13.6 Butterfly needle for peripheral access, schematic. Source:
access. The diameter of peripheral small veins is 0.1–1 mm. Recepteerkunde 2009, #KNMP
These veins can be punctured with a needle, a butterfly
needle or a venous cannula.
13.10.3.1 Peripheral Access Devices

Butterfly needles are short steel needles with flexible plastic
wings that are fold before insertion and lay flat with tape on
the skin for stabilisation (see Fig. 13.6). Fig. 13.7 Cannula or venous catheter for peripheral access, schematic.
Since the butterfly needle uses a flexible tube, there is less Source: Recepteerkunde 2009, #KNMP
chance causing damage if the patient moves during the
manipulation. The wings allow grasping the needle very over a prolonged period and can also be used for drawing
close to the end to ensure accurate insertion. Butterfly needles blood samples. It is composed of:
are only suitable for short term use because the steel cannula • A small tube for insertion into the vein
can dislodge and puncture the vein. For subcutaneous admin- • Wings for manual handling and securing the catheter with
istration butterfly needles can be inserted into the skin. adhesives
A peripheral venous catheter or indwelling venous can- • A valve to allow injection of medicines with a syringe
nula (see Fig. 13.7) is the most commonly used vascular • An end which allows connection to an intravenous infu-
access. Often these infusion devices are named by their sion line and capping in between uses
brand name such as Venflon ® marketed by BD or • The needle which serves only as a guide wire for inserting
Braunüle® marketed by B.Braun Melsungen. The cannula the cannula
or peripheral venous catheter is inserted into a peripheral Lately the catheters have been equipped with additional safety
vein at the hand or the arm to administer infusion solutions features to avoid needle stick injuries (see Sect. 26.10).
The tube consists of synthetic polymers such as large vein in the neck (internal jugular vein), chest (subcla-
fluorinated ethylene propylene (FEP) or polyurethane (PU). vian vein or axillary vein) or seldomly in the groin.
For infusion of viscous fluids such as blood and for rapid Depending on the reason for use, the catheters have 1, 2
infusion cannulas with diameters of 14–16 G have to be and 3 lumens. Some catheters even have 4 or 5 lumens for
used. Smaller size diameters (18–24 G) of catheters are intensive infusion therapy. The catheter is usually held in
suitable for continuous and intermittent administration of place by an adhesive dressing, suture, or staple which is
parenteral solutions. Thorough management of the device covered by an occlusive dressing at the site of insertion.
(e.g. flushing, dressing, daily inspection) reduces Tunnelled catheters are passed under the skin from the
complications (e.g. phlebitis) caused by a peripheral access. insertion site to a separate exit site, where the catheter and
The need to replace the cannulas routinely is debated. its attachments emerge from underneath the skin.
13.10.3.2 Midline and Peripherally Inserted 13.10.3.4 Central Access Devices: Port Systems
Central Catheters A port is similar to a tunnelled catheter but is left entirely
Midline catheters and peripherally inserted central catheters under the skin. The system consists of a reservoir compart-
(PICC) are inserted in a peripheral vein but the tip rests in a ment that has a septum for needle insertion, with an attached
larger vein. The infusion fluid flows directly in the larger catheter (see Fig. 13.8).
vein which diminishes the chance of phlebitis. Both types of The catheter is connected to the reservoir, made from
catheters are typically inserted in a vein in the upper arm. e.g. titanium, and is inserted into a large vein (usually the
The midline catheter ends at armpit height; the tip of the jugular vein, subclavian vein, superior vena cava). The sep-
PICC rests in the vena cava superior. The PICC may have tum is made of a special self-sealing silicone rubber; it can
single or multiple lumens. The PICC line can be used as a be punctured hundreds of times with non-coring 90 ‘Huber’
central venous catheter for infusion which needs fast dilution needles. Ports are typically used in patients requiring only
or distribution or both such as antibiotics, pain medicine, occasional venous access over a long duration course of
chemotherapy, nutrition, etc. therapy. Prior to use the port is flushed with a saline solution.
After each use, a heparin lock is made by injecting a small
13.10.3.3 Central Access Devices: Central Venous amount of heparinised saline into the device. This prevents
Catheters occlusion and clotting within the port or catheter. The port
Central venous catheters (CVC) are directly inserted by can be left accessed for as long as required. Due to its design,
different techniques (mostly Seldinger technique) into a there is a low infection risk.
Fig. 13.8 Port system. Source:

Recepteerkunde 2009, #KNMP silicone rubber
membrane (septum)
skin surface
reservoir
catheter muscular tissue with sutures
vein
13 Parenteral 295
13.10.4 Infusion- and Administration Systems
A tube or line is necessary for the transport of the infusion

solution from the container to the venous access device. The
administration can be done by gravity or pump-infusion or
by syringes and syringe pumps.
Infusion pumps deliver the infusion fluid by pressure at a
constant rate. They are electrically or mechanically driven.
The different types of pumps used are:
• Syringe pump, which pushes the plunger of a syringe at a
constant rate
• Infusion pump
• Portable elastomeric pumps
Various types of administration sets, e.g. gravity tubing,
pump tubing, flow-regulating devices, and volume-
PRODUCT DESIGN
controlled tubing are available. The administration sets are
delivered sterile, particle-free and pyrogen-free. Lines are
flexible, transparent and made of different plastic materials.
The different components (e.g. catheter or cannula and line
or administration set) are usually connected via screw tight
Luer lock fittings. With stopcocks the caregiver or patient
can adjust the desired flow directions or stop fluids in order
to control the administration. Moreover stopcocks are used
as an access to inject medicines or to withdraw blood. One or
more infusions can be administered in parallel to the patient
via the female accesses in IV-Sets (Y-site). For applications
where several stopcocks are needed simultaneously 3-gang
and 5-gang manifolds can be used.
13.10.4.1 Infusion by Gravity

Standard administration sets are used to administer infusion
fluids by gravity. The basic product features, including a
clear tubing, are (see Fig. 13.9):
The spike is used to connect the system to an infusion bag Fig. 13.9 Administration set for infusion by gravity (1. Spike; 2. Drip
(or a bottle). The drip chamber is used in combination with chamber; 3. Access point for the connection of another infusion bag;
4. Roller clamp; 5. Luer fitting). Source: Recepteerkunde 2009,
the roller clamp to control the flow rate. The drip chambers #KNMP
of the administration systems are equipped with 15 μm filters
which ensure particle removal. The system is connected to
(e.g. 10 mL/h to 250 mL/h). A constant flow rate with low
an access point (e.g. venous cannula) with a Luer fitting.
deviation is given if other flow determining factors remain
Often access points are available to connect a second
unchanged, such as fluid viscosity and pressure determined
infusion.
by the level difference of the container and patient.
The flow is maintained by gravity and therefore the con-
tainer with the infusion solution has to be attached to a pole in
an elevated position. With gravity flow, the flow stops when 13.10.4.2 Syringe Pump
occlusion occurs and thereby extravasation is unlikely. The A syringe pump is used to inject small volumes of infusion
use of infusion pumps increases the chance of extravasation fluids in a continuous and precise manner. The infusion fluid
because the pump overcomes back pressure. However the is drawn into a syringe (usually 50 mL or 10, 20, 30 mL) and
pumps are designed to give alarm when the pressure increases. placed in a syringe-holder of the pump. The tip of the syringe
When gravity infusion with precise infusion rates is is connected to an in infusion line (PVC, PE) ending at the
intended, administration sets with precision flow regulators patient’s venous access. After safe fixation of the syringe
are to be used. Infusion rates can be set over a wide range plunger the piston brake releases and the plunger of the
syringe is moved forward to infuse the fluid at a preselected the medicine flows. The features of infusion pumps are
rate. Injection rates can be precisely adjusted starting from similar to these of the syringe pumps. In intensive care
0.1 mL per hour. The accuracy is about 2 % of set deliv- units various pumps are used to manage the complex paren-
ery rate. To minimise the risk of administration errors the teral therapy individually. Bedside-docking systems are used
pumps are equipped with different safety features (e.g. air to keep the high number of infusion pumps manageable.
sensor, occlusion detection, low battery alarm, customisable Patient-controlled pumps are specific infusion pumps that
medicine library in so called smart pumps with information can be activated by the patient via a pressure pad or button. It
about the medicines to be infused). Syringe pumps (see is the method of choice for patient-controlled analgesia
Fig. 13.10) are used to infuse active substances such as (PCA), in which repeated small doses of opioid are deliv-
catecholamines, analgesics, heparin, insulin, electrolytes, ered, with the device coded to stop when the maximum dose
anaesthetics and other medicines in particularly accurate per interval is reached.
manner to patients in intensive care units and operating
theatres. 13.10.4.4 Portable Pumps
A number of ready-to-use products are commercially The term portable pumps is often used as synonym for
available to be filled into the 50 mL syringes. If not available elastomeric pumps although electricity driven syringe
products are to be prefilled, possibly after dilution, it has to pumps are also designed as portable pumps. These pumps
be performed in the syringe as primary container. Often the are infusion pumps that commonly are used by outpatients or
doctor prescribes the dosage in milligram per minute or per patients that require a high level of mobility. The elasto-
hour. The right infusion rate depends on the concentration of meric pumps can easily be carried in a pouch. They are used
the solution; the rate has to be calculated by the nurse or can to administer antineoplastics to oncology patients,
be found in tables. antibiotics for e.g. cystic fibrosis patients, and pain therapy.
Elastomeric pumps are designed for single use. They are
A 250 mg ampoule of furosemide-Na is diluted to available from different companies with different designs,
50 ml resulting in a concentration of 5 mg/ml. When filling volumes (e.g. 50 mL, 100 mL, 250 mL) and flow rates
0.5 mg/min (30 mg/h) furosemide is prescribed by the (e.g. 100 mL/h, 2 mL/h) (Fig. 13.11).
physician, the injecting rate of 6.0 ml/h is to be set. The pressure for administrating the medicine comes from
the elastomeric layer that is molded inside the pump. The
elastic constriction drives the liquid through the tubing
Over the last years many hospitals have adopted standard equipped with a flow restrictor (glass capillary or steel
concentrations of injectable medicines to improve safety. It cannula). Filling of the reservoir is done through a
makes prescribing safer, especially when concentrations are one-way valve using a syringe or peristaltic repeater pump.
predefined in the electronic prescribing software. The A clamp is used to start and stop infusion.
chance of preparation and administration errors is also
reduced, especially when the type of medicine and the
administration rate can be chosen from a medicines library
13.10.5 Filters
in the pump or identified by barcode when placed in the
syringe holder.
Particle contamination of a ready to administer injection or
infusion solutions can result from cracking glass ampoules
13.10.4.3 Infusion Pump and from piercing rubber stoppers. Particles can also origi-
Infusion pumps are used to infuse large fluid volumes when nate from not fully dissolved powders or aggregation of
precise control of the flow rate and total amount delivered is protein substances. In general drip chambers of the adminis-
necessary. The large volume pumps usually use some form tration systems are equipped with 15 μm filters which ensure
of peristaltic pump. Computer-controlled rollers compress a particle removal and allow a sufficient flow even when
silicone-rubber tube of the administration line through which gravity infusion is performed. Filters with smaller pore
Fig. 13.10 Example of a syringe

pump: Perfusor® Space
(Copyright#”2014” B.Braun
Melsungen AG)
13 Parenteral 297
PRODUCT DESIGN
Fig. 13.11 Example of a portable elastomeric pump (Copyright #
Baxter Deutschland GmbH)
sizes require higher pressure to ensure a reasonable flow rate,

but are more effective in reducing the particle load. In-line
filters reduce the incidence of infusion-related phlebitis. They
are positioned between the administration line and the venous
access device of the patient and connected with Luer lock
fittings. Filters with a pore size of 1.2 μm are suitable to filter
lipid emulsions because the lipid drops have a 0.8 μm size and
are not retained. Filters with a pore size of 0.2 μm significantly
reduce the particle burden and remove bacteria and fungi.
They are to be exchanged after 24 h. Additionally filters with
a positively charged membrane are sometimes used to retain
endotoxins. In-line filters are recommended for preventing Fig. 13.12 Decision models for the selection of adequate venous
particles entering the blood stream. They are not considered access devices. Therapy related factors, such as duration and frequency
of administration (upper part of the decision model) and characteristics
to control infection, because a positive impact on the rate of of the infusion solutions (lower part of the decision model) determine
catheter-associated septicaemia is not evident [73–75]. One the selection of proper venous access devices [76] (Copyright # C.R.
reason for the lack of that result may be that the filters are Bard Inc)
blocked by particles and higher viscous solutions, thereby
increasing the number of line manipulations and thus increas- • Hydration and plasma expander solutions
ing opportunities for infection. • Cardiovascular medication
• Pain therapy
• Parenteral nutrition
13.10.6 Management of Parenteral • Anti-infective therapy
Administration Another sophisticated category of infusion therapy applies
to the administration of parenteral medication in cancer
Administration of fluids and medicines by the parenteral patients.
route is a demanding technology, especially when patients Often local or national guidelines are implemented in
receive intensive care with multiple infusion therapies order to enhance the safety of the infusion management.
such as: Health care staff should be educated and trained in the use
of catheters and infusion devices [75]. Moreover, decision 17. Mottu F, Laurent A, Rüfenacht DA et al (2000) Organic solvents for
models for the selection and use of the right infusion tech- pharmaceutical parenterals and embolic liquids: a review of toxic-
ity data. PDA J Pharm Sci Techn 54(6):456–469
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therapy related factors (compare Fig. 13.12), device related 16:307–321
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Irrigations and Dialysis Solutions
14
Daan Touw and Olga Mučicová
Contents Abstract
Irrigations are sterile solutions that are used in many
14.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
14.1.1 Irrigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 ways, such as flushing a catheter, the bladder, the urethra,
14.1.2 Dialysis Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 wounds, body cavities, and the operation area or for
14.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 drenching a bandage.
A special form of irrigations are solutions for dialysis
14.3 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
that are necessary for the different types of dialysis such
14.4 Product Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 as haemodialysis, haemo(dia)filtration and peritoneal
14.4.1 Irrigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 dialysis.
14.4.2 Dialysis Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Because irrigations are used in or on body areas that
14.5 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 are usually sterile or have a low degree of contamination,
14.6 Containers and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 there are strict requirements for their production and
14.6.1 Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 quality control. In this chapter the use, the design of
14.6.2 Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
formulation and preparation method as well as the on
14.7 Release Control and Quality Requirements . . . . . . . . . . 306 site preparation of irrigations will be discussed. With
14.8 Storage and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 regard to solutions for various types of dialysis, the use
of concentrates, the water quality and the requirements
14.9 Administration and Dosage Delivery Devices . . . . . . . . 306
for bacterial endotoxins are fully discussed.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Irrigations have various uses, and therefore various
users. Not only the one who prepares and dispenses
them should know their purpose, but also the patient or
the professional caregiver. Solutions for the different
types of dialysis form a separate category. Surveillance
and monitoring of the whole process, but especially the
quality management of the installation for the production
of water for the dilution of concentrated solutions, are
often more difficult than the preparation of the
concentrates themselves.
Keywords
Formulation Preparation Irrigations Dialysis
solutions Peritoneal dialysis Haemofiltration
Based upon the chapter Spoel- en dialysevloeistoffen by Suzy Dreijer

and Roel Bouwman in the 2009 edition of Recepteerkunde.
D. Touw (*)
Department of Clinical Pharmacy and Pharmacology, University O. Mučicová
Groningen, University Medical Center Groningen, Groningen, Hospital Pharmacy, Masaryk Hospital Ústı́ nad Labem, Ústı́ nad
The Netherlands Labem, Czech Republic
e-mail: [email protected] e-mail: [email protected]

302 D. Touw and O. Mučicová
With haemofiltration the transport of fluid and waste

14.1 Orientation products under pressure (ultrafiltration) is the main process.
The pores in these membranes are a little larger than those at
14.1.1 Irrigations haemodialysis and the filtered fluid has to be substituted. The
advantage is that waste products with a larger molecular
Irrigations come in contact with blood vessels, wounds or weight are also removed, thus better resembling the filtration
damaged mucosa or enter body cavities that normally have a process in the normal kidney. This may have a favourable
low microbial count or are sterile. Therefore irrigations have effect on cardiovascular health [2].
to be sterile. The purpose of irrigations is usually a mechani- In practice a combination of dialysis and filtration is used,
cal cleaning. A physiologic salt solution is suitable for this haemodiafiltration. Haemodiafiltration (HDF) is a combina-
purpose. Often a disinfecting action is also required, espe- tion of diffusion and convection. Diffusion is mainly effective
cially when the irrigation remains in a body cavity. For this for the removal of small waste molecules such as urea and
purpose chlorhexidine (0.02–0.1 %, see Table 14.1) or creatinine. Larger molecules, for example beta-2-
iodinated povidone are used. microglobuline, may only be removed from the blood by
Bladder irrigations with the purpose of eliminating blad- convection. For sufficient convective transport per HDF treat-
der stones, or preventing the formation of bladder stones are ment an equivalent of 60 L of plasma is filtrated. At the same
another group. As well as a mechanical cleaning action a time the same volume is given back to the patient in the form
chemical reaction is necessary to dissolve the stone or slivers of substitution solution. The substitution solution enters the
of stone, which consist of calcium and magnesium circulation of the patient. This is the same process as the
compounds. Therefore complexing agents such as citrate administration of an infusion, which is why some European
and edetate are added. Inspectorates regards solutions for HDF as parenterals.
With transurethral prostate resection the bladder has to be With peritoneal dialysis the peritoneum, which is well
irrigated with large quantities of solution to ensure that the supplied with blood vessels, functions as a semipermeable
view during the operation is not reduced by the presence of membrane. Peritoneal dialysis solutions are sterile hyper-
blood. osmotic solutions. These solutions withdraw water from
There are also solutions for intravesical use (use in the the blood through the peritoneum. The transport of small
bladder) that have to act locally in disorders of the bladder ions takes place at the same time.
and are not meant to irrigate. Examples are aluminium for Peritoneal dialysis is often self-administered, the solution
bladder bleedings, antineoplastics for bladder cancer and has to be changed four to five times a day. This is known as
oxybutinin for urge incontinence. continuous ambulant peritoneal dialysis (CAPD).
Eye lotions (irrigations for the eye) are discussed in Sect. Another method is automatic peritoneal dialysis (APD),
10.6.2. Vaginal solutions that don’t need to be sterile are whereby a machine performs the irrigation during the night.
discussed in Sect. 11.12. Whole bowel irrigations are used There are advantages and disadvantages to haemodialysis
before diagnostic examination. Those solutions for oral or and peritoneal dialysis.
rectal use are not described in this chapter. Peritoneal dialysis gives the patient more freedom than
haemodialysis, but requires a suitable space at home and
appropriate skills. The patient may gain weight from these
14.1.2 Dialysis Solutions glucose containing solutions.
Haemodialysis almost always takes place in a dialysis
Dialysis serves the purpose of removing waste products from centre, mostly three times a week during several hours or
the body when the kidneys cannot do this anymore. There during night hours. It may in principle also be done at home,
are various forms of dialysis with their own characteristics. but hygiene and precision are very much required.
With haemodialysis the blood passes an artificial kidney Haemodialysis has the disadvantage that the patient usually
via extracorporeal circulation. The artificial kidney removes is not allowed to drink much fluid and is restricted to a
waste products and fluid. This happens mainly by osmosis specific diet.
(diffusion) via a semipermeable membrane, and partly by
convection that is via the transport of water and waste
products forced by pressure (ultrafiltration). 14.2 Definitions
Table 14.1 Chlorhexidine Digluconate Irrigation 0.1 % [1]
Chlorhexidine digluconate solution 0.53 g The Ph. Eur. describes irrigations (Preparations for irriga-
Acetic Acid (6 %) B.P. q.s. tion) as follows [3]: “Preparations for irrigation are sterile,
Water for injections ad 100 mL aqueous, large-volume preparations intended to be used for
irrigation of body cavities, wounds and surfaces, for
14 Irrigations and Dialysis Solutions 303
example during surgical procedures. Preparations for irriga- close to the electrolytic composition of plasma.” Because
tion are either solutions prepared by dissolving one or more they are considered as parenterals they must be sterile (that
active substances, electrolytes or osmotically active is, they must comply with the test for sterility as described in
substances in water complying with the requirements for the Ph. Eur.).
Water for injections (0169) or they consist of such water Peritoneal dialysis solutions (Solutions for peritoneal
alone. In the latter case, the preparation may be labelled as dialysis) according to the Ph. Eur. are: “Preparations for
‘water for irrigation’. Irrigation solutions are usually intraperitoneal use containing electrolytes with a con-
adjusted to make the preparation isotonic with respect to centration close to the electrolytic composition of
blood.” plasma.” Although it is not mentioned in the description
This definition is valid for irrigations for the bladder, but that they have to be sterile, they must comply with the test
also for other solutions for intravesical use. for sterility.
Haemodialysis solutions (Solutions for haemodialysis)
according to the Ph. Eur. are: “Solutions of electrolytes in
a concentration close to the electrolyte composition of 14.3 Biopharmaceutics
plasma (. . .). Because of the large volumes used,
PRODUCT DESIGN
haemodialysis solutions are usually prepared by diluting a Solutions for intravesical use are meant to remain in the
concentrated solution with water of suitable quality (see the bladder for a longer period and to exert a pharmacological
monograph Haemodialysis solutions, concentrated, water effect, for example oxybutinin bladder irrigation for urine
for diluting (1167)), using for example an automatic dosing incontinence. The addition of bioadhesive polymers, for
device.” They are prepared in a way that ensures a contami- example hypromellose, may prolong the effect.
nation level as low as possible. Haemodialysis solutions do Solutions for CAPD are inserted into the abdomen via a
not have to be sterile, they are not in direct contact with the catheter (Fig. 14.1).
blood. However, new dialysis membranes with larger pores The abdomen is surrounded by the peritoneum, an endo-
may entail a considerable amount of back-filtration which in thelial, single cellular layer that functions as dialysis mem-
the near future probably will result in stricter requirements brane for water and small molecules. By using a hyper-
for these haemodialysis solutions. osmotic solution for peritoneal dialysis water and small
Haemofiltration and haemodiafiltration solutions molecules are withdrawn from the blood. After several
(Solutions for haemofiltration and for haemodiafiltration) hours the fluid is rinsed out and replaced with new CAPD
according to the Ph. Eur. are: “Preparations for parenteral solution. Solutions for peritoneal dialysis are made iso to
administration containing electrolytes with a concentration hyper-osmotic with glucose to remove water from the body.
Fig. 14.1 Continuous ambulant liver

peritoneal dialysis. Source:
pancreas
stomach
peritoneum
abdominal cavity
small intestine
rectum
CAPD-catheter
bladder
The glucose concentration is 1.36–4.25 %. The absorption 14.4.1.4 Viscosity

of glucose from the dialysis solution may therefore be Irrigations for rinsing should not normally be viscous. In
considerable. solutions for intravesical use the use of a viscosity enhancer,
like hypromellose, may exert a prolonged effect [4].

14.4.1.5 Stability
The chemical stability of the active substances is important
14.4.1 Irrigations
with regard to the choice of sterilisation method and the
pH. For example during sterilisation chlorhexidine degrades
Irrigations are aqueous solutions. Active substances to be
to 4-chloro-aniline and other related substances. By
added have to be sufficiently water soluble.
adjusting the pH of the solution to 5 this degradation remains
within acceptable limits (4-chloro-aniline < 0.5 %, total
14.4.1.1 Bacterial Endotoxins
other related substances < 3.5 %).
The Ph. Eur. requires irrigations to contain maximally
Irrigations are meant for single use and do not contain a
0.5 IU/mL bacterial endotoxins. This requirement, therefore,
preservative.
is indicative as to how irrigations should be prepared. For
irrigations for superficial wounds the need for the absence of
bacterial endotoxins may be questioned. Apart from the 14.4.1.6 Sterilisation Method
situation with deep surgical wounds, for example during For irrigations steam sterilisation in its final container for
major surgery, the absorption of bacterial endotoxins is 15 min at 121 C (see Sect. 30.5.1) is preferred. These are the
unlikely. same requirements as for parenteral solutions. An aseptic
Endotoxin-free solutions require the use of bacterial preparation method with bacterial filtration through a 0.2 μm
endotoxin free starting materials. For dialysis solutions sep- filter, followed by heating at 100 C for 30 min (or another
arate requirements exist, see Sect. 14.4.2. proper combination of temperature and time or validated
aseptic conditions) is an alternative when one of the
14.4.1.2 Osmotic Value substances is sensitive to a higher temperature. If an active
Irrigations to rinse a surgical area or a deep wound should substance is not heat resistant at all, only an aseptic prepara-
be iso-osmotic. For disinfection or cleansing of superficial tion with bacterial filtration over a 0.2 μm filter is possible.
wounds this is not strictly necessary. Historically, a sterile In such cases the starting materials should be sterile or have
hyperosmotic solution (NaCl 3 %, for example) is prepared a low bioburden and the irrigation should be prepared asep-
for rinsing superficial moist wounds and bedsores. Hyperto- tically. See also Sect. 30.6.
nicity is in fact the mechanism of action; the solution has a
desiccating effect. For irrigations for the bladder iso-osmosis
is less important. Hypo-osmosis is more problematic than
14.4.2 Dialysis Solutions
hyper-osmosis, because the osmotic value of urine is twice
to trice the osmotic value of blood [4].
Irrigations for transurethral prostate resection (TURP)
Concentrates (concentrated solutions) for haemodialysis are
should not contain salts. A transurethral prostate resection
diluted with water in the dialysis machine prior to use.
is performed with an electrosurgical instrument
(resectoscope). The conventional TURP method in tissue
removal utilises a wire loop with electrical current flowing 14.4.2.2 Bacterial Endotoxins
in one direction through the resectoscope to cut the tissue. A The Ph. Eur. requires solutions for haemodialysis, after
grounding pad and irrigation by a nonconducting fluid is dilution, to contain not more than 0.5 IU/mL. Solutions for
required to prevent this current from disturbing surrounding haemo(dia)filtration and peritoneal dialysis have to be sterile
tissues. For making irrigations iso-osmotic for such surgeries and should not contain more than 0.05 IU/mL bacterial
mannitol, sorbitol or glycine may be used. endotoxins according to the present Ph. Eur. requirements
(Ph. Eur. 8.0). During a haemo(dia)filtration treatment a
14.4.1.3 pH large volume of the solution is administered parenterally to
Wound irrigations have to be iso-hydric (pH 7.4) or should the patient (about 60 L per dialysis session). The more
have a very low buffer capacity. For irrigations for the stringent requirement for bacterial endotoxins in solutions
bladder larger limits are allowed, but at pH < 3 irritation for haemo(dia)filtration compared to that for solutions for
may occur [5]. Irrigations for dissolving bladder stones often haemodialysis is due to the large volume of solution
contain citric acid as the active substance (pH 3.5–4). administered with the first technique.
consideration. The biological availability of the antibiotic

However, the limit should be even lower: a patient may decrease due to chemical instability.
receives 60 L of water per dialysis treatment. A treat-
ment lasts for 3 h. That means an intravenous admin-
istration of 20 L in 1 h. According to the Ph. Eur. the 14.5 Method of Preparation
allowed maximum amount of bacterial endotoxins for
parenteral use is 5 IU per kg bodyweight in 1 h. This The preparation of irrigations occurs in the same way as that
means for a 60 kg patient that 300 IU bacterial of infusion solutions. See Sect. 13.7. Many irrigations are
endotoxins are allowed to be present in 20 L resulting also available as medical devices.
in a requirement of <0.015 IU/mL. At this moment the Concentrates for haemodialysis are regarded as medical
assay technique allows an endotoxin limit of 0.025 IU/ devices. However, they have to be diluted with water of
mL to be detected and present water treatment units which the quality is defined by the Ph. Eur. When a concen-
are able to produce water of this quality. This topic and trate is diluted this should be done with water for injections
other requirements are under discussion within the but for practical purposes highly purified water is used.
Ph. Eur. committee on dialysis solutions. With online haemo(dia)filtration the dialysis machine
PRODUCT DESIGN
produces the diluent solution near the patient, so-called
‘online’. In some countries the pharmacist is responsible
for the quality of the solutions, because health inspectorate
14.4.2.3 Water Quality
regards this as the preparation of a medicine.
It is obvious that for the preparation of solutions for
The requirements for the water which is used in an infu-
haemodialysis or haemo(dia)filtration special requirements
sion during HDF are described in the Ph. Eur.: Water for
are needed to control the quality of water.
injections. It is important to realise that in this monograph
The Ph. Eur. gives formulations for all common dialysis
under the section heading ‘Water for injections in bulk’ next
solutions. Sodium, potassium, calcium, magnesium, acetate,
to chemical and biological requirements the method of prep-
hydrogen carbonate or lactate, chloride and glucose are
aration is also described (see also Sect. 23.3.1.3). This
specific components for this type of preparations. In the
method of preparation is distillation, a technique that is not
Ph. Eur. ranges are stated for the concentrations of these
used in the preparation of water for dialysis in dialysis
components. When the formulation contains hydrogen car-
centres. In ISO 13959:2009 [6] this problem is overcome
bonate, sodium hydrogen carbonate should be dispensed in a
by advising the use of Highly Purified Water plus an extra
separate package or a separate compartment. Sodium hydro-
filtration step for the preparation of the substitution solution
gen carbonate can only be added to the solution just prior to
for online haemodiafiltration. For the preparation of Highly
administration because it may precipitate with divalent
Purified Water an in series connected double reverse osmo-
cations. Furthermore solutions for haemo(dia)filtration and
sis installation is necessary followed by an electro-deioniser
peritoneal dialysis are not allowed to contain metabisulfite or
(see Sects. 28.4.3 and 28.4.4) or an ultrafilter. Also required is
other anti-oxidants. These special requirements are neces-
a system of periodical controls of the process to immediately
sary because haemo(dia)filtration patients are exposed to
detect deviations from the required quality. Where the phar-
about 180 L of fluid per week via the blood circulation. As
macist is responsible for the release of the preparation pro-
a comparison: the Dutch law on potable water quality, that
cess, to be able to accept this responsibility, satisfactory
defines the requirements for drinking water, starts from an
agreements are necessary. In order to be able to take suitable
exposure of 2 L per day or 14 L per week via the gastro
action in time, if there are deviations in the required quality, a
intestinal tract. Quality and purity of starting materials are
procedure, which lays down consultation between the user
defined by the Ph. Eur. A specific monograph (for informa-
(usually the leader of the dialysis department or the treating
tion) exists for water for preparation of haemodialysis
nephrologist) and the responsible pharmacist is indispensable.
solutions: Water for diluting concentrated haemodialysis
solutions. It sets an even stricter limit for specific impurities
e.g. aluminium, when materials are used for preparation of
haemodialysis solutions.
14.6.1 Containers
14.4.2.4 Stability of Added Active Substances
To solutions for peritoneal dialysis active substances may be According to Ph. Eur. “Preparations for irrigation are sup-
added, for example antibiotics to treat peritonitis. In that plied in single-dose containers.”, for all sterile irrigations
case, their stability in a warm (37 C) solution, in which in and dialysis solutions, with the exception of the concentrated
addition the pH will rise during dialysis, has to be taken into solutions for haemodialysis, the container and the closure
should comply with the Ph. Eur. requirements for containers • Content of active substance(s)
for parenteral use. According to the Ph. Eur. “the adminis- • pH;
tration port of the container is incompatible with intravenous • Sterility
administration equipment and does not allow the preparation • Bacterial endotoxins
for irrigation to be administered with such equipment.” Irrigations unlike parenterals don’t require a test on sub-
Irrigations are packaged in glass or plastic bottles or bags visible particles.
(see Sects. 24.4.6 and 24.4.13). For bladder irrigations spe- Quality requirements for concentrates for dialysis, the
cial bags exist. When bottles are being used, it is important water for dilution and solutions for haemo(dia)filtration are
to have, after opening, a clear indication that the bottle has to be found in the Ph. Eur. and in ISO 13959:2009 [6]. Qual-
been opened, in order to prevent its re-use. This also applies ity requirements for concentrated solutions for haemo(dia)
to licensed medicines. Bottles with a crimp cap that is filtration and water to dilute them, are not yet defined in the
removed completely are suitable. Bottles with a screw clo- Ph. Eur.
sure are also suitable provided that they are sealed after
filling. For small quantities, bags or ampoules that are not
re-closable are a good alternative. 14.8 Storage and Stability
Plastic bags are usually made of PVC, through which
water may diffuse and evaporate. Therefore a secondary See General instructions for storage (Sect. 22.7) for back-
package is necessary that is a better barrier to water vapour, ground discussion. For chemically and physically stable
but the shelf life is less than in a glass bottle anyway because sterilised irrigations, in a glass container, a maximum shelf
of an increase of concentration. Next to this increase, the life of 36 months at <25 C, not in a refrigerator, is applied.
concentration of the active substance may decrease at the For irrigations in plastic bags this term is shorter: maximally
same time by sorption to glass or plastic. Chlorhexidine 12 months because of water diffusion through the plastic
solutions are an example of this, but this is only relevant bag. This also applies for dialysis concentrates. For standard
when low concentrations are present (<0.5 mg/mL). formulations the shelf life will be investigated and specifi-
cally indicated. With unknown chemically and/or physically
stability the shelf life is maximally 1 month stored at
14.6.2 Labelling <25 C, not in a refrigerator.
The microbiological shelf-life of irrigations and dialysis
See Sect. 37.3 for general aspects of labelling. The intended solutions prepared by aseptic handling depends on the
use should be mentioned in the name of the irrigation as circumstances during the preparation. See Sect. 31.3.6.
much as possible. Irrigations are meant for single use. Any opened con-
The label should indicate that the solution is meant for tainer may only be stored for 24 h at maximum.
single use, and that the remainder should be discarded, and, The diluted solutions for haemodialysis and haemodia-
for irrigations, that the solution is not meant for injection or filtration that are prepared from the concentrate do not have
infusion. The labelling of irrigations that are licensed as a shelf life, because they are prepared in the dialysis machine
medical device is covered by the EU directive for medical immediately before use.
devices [7]. Symbols or pictograms are usually part of the
information.
14.9 Administration and Dosage Delivery
Devices
14.7 Release Control and Quality
Requirements Irrigations for the bladder are administered via a catheter.
Bags for irrigations therefore have mostly a conical
Irrigations should be checked for appearance, container and connection.
labelling. Control on appearance means a check on clarity For solutions for intravesical use, packaged in infusion
and absence of particles. This usually happens before bottles, a catheter with a Luer-lock connection is an alterna-
labelling. tive. After aspiring with a syringe from a bottle the needle
For irrigations the following quality requirements apply may be replaced by the catheter. This variant is used mostly
(see also Table 32.2): in the home situation, where no risk exists of mistaken
• Identity intravenous administration.
• Appearance (clarity, no precipitation, sediment or foreign Irrigations and haemodialysis solutions are mostly
particles) administered by a physician or a specialised nurse.
Peritoneal dialysis may be performed by a patient with in chronic hemodialysis patients – the Dutch CONvective TRAns-
proper instruction. port STudy (CONTRAST): rationale and design of a randomised
controlled trial. Curr Control Trials Cardiovasc Med 6:8. doi:10.
Dialysis occurs in specialised centres with staff that have 1186/1468-6708-6-8
the required knowledge. Also with irrigations it is important 3. Preparations for irrigation (2014) European pharmacopoeia, 8th edn.
that professional caregivers know how to deal with them. Council of Europe, Strasbourg, p 1116
4. Hanawa T, Tsuchiya C, Endo N et al (2008) Formulation study of
intravesical oxybutynin instillation with enhanced retention in blad-
der. Chem Pharm Bull 56:1073–1076
References 5. Goldhoorn PB (1978) Onderzoek naar de verdraagbaarheid van
amandelzuur 1 % katheterspoeling versus Solutio R FNA katheter-
1. Chloorhexidinedigluconaatspoeling 0,1% FNA. Jaar 2009. spoeling. Pharm Weekbl 113:917–920
Formularium der Nederlandse Apothekers. Den Haag: Koninklijke 6. ISO 13959:2009 (2009) Water for haemodialysis and related
Nederlandse Maatschappij ter bevordering der Pharmacie therapies. International Organization for Standardization, Geneva
2. Penne EL, Blankestijn PJ, Bots ML, van den Dorpel MA, Grooteman 7. Council Directive 93/42/EEC of 14 June 1993 concerning medical
MP, Nubé MJ et al (2005) Effect of increased convective clearance devices. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?
by online hemodiafiltration on all cause and cardiovascular mortality uri¼CELEX:31993L0042:EN:HTML). Accessed 7 Nov 2013
PRODUCT DESIGN
Radiopharmaceuticals
15
Rogier Lange, Marco Prins, and Adrie de Jong
Contents Abstract
Radiopharmacy is a discipline concerned with the prepa-
15.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
ration and quality control of radiopharmaceuticals. The
15.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 term radiopharmacy is also used for the pharmacy where
15.3 Radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 these activities are carried out. Radiopharmaceuticals are
15.4 Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 medicinal products that contain radionuclides (radioac-
15.4.1 Use of Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 tive isotopes). Radionuclides are produced in nuclear
15.4.2 Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 reactors or in cyclotrons. The most important
15.4.3 Parenteral Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . 312 radionuclides used in nuclear medicine are 99mtechnetium
15.4.4 Oral Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
15.4.5 Radiopharmaceuticals for Inhalation . . . . . . . . . . . . . . . . . . . . 313 and 18fluoride.
Many radiopharmaceuticals are used for diagnostic
15.5 Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
15.5.1 Sources of Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
purposes; some are developed for therapeutic or palliative
15.5.2 Radiopharmaceuticals with a Marketing Authorisation . 313 use. They are administered parenterally, orally or by
15.5.3 Radiopharmaceuticals to be Used in Clinical Trials . . . . 313 inhalation. When radiopharmaceuticals are used for diag-
15.5.4 Good Manufacturing Practice (GMP) . . . . . . . . . . . . . . . . . . . 313 nostic purposes minute quantities are used. The radio-
15.5.5 Product Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
15.5.6 Extemporaneously Prepared Radiopharmaceuticals . . . . . 314
pharmaceutical accumulates in target tissues and emits
15.5.7 Legislation on Radiation Protection . . . . . . . . . . . . . . . . . . . . . 314 gamma-radiation that can be detected by imaging
15.5.8 Interpretation of Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 instruments. Therapeutic or palliative use requires higher
15.6 Preparation and Dispensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 dosages of alpha- or beta-emitting radiopharmaceuticals.
15.6.1 Location of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 Its ionising radiation is directed to damage the target
15.6.2 Prescription and Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 tissue causing minimal damage to other parts of the body.
15.6.3 Layout of the Radiopharmacy Department . . . . . . . . . . . . . . 316
Radiopharmaceuticals are regulated both as medicinal
15.6.4 Equipment in the Radiopharmacy . . . . . . . . . . . . . . . . . . . . . . . 317
15.6.5 Preparation and Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 products and as radioactive substances. Therefore, both
15.6.6 Packaging and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 medicine legislation and nuclear safety regulations
15.6.7 Quality Control and Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 (nuclear energy legislation) are applicable. These
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 regulations dictate both design and layout principles of
the radiopharmacy and the general handling and control
procedures that should be applied when preparing and
dispensing radiopharmaceuticals.
Radiopharmaceuticals used in hospitals are prepared,
tested and released under the responsibility of a (radio)
R. Lange (*) pharmacist. In this chapter the most important pharma-
Meander Medisch Centrum, Amersfoort, The Netherlands ceutical aspects of radiopharmaceuticals are highlighted.
A.M.A. Prins Keywords
Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, The Netherlands
Radiopharmacy Radionuclides Radiopharmaceuticals
Radiolabelling Nuclear medicine Alpha-emitters
A.P. de Jong
Medisch Centrum Alkmaar, Alkmaar, The Netherlands
Beta-emitters Gamma-emitters Positron emitters
e-mail: [email protected] SPECT PET

310 R. Lange et al.
15.1 Orientation 15.2 Definitions
Radiopharmacy is a discipline concerned with the prepara-

tion and quality control of radiopharmaceuticals. Radiophar- ALARA “As Low As Reasonably Achiev-
maceuticals are defined by the European Pharmacopeia able”, an occupational safety and
(Ph. Eur.) as “medicinal products which, when ready for health principle pursuing minimal
use, contain one or more radionuclides (radioactive isotopes) radiation exposure.
included for a medicinal purpose”. Alpha radiation Ionising radiation by alpha particles
Radiopharmaceuticals are regulated both as medicinal (¼ 4He2+-ions). In comparison with
products and as radioactive substances. Therefore, both beta and gamma radiation, alpha radi-
medicine quality regulations (GMP) and safety regulations ation has the least penetrating power
(nuclear energy legislation) are applicable. Radiopharma- and the highest linear energy transfer.
ceuticals must be handled (often aseptically) as quickly as Alpha emitter Radionuclide that decays to a more
possible, with shielding, to avoid unnecessary exposure to stable nuclide by emission of an
radiation. alpha particle.
Most radiopharmaceuticals are used for diagnostic Annihilation Two gamma rays with an energy of
purposes, some for therapeutic or palliative use. They are radiation 511 keV that are emitted at an angle
administered parenterally, orally or by inhalation. When of 180 after collision of a positron
radiopharmaceuticals are used for diagnostic purposes with an electron.
minute quantities are used. The radiopharmaceutical Becquerel Unit of radioactivity: 1 Becquerel
accumulates in target tissues and emits gamma radiation (Bq) is equivalent with 1 disintegra-
that can be detected by imaging instruments. Therapeutic tion per second (kBq ¼ 1,000 Bq,
or palliative use requires higher dosages of alpha- or beta- MBq ¼ 106 Bq).
emitting radiopharmaceuticals. Its ionising radiation is Beta radiation Ionising radiation by beta+ (¼ posi-
directed to damage the target tissue causing minimal damage tron) or beta (¼ electron) particles.
to other parts of the body. Alpha or beta emitters are suitable Beta emitter Radionuclide that decays to a more
for this purpose because of the limited pathway of their stable nuclide by emission of a
radiation in tissue [1, 2]. beta+ (¼ positron) or a beta (¼
Radiopharmaceuticals are used in the hospital department electron) particle.
of nuclear medicine or in research institutes. For diagnosis Computed Technology that uses X-rays to pro-
essentially two techniques are used: SPECT (single-photon tomography (CT) duce images (virtual slices),
emission computed tomography) and PET (positron emis- allowing to see inside the body.
sion tomography). SPECT is an imaging technique detecting Cyclotron Equipment in which charged
gamma rays. In SPECT imaging a gamma camera acquires particles, after acceleration in a cir-
multiple two dimensional images (also called projections) cular pathway, are directed onto a
from multiple angles. With the aid of tomographic recon- target for evoking a nuclear reaction.
struction algorithms a three-dimensional image is Decay Spontaneous reaction of a radionu-
calculated. clide to form another (radio)nuclide
Positron emission tomography also produces three- accompanied by the release of
dimensional pictures of organs and functional processes in ionising radiation.
the body. In PET pairs of gamma rays emitted indirectly by a Electronvolt (eV) Kinetic energy gained by an electron
positron-emitting radionuclide are detected. Computer when accelerated through a potential
programs reconstruct PET images. field of 1 volt (keV ¼ 1,000 eV).
Several techniques from radiology and nuclear medicine Gamma radiation High energy photons that are emit-
have been combined in hybrid imaging techniques, such as ted during radioactive decay.
SPECT-CT, PET-CT and PET-MRI. In these hybrid systems Gamma emitter Radionuclide that emits gamma
the use of radiopharmaceuticals (sometimes next to conven- rays during radioactive decay.
tional contrast agents) remains essential. Generator A device in which a daughter radio-
Radiopharmaceuticals used in hospitals are prepared, nuclide with a shorter half-life is
tested and released under the responsibility of a (radio)phar- separated from a mother radionu-
macist. In this chapter the most important pharmaceutical clide with a longer half-life.
aspects of radiopharmaceuticals are highlighted. Half-life The characteristic of a radionuclide
that defines the time during which
15 Radiopharmaceuticals 311
the radioactivity of a radionuclide is Table 15.1 Common radionuclides and their use
reduced to half of its original value. Diagnostic use Diagnostic Therapeutic/
Kit for labelling Composed set of all non-radioactive (SPECT) use (PET) palliative use
51 11 32
reagents in appropriate quantities Cr C P
67 13 89
for the preparation of a specific Ga N Sr
81m 15 90
radiopharmaceutical. Kr O Y
99m 18 131
Magnetic resonance A medical imaging technique to Tc F I
111 68 153
imaging (MRI) investigate the anatomy and physi- In Ga Sm
123 82 177
I Rb Lu
ology of the body using strong mag- 133 89 188
Xe Zr Re
netic fields. 201 124 223
Tl I Ra
Nuclear reactor Installation for the production of
radionuclides by nuclear fission of
e.g. 235uranium. short decay times (half-lives from hours to days) and ease
PET Positron emission tomography: an of incorporation in the final molecule. The energy of the
imaging technique that makes use emitted radiation ranges from about 150 kiloelectronvolt
PRODUCT DESIGN
of a radiopharmaceutical that is (keV) (gamma-photons for diagnostics) to around
labelled with a positron emitter 1,000 keV (beta-particles for therapy). The newer imaging
(e.g. 11C, 13N, 18F). technique of positron emission tomography (PET) uses
Positron A beta+ particle that, after collision radionuclides with half-lives going down to 2 min, emitting
with an electron, annihilates to two positrons that annihilate to gamma-photons of 511 keV.
gamma rays of 511 keV. Radionuclides either originate from a nuclear reactor or
Radioactivity Spontaneous process in which an are produced by a cyclotron. The description of the produc-
unstable radionuclide transforms to tion methods of radionuclides in nuclear reactors and
a more stable (radio)nuclide releas- cyclotrons goes beyond the scope of this book and can be
ing energy in the form of particles found elsewhere [1, 2].
(alpha or beta particles) or photons The most important pharmaceutical radionuclide pro-
(gamma rays). duced by a nuclear reactor is 99molybdenum. This element
Radiochemical Any compound containing one of is the mother radionuclide in a 99Mo/99mTc-generator (see
more atoms of a radioactive isotope. Sect. 15.6.4). During separation in this generator sodium
Radiochemical Fraction of the total radioactivity 99m
technetium pertechnetate is formed. 99mTc-pertechnetate
purity present in the desired is the most frequently used radiochemical for coupling to a
radiochemical form. pharmaceutical ligand in the preparation of diagnostic
Radiolabelling Process of attaching a radionuclide radiopharmaceuticals.
to a non-radioactive molecule. Cyclotrons are found in nuclear industry, but their pres-
Radionuclide An unstable nuclide that decays ence and use in hospitals is increasing. The principal radio-
spontaneously by the emission of nuclide from cyclotrons is 18F-fluoride. This radionuclide is
particles (alpha or beta particles) or often incorporated into 18F-fludeoxyglucose through an
photons (gamma rays). automated synthesis procedure. 18F-fludeoxyglucose is the
Radionuclidic purity Fraction of the total radioactivity major radiotracer used in PET.
present as the desired radionuclide. The most frequently used radionuclides and their use are
Radiopharmaceutical A pharmaceutical substance that mentioned in Table 15.1.
contains one or more radionuclides.
SPECT Single-photon emission computed
tomography: an imaging technique
that makes use of a radiopharma- 15.4 Radiopharmaceuticals
ceutical that is labelled with a
gamma emitter. 15.4.1 Use of Radiopharmaceuticals
A radiopharmaceutical is a radioactive medicinal product for

diagnostic, therapeutic or palliative use. Parenteral
15.3 Radionuclides radiopharmaceuticals usually consist of a radionuclide cou-
pled to another pharmaceutical compound, also called a
Radionuclides (radioactive isotopes) are the most important ligand. Some radionuclides are administered as such. Alter-
components of radiopharmaceuticals. Desirable properties native dosage forms are capsules for oral use or a radioactive
of radionuclides in radiopharmaceuticals are relatively gas for inhalation. All dosage forms are shielded, in lead or
312 R. Lange et al.
tungsten for gamma and positron emitters and in plastics for used, for positron-emitters a PET-camera has to be used. See
beta and alpha emitters. also next sections.
The physical and biopharmaceutical properties of a radio- Adverse effects of radiopharmaceuticals for diagnosis are
pharmaceutical determine its potential use [1, 2]. extremely rare [3]. Radiopharmaceuticals for therapy may
The design of radiopharmaceuticals is based upon the have adverse effects, for example bone marrow depression if
physiological function of the target organ. The mechanism used for treatment of bone metastases. Radiopharma-
of targeting a particular organ can be different, for example ceuticals can interact with other (non-radioactive) medicines
physical trapping of particles, binding to structures in tissues given to the same patient [4]. Food and glucose in food can
or organs or an antigen-antibody reaction. In general, a high disturb the quality of certain types of imaging (interaction of
target-to-background ratio is pursued. glucose (dextrose) with 18F-FDG in PET imaging).
A radiopharmaceutical emitting alpha or beta radiation
can be used for therapeutic or palliative purposes. These
types of radiopharmaceuticals deposit their energy on very 15.4.3 Parenteral Radiopharmaceuticals
short distances. For alpha emitters this distance is much
shorter than for beta emitters. This high-dose locally Parenteral radiopharmaceuticals are available as a simple
accumulated radioactivity is used in radionuclide therapy radionuclide in solution, for instance 131I-sodium iodide
(pain palliation of bone metastases, therapy for some spe- solution for injection, or are prepared by labelling a
cific types of cancer). non-radioactive pharmaceutical moiety (ligand) with a
Some radionuclides are emitting a combined spectrum of radionuclide. Many kits or ligands for the preparation of
radiation. One type of the radiation spectrum (alpha or beta) radiopharmaceuticals are available in the form of sterile,
is used for its therapeutic properties; the other type of the freeze-dried powders in an injection vial. These kits are
radiation spectrum (gamma) might be used for localisation non-radioactive.
of the tracer and the targeted tissue or for dosimetry. These Radiopharmaceuticals for parenteral use must comply
radiopharmaceuticals are called theranostics. with the Ph. Eur. monograph for parenteral preparations, so
Sometimes other medicines are used in combination with they have to be sterile and with a very low or absent endo-
the radiopharmaceutical, as co-medication in the diagnostic toxin concentration. For parenteral administration a sterile
process, e.g. intravenous diuretics to promote renal clear- injection in a disposable injection syringe is often filled from
ance, adenosine to induce pharmacological stress and thy- a multiple dose solution in a glass vial.
roid stimulating hormone in thyroid studies. These
pharmacological interventions increase the sensitivity or
specificity of a procedure used in nuclear medicine. 15.4.3.1 Technetium-99m Radiopharmaceuticals
99m
Technetium labelled radiopharmaceuticals form a major-
ity within all prescribed radiopharmaceuticals. 99mTc
15.4.2 Biopharmaceutics sodium pertechnetate is used for the labelling of the ligand
of choice according to fixed preparation procedures. The
Most radiopharmaceuticals are administered intravenously. ligand is a non-radioactive pharmaceutical substance that is
After injection, the radioactive substance is distributed fast part of a “kit for labelling”. Most kits contain additionally a
to the target site thereby avoiding unnecessary radiation dose stannous salt that brings the 99mTc in the right oxidation
to the stomach and gut after oral dosing. Scanning may start state for the radiochemical reaction with the ligand. Some-
immediately or after a certain period. times the reaction has to be accelerated by increasing the
The selective biodistribution and pharmacokinetics of the temperature. Many 99mTc-labelled compounds are prepared
radiopharmaceutical within the body are determined by the using this technique.
properties of the pharmaceutical agent, the stability of the
labelling, the physical and radiochemical properties of the 15.4.3.2 PET Tracers
radiopharmaceutical, the purity of the radiopharmaceutical PET imaging is performed with positron emitting radiophar-
preparation, the pathophysiologic status of the patient and maceuticals. After collision of the emitted positrons with
the possible influence of interfering medicines. electrons, pairs of gamma-rays are formed that are detected
By choosing the radionuclide the diagnostic use of the by the PET camera. The most important PET tracer is
18
radiopharmaceutical can be determined: gamma emitters or F-Fludeoxyglucose (18F-FDG) with a physical half-life
positron emitters can be used for diagnostic procedures by of 110 min. 18F-FDG is nowadays synthesised by nucleo-
providing static or dynamic images following the distribu- philic substitution of the precursor mannose triflate using
tion of the radiopharmaceutical within the body. For the fully automated synthesis procedures and cyclotron-
detection of gamma radiation a classical gamma camera is produced 18F-fluoride ions. After purification the resulting
18
F-FDG is diluted with saline, sterile filtered and dispensed scale) preparation and dispensing of radiopharmaceuticals
in multiple dose vials or in syringes. are summarised below.
Because FDG accumulates in tissues with a high glucose
uptake, 18F-FDG can be used for the imaging of tumours, for
the tracing of infections and for neuroimaging. 18F-FDG is 15.5.2 Radiopharmaceuticals with a Marketing
also useful for monitoring of therapy response. Authorisation
15.4.3.3 Complex Parenteral Like other medicinal products, licensed radiopharma-

Radiopharmaceuticals ceuticals are covered by EU Directive 2001/83/EC [5]. The
Some radiopharmaceuticals are rather complex dosage forms. most important requirements are a marketing authorisation
Radiolabelled nanospheres, nanoparticles, nanocolloids, and a manufacturing license.
peptides, monoclonal antibodies and glass particles for A marketing authorisation is mandatory for the produc-
radioembolisation are a few examples. Also autologous tion of radionuclide generators, radionuclide kits and radio-
blood cells can be radiolabelled, outside or inside the body. nuclide precursors.
The radiolabelling of blood cells is used in routine practice.
PRODUCT DESIGN
15.5.3 Radiopharmaceuticals to be Used
15.4.4 Oral Radiopharmaceuticals in Clinical Trials
Oral radiopharmaceuticals are administered as gelatin For all investigational medicinal products (IMPs) used in a
capsules. Absorption after oral use is relatively slow so it clinical trial EU Directive 2001/20/EC (“Clinical Trial
will take time before the content is distributed in the body Directive”) and GMP Annex 13 are applicable [6, 7], see
and delivered to target organs or tissues (the bone, the heart, Sect. 35.5.10. The clinical trial directive has recently been
the thyroid, brain etc.). replaced by the new and less stringent EU regulation
123
I and 131I Sodium iodide are examples of radiophar- 536/2014 [8, 9]. In this regulation, GMP and a manufacturing
maceuticals that can be administered in capsules for oral license will no longer be required for the preparation of
administration. diagnostic radiopharmaceuticals used in clinical trials when
they are prepared in a hospital radiopharmacy from licensed
sources and used within the Member State.
15.4.5 Radiopharmaceuticals for Inhalation
Some radiopharmaceuticals are administered by inhalation 15.5.4 Good Manufacturing Practice (GMP)
in the form of a radioactive gas. 81mKrypton is an example of
a gaseous inhalation radiopharmaceutical that is used in Annex 3 (Manufacture of Radiopharmaceuticals) is the only
inhalation or ventilation/perfusion studies. part of the GMP framework entirely dedicated to radiophar-
maceuticals [10]. Preparation of radiopharmaceuticals using
authorised generators and kits is excluded from this Annex.
15.5 Legislation The production of radionuclides in reactors and cyclotrons is
a physical process and is regarded as a non-GMP activity.
15.5.1 Sources of Legislation Annex 3 describes general GMP principles (quality assur-
ance, personnel, premises and equipment, documentation,
Since radiopharmaceuticals are medicines, the purchasing, production, quality control, reference and retention samples,
preparation, quality control and handling are subject to the distribution) in relation to radiopharmaceuticals. As with
same legislation and guidelines as other medicines (see Sect. other medicinal products, other GMP annexes may be appli-
35.5). However, radiopharmaceuticals are regulated as cable, for instance Annex 1 Manufacture of Sterile Medici-
radioactive substances as well. Therefore, two sources of nal Products [11].
legislation: medicine legislation and nuclear safety
regulations (e.g. nuclear energy legislation) are applicable.
Sometimes this can lead to conflicting situations, see 15.5.5 Product Quality
Sect. 15.6.3 for the discussion about pressure hierarchy in
pharmaceutical clean rooms, where GMP rules demand rel- The General Monograph 0125 Radiopharmaceutical
ative overpressure and radiation safety rules ask for relative preparations provides general information about the prepara-
underpressure. The most important regulations for the (small tion and quality control of radiopharmaceuticals [12]. More
314 R. Lange et al.
than 65 radiopharmaceutical monographs are available in the (as low as reasonably achievable; this means aim for the
Ph. Eur., in which specific requirements are elaborated. lowest possible exposure) and exposure limits (dose limits
Recently a new General Chapter has been drafted on for ionising radiation).
extemporaneous preparation of radiopharmaceutical
preparations [13]. This new chapter will provide minimal
requirements for kit-based preparations, PET radiopharma- 15.5.8 Interpretation of Legislation
ceuticals and radiolabelled blood cells. As with all General
Chapters it will not be obligatory, unless mentioned in a It is not easy to interpret all above mentioned legislation and to
product monograph. give uniform guidance for each country and each situation.
The determination of adequate quality assurance measures, for
example the GMP-classification of the clean room, should be
15.5.6 Extemporaneously Prepared the result of a risk assessment [20]. Table 15.2 gives a practical
Radiopharmaceuticals overview of the applicable guidance and the appropriate qual-
ity assurance level when preparing radiopharmaceuticals.
Legislation for extemporaneous preparation of radiopharma-
ceuticals is in principle not different from extemporaneous
preparation in general (Sect. 35.5). There is a great variation 15.6 Preparation and Dispensing
in interpretation and approach in Europe [14]. In some
countries radiopharmaceuticals are prepared based on the 15.6.1 Location of Preparation
pharmacy status of the radiopharmacy unit. In other
countries radiopharmaceuticals are prepared in laboratories, Preparation and dispensing of radiopharmaceuticals is lim-
in university institutions or research laboratories without ited to dedicated radiopharmacies. Radiopharmaceuticals for
pharmacy status, with authorisation based on radiation pro- patient use are usually prepared, controlled and dispensed in
tection legislation only. a hospital radiopharmacy department, but can also be dis-
Anyway, several guidance documents are available, pensed on a named patient base by a centralised
which can be used as standards. The European Association radiopharmacy (‘compounding centre’) that operates on a
of Nuclear Medicine (EANM) issued guidance on current commercial basis or by a centralised hospital pharmacy. The
good radiopharmacy practice (cGRPP) for the small-scale hospital (radio)pharmacist has the final responsibility for the
preparation of radiopharmaceuticals [15, 16]. In these quality of radiopharmaceuticals, also when purchased from
guidelines GMP and radiation safety requirements are an external (commercial) site. The responsible hospital phar-
interpreted for radiopharmaceuticals not intended for com- macist has to audit the external site and obtain a quality
mercial purposes. agreement, clarifying the mutual responsibilities.
Annex 3 of the PIC/S guide to good practices for prepa- Since radiopharmaceuticals are only used in a hospital
ration of medicinal products in healthcare establishments setting and usually have very short shelf lives,
interprets GMP issues for the small-scale preparation of radiopharmacies are often located in or nearby a hospital
radiopharmaceuticals [17] (see also Sect. 35.5.5). or imaging centre. Only for radiopharmaceuticals with a
longer radioactive half-life the preparing radiopharmacy
might be located at longer distance. Some PET radiophar-
15.5.7 Legislation on Radiation Protection maceuticals with a very short half-life require the presence
of both a cyclotron and a radiopharmacy in the
Directive 96/29/EURATOM (Basic safety standards) neighbourhood of the imaging centre. 82Rb is a PET radio-
provides safety standards for the protection of health pharmaceutical that must be prepared in a dedicated rubid-
workers and the general public against the dangers of ium generator next to the patient because of its very short
ionising radiation [18]. Directive 97/43/EURATOM (Medi- half-life.
cal exposure directive) gives rules concerning radiation in Radiopharmaceuticals must be handled (often asepti-
relation to medical exposure and provides dose limits [19]. cally) as quickly as possible to avoid unnecessary exposure
The International Commission on Radiological Protec- to radiation.
tion (ICRP) has issued many recommendations and guidance
documents on radiation protection. In addition to European
legislation, national and local provisions can be applicable. 15.6.2 Prescription and Dose
Radiation safety is based on general occupational safety
and health risk mitigation principles (see also Sect. 26.7): Diagnostic radiopharmaceuticals are given in extreme low
justification (of the use of ionising radiation), ALARA doses in order to minimise radiation exposure. This can be
Table 15.2 Overview of the guidance and main quality assurance issues of the different steps in the extemporaneous preparation of
radiopharmaceuticals
Type of activity/ Microbiological Local validation and product
process Guidance GMP-classification Quality control control dossier
A. Obtaining a radionuclide
Elution of a licensed generator (in particular, the Mo/Tc-generator)
Aseptic handling National Elution in class A; background: at At the start of every Microbiological No validation
guideline least class Da working day; example: monitoring of No product dossier
99
Mo-breakthrough) the eluate
Elution of an unlicensed generator
Aseptic handling National Elution in class A; background: at At each elution (extent Microbiological Product dossier with
guideline least class Da depending on risk monitoring of validation data on elution and
assessment) the eluate; QC; supplier assessment
endotoxins
Production of radionuclides using a cyclotron
High- Non-GMP
technologic [10];
PRODUCT DESIGN
process radiation
safety
legislation
Purchase of a radionuclide (licensed or unlicensed)
Administratively Not Not applicable If unlicensed: assay as Not applicable If unlicensed: supplier
applicable active substance (raw assessment
material)
B. Obtaining a pharmaceutical substance to be labelled
Purchase of a kit (licensed or unlicensed)
Administratively Not Not applicable If unlicensed: assay as an Not applicable If unlicensed: supplier
applicable active substance (raw assessment
material)
Production of a kit or starting materials for preparation of a radiopharmaceutical
Production from National Production and filling: class D if Every batch Environmental Product dossier with
starting materials guideline terminally sterilised monitoring; validation data on production
(regular bioburden; and QC
pharmacy endotoxins
production)
C. Obtaining a radiopharmaceutical
Preparation of a radiopharmaceutical using a licensed kit
Aseptic National Preparation in class A; background: Radiochemical purity Environmental No validation
preparation guideline at least class D according to SmPC; monitoring No product dossier
periodically, e.g. once a
month or at each new
batch
Preparation of a radiopharmaceutical using an unlicensed kit
Aseptic National Preparation in class A; background: At each batch; extent Environmental Depending on characteristics:
preparation guideline class D depending on risk monitoring radiochemical/
assessment radiopharmaceutical
validation of labelling;
limited product dossier
Labelling of blood cells and other complex preparations
Aseptic National Preparation in class A; background: According to SmPC or Environmental If licensed: no validation, no
preparation guideline at least class D; dedicated premises own method, at each monitoring product dossier
(preferred) or separation in time to preparation If unlicensed: product dossier
prevent cross contamination with validation data
Synthesis and purification of (PET) radiopharmaceuticals
Complex GMP Part Preparation in class A; background: According to SmPC or Environmental If licensed: no validation, no
radiochemical II and I depending on risk assessment own method, at each monitoring product dossier
synthesis and including preparation If unlicensed: product dossier
aseptic relevant with validation data
preparation annexes
Purchase of a ready to use or ready to administer radiopharmaceutical (licensed or unlicensed)
Administratively Not Not applicable If not licensed: assay as Not applicable If not licensed: supplier
applicable an active substance (raw assessment
material)
(continued)
316 R. Lange et al.

Type of activity/ Microbiological Local validation and product
process Guidance GMP-classification Quality control control dossier
D. Aliquotingb of a radiopharmaceutical
Aliquoting of an extemporaneously prepared or ready to use radiopharmaceutical
Aseptic handling National Aliquoting in clean environment, if Not applicable Not applicable No validation
guideline administered within 8 h No product dossier
E. Preparation of a radiopharmaceutical for use in clinical trialsc
One or more of GMP annex Preparation: class A; background: According to IMPD, at Environmental Manufacturing license
the 3, 1 and 13 classification depending on risk each batch, release by monitoring, required; IMPD with
abovementioned assessment QP extent validation data required
depending on
risk assessment
a
Generators for very short living radionuclides (for example a 82Sr/82Rb-generator) are situated next to the patient, in an unclassified background.
The eluate is transferred directly into the patient
b
Aliquoting is individual dose dispensing from a multidose vial
c
New clinical trial regulation is less stringent for diagnostic radiopharmaceuticals [9]
achieved by extending the imaging time of the camera. For The requirements for radiation safety (nuclear energy
therapy or palliation (e.g. thyroid gland, bone metastases) regulations) as well as aseptic processing (GMP guidelines)
higher dosages of radionuclides with high energy transfer must be met. For radiation safety the pressure within the
are applied. rooms of the radiopharmacy department where radioactive
Diagnostic as well as therapeutic radiopharmaceuticals material is processed must be negative relative to the outside
are prescribed as medicines. The radioactive dosage is usu- world. The level of underpressure needed in the preparation
ally calculated on the basis of the body weight or (in therapy) room depends on the maximal amount of radioactivity pres-
the weight and shape of the target organ. ent in operation and must meet local regulations. A pressure
After verification and acceptance of the prescribed dose difference of 10 Pa relative to the outside world is a typical
the prescription is transformed into a standardised prepara- value for a radiopharmacy clean room where kits are being
tion instruction (see Sect. 33.5). The requested dose is labelled and PET radiopharmaceuticals are being handled.
always corrected upwards for decay of the radionuclide However, for the maintenance of aseptic circumstances
during the time from preparation until administration to the GMP requires that the pressure in this room must be
patient. 10–15 Pa higher than in adjacent rooms of a different GMP
class. The airflow must be directed from the cleanest envi-
ronment towards less clean areas.
The classification of the clean room for preparation of
15.6.3 Layout of the Radiopharmacy radiopharmaceuticals should be the outcome of a risk assess-
Department ment and could be class B, C or D [11, 16, 17]. The risk
assessment should take into account the use of closed
For the design of premises reference is made to Sect. 27.2, systems, the time between preparation and use and the nature
including aseptic processes and the pressure conflicts that may of the product. The critical working zone should be class A
occur when product safety as well as personnel safety have to and can be realised with a radiopharmacy safety cabinet, an
be dealt with. A typical radiopharmacy department consists of isolator or a hot cell (see Sect. 15.6.4). A compromise to
one or more clean rooms, a quality control room and adjacent respond to these demands could be an extra airlock between
rooms such as locks for people and goods, a room for admin- the clean room clothing area (first lock) and the preparation
istration/storage, a room for cleaning materials and a waste clean room [21]. The first lock has an overpressure of
disposal room [1, 2, 21]. Often the radiopharmacy department 10–15 Pa to the outside world for keeping out particulate
is called hot lab, while this term originally refers to the matter (product protection). The second lock has an extra
room(s) where radioactive materials are handled. underpressure of 10 to 15 Pa relative to the clean room to
Ideally the radiopharmacy department in a hospital is realise a deep underpressure (the so-called sink) for radio-
situated next to or integrated in the nuclear medicine depart- protection and ‘GMP-overpressure’ of 10 to 15 Pa between
ment. Restricted access to the radiopharmacy department the clean room and this extra lock. See also Fig. 27.1.
must be assured for both radiation protection and GMP In some situations a simpler air pressure regimen, for
reasons. example an underpressured isolator in an overpressured
clean room might be sufficient to meet all regulations [21]. equipped with manipulators to perform all operations by an
However, this is subject to local requirements. operator from outside or a robot inside. When the chamber is
The pressure cascade inside the radiopharmacy premises a GMP class A working zone, the material is introduced by
has to be controlled, monitored and documented. the operator from a separate class B chamber, giving access
It should be stressed that pressure differences are not a to the class A working area. Materials enter the class B
guarantee for safe working conditions. Spreading of radio- chamber from a GMP class C clean room environment.
activity can easily take place by contaminated shoes, gloves An isotope dose calibrator is shaped as a cylinder and is
or materials, which only can be prevented by a safe working often built in beneath the working area in the safety cabinet. It
procedure. measures the radioactivity of a prepared dose in a vial or
Similarly to conventional clean rooms, qualification and syringe. Each individual radionuclide can be measured accu-
periodic requalification of the clean room conditions, the rately. Other equipment to measure radioactivity are scintilla-
aseptic workstations and personnel have to be carried out. tion counters (e.g. the NaI well counter) and semiconductor-
The scale-size, organisation and facilities of the based instruments (e.g. the Germanium detector).
radiopharmacy depend on the size and the demand of the A survey counter is a gas filled detector used to detect
nuclear medicine department and can range from simple spilled radioactive materials that can be hazardous for the
PRODUCT DESIGN
dispensing of commercial available radiopharmaceuticals to operators or may disturb accurate dose measurements. Sur-
complex synthesis of short-lived PET-radiopharmaceuticals. vey counters can be mounted at critical places to measure the
In most radiopharmacy departments one or two 99m-tech- radiation level in rooms continuously. A hand-foot-clothing
netium generators are in place. monitor is a suitable and obligatory instrument to detect
In larger departments facilities for the synthesis of PET possible contamination before leaving the area where radio-
radiopharmaceuticals are available for which a local cyclo- active materials are handled.
tron may be needed. The use of PET tracers may have A thin layer chromatography (TLC) scanner is used for
advantages in terms of speed, image resolution and radiation the quality control of a radioactive labelled product. It firstly
burden. Reasons for installing a local cyclotron are the separates the different radiochemical forms by chromatog-
extent of PET diagnostics and research, the demand for raphy and subsequently measures the radiation of the spot of
very short-lived PET radiopharmaceuticals (e.g. based on the intended radiopharmaceutical and the unwanted
13
N and 15O) and the lack of FDG availability from com- by-products (see Sect. 15.6.7 quality control).
mercial suppliers. A fume cupboard provides safe working conditions when
In some departments facilities are in place for the label- heating is needed, as some radiopharmaceuticals must be
ling of peptides or proteins (e.g. antibodies) and blood cells. heated in a water bath for some time to finish the labelling. A
When handling blood cells cross contamination or mix-up fume cupboard is also used with the preparation of radioac-
must be prevented by working in a separate dedicated room. tive diagnostic pancakes and when working with organic
volatile solvents as in thin layer chromatography for the
quality control of radiopharmaceuticals.
15.6.4 Equipment in the Radiopharmacy
15.6.4.1 Radionuclide Generators
A radiopharmacy has dedicated equipment for synthesis, Radionuclide generators are loaded by the manufacturer
preparation and quality control of radiopharmaceuticals. with a mother radionuclide. This radionuclide decays con-
The workbench for the safe and aseptic preparation of tinuously to a daughter radionuclide with suitable properties
radiopharmaceuticals is often a sufficiently lead shielded for the preparation of radiopharmaceuticals. These
radiopharmacy safety cabinet with downflow HEPA filtered generators can be used on site for a period of a week to
laminar air providing a GMP class A working zone. The several months, depending on the type of generator [1, 2].
exhaust air is filtrated and expelled outside the The radiopharmacist is responsible for the proper use and
radiopharmacy to the roof on top of the building. The cabinet pharmaceutical quality of radionuclide generators. Most
has built-in radiation protection by installed lead plates in radionuclide generators have to be eluted with a
the walls and in the working field, a horizontally movable non-radioactive infusion fluid such as sterile sodium chlo-
lead containing glass window, lead shielded instruments for ride 0.9 %. The most commonly used generator is the
99
radiation measurement and waste containment and special Mo/99mTc- generator, which is described more in detail.
equipment for automatic preparation and dispensing such as
99
a barcode scanner, printer, screen and mouse pad. 15.6.4.2 Molybdenum/99mTechnetium
A hot cell is a lead shielded locked containment chamber Generator
with underpressure, often used for handling highly radioac- The daily preparation of 99mTc-compounds requires the use
tive radionuclides and products. Hot cells are usually of a 99Mo/99mTc generator (see Fig. 15.1). A technetium
318 R. Lange et al.
Fig. 15.1 Structure of a Lead shielding

99
Mo/99mTc generator. Evacuated vial
#P.M.Berkemeyer
Eluted daughter
radionuclide 99mTc Sterile saline solution
Air vent
Sterilising filter
Glass column
Parent radionuclide 99Mo

adsorbed on alumina
Lead shielding
generator is made up of a glass column containing the quality control of generator systems has to be determined
reactor fission product molybdenum-99 adsorbed on alu- by risk assessment.
mina. 99Mo has a half-life of 66 h and decays to 99mTc
having a half-life of 6 h. The glass column is fitted within
a lead container for radiation protection. The 99mTc is eluted 15.6.5 Preparation and Handling
from the column by a sterile saline solution into an
evacuated sterile empty glass vial. The underpressure in Radiopharmaceuticals for use in a hospital are prepared or
the evacuated vial is the driving force. The resulting sterile aliquoted, labelled and dispensed for each individual patient.
solution of sodium pertechnetate is called the eluate. The Usually no stock production or storage of radionuclides
sterile eluate can be used for radiolabelling of ligands or for takes place in the radiopharmacy because of their short
preparation of a solution for injection. The 99mtechnetium shelf lives due to radioactive decay. Most radiopharma-
generator is typically eluted once or twice a day. After ceuticals are administered within a working day.
elution, the 99mTc-activity has to build up again by decay The preparation and aliquoting of radiopharmaceuticals
of the mother radionuclide to the daughter radionuclide. can be performed by pharmacy technicians, nuclear
After delivery from the supplier the new generator has the technicians or analysts, but is always the responsibility of
highest activity, every day the activity decreases. After 1–2 a (radio)pharmacist. Gowning with clean room clothing is
weeks, the generator is returned to the reactor site for similar to gowning for other clean rooms (see Sect. 31.3.4).
regeneration. Disposable gloves are used in all rooms where radioactive
The quality of the generator system should be monitored materials are handled to prevent radioactive contamination
every working day. Quality control consists of performing of the hands. Personal dosimeters must be worn during
the 99Mo breakthrough test (radionuclidic purity) and all operations with radioactive materials. When handling
assaying the aluminium content, the pH, sterility and endo- radioactive materials, exposure must be minimised by
toxin level of the eluate. The radiochemical purity test is a limiting the handling time, maximising the distance to the
routine test to quantify the different (wanted and unwanted) source (e.g. by using a tong or forceps) and the use of
chemical forms of the radionuclide (e.g. 99mTcO4 and shielding.
99m
TcO2). Not all above mentioned tests have to be Most radiopharmaceuticals are administered intrave-
performed on a daily basis. The extent and frequency of nously and must therefore be sterile. Since terminal
sterilisation is usually not possible due to the radionuclide’s the safety cabinet. Longer living radionuclides must be
short half-life, these products have to be prepared following stored in dedicated lead shielded storage cabinets that may
aseptic procedures. The most appropriate procedure is the be placed in a separated waste disposal room with negative
closed system technique. In this procedure the starting pressure. Also expired generators may be stored there,
materials and medical devices are sterile and processed in waiting for transportation. An authorised firm can take the
a clean room without direct contact with the environment. longer living radioactive residuals to a special storage site.
The most common preparation process is the so-called kit
preparation, which comprises the following steps:
• Aseptical elution of the generator. 15.6.6 Packaging and Labelling
• Quality control of the eluate (see Sect. 15.6.7).
• Aseptic transfer of a measured eluate dose to the kit vial Like other preparations, radiopharmaceuticals must be
for incubation; the radiopharmaceutical is synthesised, labelled with the required information. In most situations,
sometimes under heating. the label has to be attached to the shielding needed for
• Quality control of the radiopharmaceutical (see radiation protection.
Sect. 15.6.7). Apart from the general requirements (see Sect. 37.3) the
PRODUCT DESIGN
• Aliquoting (aseptic transfer of the radiopharmaceutical) label has to bear the following items:
into ready to administer dosage delivery devices. This • Dose in combination with the calibration time (usually
includes the measurement of the calculated dose taking the time of administration)
into account the half-life of the radionuclide and the time • Radioactivity symbol
up to administration.
• Release and dispensing (see Sect. 15.5.7).
The reconstitution and quality control should follow the 15.6.7 Quality Control and Release
instructions of the manufacturer, the Ph. Eur. monograph
or a locally validated preparation process and assay. The necessity and extent of quality control of radiopharma-
Just as with other aseptic preparation processes, a pro- ceuticals depends on the situation.
gram of environmental monitoring and personal qualifica- The quality assurance and quality control of commer-
tion for aseptic operation has to be carried out, see Sect. cially available radionuclides, non-radioactive labelling
31.6. kits and ready-to-use radiopharmaceuticals as well as their
release are the responsibility of the manufacturer.
15.6.5.1 Radioactive Stock and Waste The quality assurance, quality control and release of
Management radiopharmaceuticals prepared in the radiopharmacy and
At all times the identity and amount of radionuclides and their radionuclide precursors are the responsibility of the
radiopharmaceuticals in the radiopharmacy department must radiopharmacist.
be known. This also applies to the radioactive waste. All Sometimes real time or complete quality control is not
places where radioactive materials (including waste) are reasonably possible, especially when the radioactive dose is
stored must be protected from fire and unauthorised access. extremely high (e.g. loading of generators with mother
Radioactive waste is produced in everyday practice radionuclide) or when the half-life of the radionuclide is
within the radiopharmacy department as part of the prepara- very short. In those cases all feasible quality control tests
tion process. Examples are radioactive needles and syringes, are finalised after release, but always before administration
residuals in vials and radioactive tissues. to the patient. This two-step release requires a strict recall
In case of spilling radioactive materials, a safe procedure procedure in order to prevent administration when the
has to be followed to remove them. This leads to an extra delayed quality control results do not meet the requirements.
amount of radioactive waste. The frequency of quality control of hospital prepared
Radioactive waste must be sorted by the half-life of the radiopharmaceuticals may be determined on the basis of a
radionuclide so that it can be stored separately. Radioactive risk assessment. When using licensed generators and kits a
waste from short-lived radionuclides is often disposed of by quality control may be limited to the first vial of every new
the so-called decay in storage method. The waste is set apart batch, for example.
for a certain time period and the residual radioactivity is Quality control tests can be divided in physico-chemical
measured. If the level of radioactivity is as low as the tests (mainly radionuclidic and radiochemical purity) and
background, the material can be seen as normal hospital biological tests (sterility, endotoxins).
waste and is disposed of in closed hospital waste containers. A visual assessment of the appearance of the product
The waste of short-lived radionuclides can often be stored (e.g. the colour or clarity of the solution) may be difficult
during the working day in a lead shielded container, built in because of the radiation protection (e.g. lead glass). A visual
320 R. Lange et al.
check of the radioactive solution without radiation protec- generator system on a regular basis. For a 99mTc generator
tion may be too dangerous. Preparations containing colloids system this can be done at the end of the life cycle. Small
are not clear. volumes of the eluate are used for assuring the
microbiological quality of the generator system and its elu-
15.6.7.1 Radionuclidic Purity tion process.
A radiopharmaceutical has adequate radionuclide purity
when the fraction in the form of the wanted radionuclide is 15.6.7.5 Endotoxins
high enough to meet the specifications. Impurities in the The Ph. Eur. gives limits for radiopharmaceuticals in general
finished radiopharmaceutical may arise from impurities in but for some individual radiopharmaceutical preparations as
the target material or from fission in the reactor. Radionu- well. In most radiopharmacy departments the endotoxin
clide generators could also release unwanted impurities, for content of radiopharmaceutical preparations is not tested
example the mother nuclides. When using a 99mTc-generator before injection. In some situations, e.g. development of a
the 99Mo breakthrough has to be measured in the eluate. In new preparation process or when using generators for longer
the eluate of a 82Rb-generator 82Sr and 85Sr breakthrough periods of time (weeks to some months) endotoxin testing
have to be checked. Impurities must be limited because they may be useful (see further Sect. 19.3.4).
may impart the quality of scintigraphic images. In case of
different biodistribution of the impurities this also may lead 15.6.7.6 Quality Control of Purchased Ready
to increased radiation dose to the patient, which is of course to Use Preparations
undesirable and unacceptable. If purchased radiopharmaceuticals are used without further
processing (e.g. 99mTc-radiopharmaceuticals in syringes,
18
15.6.7.2 Radiochemical Purity F-FDG in syringes or vial, 123I in capsules), their receipt
A radiopharmaceutical has adequate radiochemical purity and supply to the nuclear medicine department is an admin-
when the fraction in the form of the wanted chemical form istrative process. On receipt the certificate of analysis is
is high enough to meet specifications. Radiolysis (degrada- checked under responsibility of the pharmacist and the
tion due to own radiation) and the usual factors that affect radiopharmaceuticals are registered. In most situations no
stability (light, oxidation, reduction, pH shifts), may cause physical or chemical quality control is necessary. It is impor-
incomplete or slow labelling, degradation and create radio- tant to purchase only from a certified supplier. However,
chemical impurities. Thin layer chromatography is the most auditing and qualifying the supplier may be necessary.
widely used technique for the analysis of radiochemical
purity. HPLC techniques may also be used, for instance for
the assessment of the radiochemical purity of PET References
radiopharmaceuticals.
1. Saha GB (2010) Fundamentals of nuclear pharmacy, 6th edn.
Springer, New York
15.6.7.3 Non-radioactive Impurities
2. Theobald T (ed) (2011) Sampson’s textbook of radiopharmacy, 4th
Sometimes non-radioactive impurities are present in edn. Pharmaceutical Press, London
radiopharmaceuticals or their precursors. To avoid undesired 3. Hesslewood SR, Keeling DH (1997) Frequency of adverse
effects of these impurities (instability, sometimes toxicity) reactions to radiopharmaceuticals in Europe. Eur J Nucl Med
24(9):1179–82
their content should be limited. Limits of well-known
4. Schreuder N (ed) (2013) Radiofarmaca Medicatiebewaking. www.
impurities can be found in Ph. Eur. monographs. radiofarmacie.nl
5. The European Parliament and the Council of the European Union
15.6.7.4 Sterility (2001) Directive 2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code relating to
Finished parenteral products prepared in the radiopharmacy
medicinal products for human use. Off J Eur Union L(311):67–128
department must be sterile. Based on a risk analysis one may 6. The European Parliament and the Council of the European Union
conclude that the risk of non-sterility is very low for standard (2001) Directive 2001/20/EC of the European Parliament and of the
radiopharmaceutical kit preparations. The risk of contami- Council of 4 April 2001 on the approximation of the laws,
regulations and administrative provisions of the Member States
nation is somewhat higher for the eluate from radionuclide
relating to the implementation of good clinical practice in the
generators, especially when they are used for a long period. conduct of clinical trials on medicinal products for human use.
The injection bottle on top of a 99mTc generator (sterile Off J Eur Union L(121):34–44
sodium chloride solution for injection) is changed asepti- 7. European Commission. Eudralex Volume 4 EU Guidelines to Good
Manufacturing Practice Medicinal Products for Human and Veteri-
cally each day; however, the inside of the generator system
nary Use – Annex 13 Investigational Medicinal Products. http://ec.
is not sterilised nor disinfected. For that reason it is europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf.
recommended to control the microbiological quality of the Accessed 14 July 2014
8. Decristoforo C, Peñuelas I, Elsinga P, Ballinger J, Windhorst A, 15. EANM Radiopharmacy Committee. Guidelines on current good
Verbruggen A et al (2014) Radiopharmaceuticals are special, but is radiopharmacy in the preparation of practice radiopharmaceuticals.
this recognized? The possible impact of the new Clinical Trials http://www.eanm.org/publications/guidelines/gl_radioph_cgrpp.
Regulation on the preparation of radiopharmaceuticals. Eur J Nucl pdf. Accessed 14 July 2014
Med Mol Imaging 41:2005–2007 16. Elsinga P, Todde S, Peñuelas I, Meyer G, Farstad B, Faivre-
9. European Parliament and Council of the European Union (2014) Chauvet A et al (2010) Guidance on current good radiopharmacy
Regulation (EU) No 536/2014 of the European Parliament and of practice (cGRPP) for the small-scale preparation of radiopharma-
the Council of 16 April 2014 on clinical trials on medicinal ceuticals. Eur J Nucl Med Mol Imaging 37(5):1049–62
products for human use, and repealing Directive 2001/20/EC. Off 17. Pharmaceutical Inspection Convention Pharmaceutical Inspection
J Eur Union L(158):1–76. http://eur-lex.europa.eu/legal-content/ Co-operation Scheme. PIC/S Guide to good practices for the prep-
EN/TXT/PDF/?uri¼OJ:JOL_2014_158_R_0001&from¼EN. aration of medicinal products in healthcare establishments. PE
Accessed 14 July 2014 010–4. http://www.picscheme.org/publication.php?p¼guides.
10. European Commission. Eudralex Volume 4 EU Guidelines to Good Accessed 14 July 2014
Manufacturing Practice Medicinal Products for Human and Veteri- 18. Council of Europe (1996) Council Directive 96/29/EURATOM of
nary Use – Annex 3 Manufacture of Radiopharmaceuticals. http:// 13 May 1996 laying down basic safety standards for the protection
ec.europa.eu/health/files/eudralex/vol-4/2008_09_annex3_en.pdf. of the health of workers and the general public against the dangers
Accessed 14 July 2014 arising from ionizing radiation. Off J No L 159:1–114
11. European Commission. Eudralex Volume 4 EU Guidelines to Good 19. Council of Europe (1997) Council Directive 97/43/Euratom of
Manufacturing Practice Medicinal Products for Human and Veteri- 30 June 1997 on health protection of individuals against the dangers
PRODUCT DESIGN
nary Use – Annex 1 Manufacture of Sterile Medicinal Products. of ionizing radiation in relation to medical exposure, and repealing
http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp- Directive 84/466/Euratom. Off J No L 180:22–7
an1_en.pdf. Accessed 14 July 2014 20. Lange R, Ter Heine R, Decristoforo C, Peñuelas I, Elsinga PH, Van
12. Ph. Eur. Radiopharmaceutical preparations 01/2014:0125. der Westerlaken MM, Hendrikse NH (2015) Untangling the web of
European Pharmacopoeia, 8th edn. Council of Europe, Strasbourg European regulations for the preparation of unlicensed radiophar-
13. EDQM (2014) General Chapter 5.19. Extemporaneous preparation maceuticals: a concise overview and practical guidance for a risk-
of radiopharmaceutical preparations. Pharmeuropa 26:1–10. http:// based approach. Nucl Med Commun 36(5):414–422
pharmeuropa.edqm.eu/TextsForComment/NetisUtils/srvrutil_ 21. Technologists Committee EANM. The Radiopharmacy –
getdoc.aspx/0L3atCJKrELmrCJamC4KkQ7Hj//51900E.pdf. A Technologist’s Guide. http://www.eanm.org/publications/tech_
Accessed 14 July 2014 guidelines/docs/tech_radiopharmacy.pdf. Accessed 14 July 2014
14. Decristoforo C, Peñuelas I (2009) Towards a harmonized radio-
pharmaceutical regulatory framework in Europe? Q J Nucl Med
Mol Imaging 53:394–401
Biopharmaceutics
16
Erik Frijlink, Daan Touw, and Herman Woerdenbag
Contents Abstract
Biopharmaceutics is the field that investigates and
16.1 From Medicinal Product to Effect and Beyond . . . . . 324
16.1.1 Design of the Medicinal Product . . . . . . . . . . . . . . . . . . . . . . . 324 describes everything that happens with a medicinal prod-
16.1.2 Pharmaceutical Availability and Bioavailability . . . . . . . 324 uct and the active substance between the moment of
16.1.3 Pharmacokinetics, Pharmacodynamics and Toxicology 325 administration, the moment it exerts its action and the
16.1.4 Solubility, Dissolution and Partition Coefficient . . . . . . . 328
moment it is eliminated from the body. Biopharmaceutics
16.1.5 Absorption and Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . 329
16.1.6 Excipient and Food Interactions . . . . . . . . . . . . . . . . . . . . . . . . 332 connects the physico-chemical properties of an active
16.1.7 Stability of the Active Substance in the Physiological substance and its dosage form with its action and fate in
Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 the living organism. It encompasses pharmacokinetics,
16.1.8 First-Pass Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
pharmacodynamics and drug delivery technology. The
16.1.9 Charge and the pH Partition Theory . . . . . . . . . . . . . . . . . . . . 334
16.1.10 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 route of administration, the way the active substance is
16.1.11 Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 released from the dosage form, and the way the body
16.1.12 P-glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 handles (absorbs, distributes, metabolises and excretes)
16.1.13 Drug Metabolising Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
the active substance, together determine its (duration of)
16.1.14 Slow Release and Flip-Flop Pharmacokinetics . . . . . . . . 337
action, its efficacy and the occurrence of adverse effects.
16.2 Dosage Forms and Routes of Administration . . . . . . . 337 This chapter explains general principles of
16.2.1 Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
16.2.2 Oromucosal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 biopharmaceutics and their implications on the design
16.2.3 Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 of medicines. It describes the general biopharmaceutical
16.2.4 Rectal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 principles that are relevant to the major routes of admin-
16.2.5 Dermal and Transdermal Administration . . . . . . . . . . . . . . 340 istration: parenteral, oromucosal, oral, rectal, dermal,
16.2.6 Nasal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
16.2.7 Pulmonary Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 nasal, pulmonary and ocular. Topics discussed include
16.2.8 Ocular Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 solubility and dissolution, bioavailability, partition coef-
16.3 New Developments and Advanced Drug Delivery
ficient and pH partition theory, the biopharmaceutical
Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 classification system (BCS), excipient-, food-, drug- and
herb-drug interactions, first-pass effects and drug metab-
16.4 Essentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
olism, bioequivalence and new developments in the field
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 of advanced drug delivery systems.
Keywords
Based upon the chapter ‘Biofarmacie’ by Erik Frijlink, Farida Kadir
and Herman Vromans in the 2009 edition of Recepteerkunde.
ADME Biopharmaceutics Bioavailability Dosage
forms Pharmacokinetics Routes of administration
H.W. Frijlink (*) H.J. Woerdenbag
Advanced drug delivery Slow release
University of Groningen, Antonius Deusinglaan 1,
9713 AV Groningen, The Netherlands
e-mail: [email protected]; [email protected]
D.J. Touw
Department of Clinical Pharmacy and Pharmacology, University
Medical Center Groningen, University Groningen, PO Box 30001,
9700 RB Groningen, The Netherlands

324 H.W. Frijlink et al.
substance and its dosage form as well as the physiological

16.1 From Medicinal Product to Effect conditions at the site of release, determine the extent and rate
and Beyond at which release will occur. However, a medicinal product
can be designed in such a way that the extent and rate of drug
16.1.1 Design of the Medicinal Product release are determined by the physico-chemical character-
istics of the dosage form. Controlled release being obtained
A medicinal product (also called medicine or drug product, in this way may affect the intensity, duration and moment
formulation or dosage form) is characterised by the quantita- of the effect. It may also affect (preferably reduce) the
tive composition (encompassing both the active substance(s) occurrence of adverse effects.
and excipients), the physico-chemical state of the active, Often, the active substance is released from its adminis-
excipients and medicinal product as a whole, as well as the tration form in a dissolved state. If this is not the case, the
structure in which the different components are present in active substance must first dissolve in aqueous environment
the medicinal product. These aspects together will determine after it has been released. Only in the dissolved state, can an
the functionality of the medicinal product and will make it active substance pass biological membranes separating the
more or less suitable for its intended use. Because the final site of administration from the systemic circulation (the
physico-chemical aspects and structure of a medicinal prod- blood circulation) via which transport to the site of action
uct are often determined by the process and process occurs. The fraction of the administered active substance
conditions used during production, a reliable, robust and that dissolves in the aqueous fluid adjacent to the biological
reproducible production is of paramount relevance for phar- membranes and thereby becomes available for passing them
maceutical preparations. is called the pharmaceutical availability. The fraction of the
The functionality of the medicinal product can be total amount of the administered active substance that ulti-
described both in technical and biopharmaceutical terms. mately reaches the systemic circulation in an unchanged
The technical terms encompass aspects such as stability, form is called bioavailability. By definition, an intrave-
uniformity of dosage and microbiological quality of the nously injected medicine will have a bioavailability of 1.0
product. The biopharmaceutical functionality of a medicinal (or 100 %). When a medicine is administered via a different
product relates to aspects such as the drug release profile, route, its bioavailability will be reduced, due to, for example,
suitability of the medicinal product for administration via incomplete dissolution or losses during the transport of
the intended route and ability of the active substance to reach dissolved active substance to the systemic circulation.
the site of action. In this chapter the basics of The transport of the dissolved active substance over the
biopharmaceutics are described and explained in relation to membranes to the blood circulation is called absorption. The
the different aspects of formulation, routes of administration extent and rate of absorption are determined by several
and therapeutic objectives. factors, including the size and charge of the active substance
Medicinal products exist in a variety of forms, to be used molecule, its lipophilicity, the volume available for active
for different routes of administration, aiming at either a substance dissolution, the surface and permeability of the
systemic or a local effect. To obtain a systemic effect, the absorbing membrane, the presence of metabolising enzymes
oral and parenteral routes are the most frequently used. and, in the case of active transport, the presence of
Alternatively, medicinal products can be given through rec- transporters. As a consequence, poor bioavailability may
tal, transdermal, nasal or pulmonary administration to be caused by incomplete dissolution of the active substance,
achieve a systemic effect. Rectal and pulmonary administra- by poor permeation over the absorbing membrane, or by
tion may also be applied for a local effect. Medicinal metabolism during absorption.
products administered to the eye, nose and ear are mostly In general, the bioavailability of an active substance is
used for a local effect. largely determined by the characteristics of the active sub-
stance and the medicinal product (which may, for example,
determine the dissolution rate), the chosen route of adminis-
16.1.2 Pharmaceutical Availability tration (different membranes show different permeability)
and Bioavailability and the administration conditions (e.g. the concomitant
intake of food with oral medicine administration). If, for
In most cases, an active substance is not administered example, a high dose of a poorly soluble active substance
directly at its site of action. As a consequence transport is is administered, the concomitant intake of two glasses of
necessary from the site of administration to the site of action. water or a meal may increase its bioavailability. If, however,
The first step in this process is the release of the active an active substance is metabolised in the liver to a large
substance from the dosage form. The delicate interaction extent, the oral route may be less suitable, making it worth-
between the physico-chemical properties of the active while to investigate whether a sublingual (under the tongue)
16 Biopharmaceutics 325
or nasal route of administration may be a better alternative. characteristics are important aspects in the design of new
Since, in contrast to the intestines, blood vessels from the medicinal products. They should be considered during the
tongue and the nose do not end up in the portal blood vessel different stages of research and development as well as during
system that immediately transports the active substance to the full subsequent lifetime of a medicine.
the liver where it is exposed to the action of metabolising To achieve the desired therapeutic effect of an active
enzymes. substance, an adequate administration form in relation to
After absorption into the systemic circulation, transport to the chosen route of administration must be used. The current
the site of action occurs. Once arrived, the active substance pharmaceutical-technological knowledge offers possibilities
can exert its action. During and after transport as well as to achieve optimal absorption of an active substance. Opti-
during and after exerting its action, distribution, metabolism mal in this context means: reliable, with a reproducible
and excretion of the active substance occur. These processes, fraction absorbed and, if necessary, with a desired control
together defined as the pharmacokinetic behaviour of the of the release profile. Already small variations in excipients
active substance, largely determine to what extent a medi- may significantly influence the pharmaceutical and
cine will be effective. The rate of absorption and elimination biological availability and hence the therapeutic and adverse
plus the volume of distribution determine the time and effects of a medicine. This applies to systemic as well as
PRODUCT DESIGN
height of the peak concentration of the active substance in local administration. Furthermore, it is to be realised that the
the blood. Therefore, they often also determine the occur- equivalence of these aspects may be of paramount impor-
rence of adverse effects. tance for generic substitution.
The following medicine-related physico-chemical
aspects may influence the release and absorption (bioavail-
ability) of an active substance and thereby its final efficacy: 16.1.3 Pharmacokinetics, Pharmacodynamics
• The chemical form of the active substance (e.g., free acid and Toxicology
or base, a salt, ester or other type of prodrug)
• The physical state of the active substance (e.g., particle Several aspects of the pharmacodynamic and toxicological
size, crystal modification) behaviour of an active substance are highly relevant to the
• The nature and quantity of excipients and their interaction desired biopharmaceutical characteristics of a medicinal
with the active substance product. The efficacy of an active substance is determined
• The dosage form (e.g., a solid dosage form or a solution) by the intrinsic receptor affinity of the compound and the
• The route of administration (e.g., oral, parenteral, rectal, receptor occupancy. Since the last parameter is difficult to
etc.) measure in man, drug blood concentrations (as measured in
• The pharmaceutical formulation (e.g. the medicinal prod- whole blood, serum or plasma) are usually taken as a surro-
uct, the quantitative composition or the structure in which gate parameter. This is based on the assumption that the drug
the active substance and excipients are present in the concentration in the blood of a patient is related to the drug
dosage form) concentration at the site of action (and thereby the receptor
Next to these factors other aspects, related to human occupancy). As well as the relationship between blood levels
physiology and external factors, may affect release and and therapeutic action, also blood levels and toxic action of a
absorption of the active substance too. These include, medicine are related. Based on this the concept of the thera-
amongst others: peutic window has been defined.
• The interaction with food or concomitantly administered The therapeutic window of an active substance is the
other medicines blood concentration range within which the desired thera-
• The presence of enzymes that metabolise the active sub- peutic effect will occur without serious side effects. The
stance before absorption lower limit of the therapeutic window is the so-called mini-
• The volume of the fluid, available at the site where the mal effective concentration (MEC). This is the lowest blood
medicine dissolves concentration of the active substance that exerts a therapeu-
• The presence of endogenous substances (such as bile tic effect. The upper limit of the therapeutic window is the
salts) that affect the solubility of active substances maximal tolerable concentration (MTC). When the MTC is
• Variations in gastro-intestinal motility reached or exceeded, unacceptable adverse effects of the
• Blood flow variations at the site of absorption active substance are likely to occur.
In summary, biopharmaceutics relates the physicochemical Figure 16.1 shows the blood concentration (can be either
characteristics of an active substance, the functionalities and a on linear as well as on log-scale) versus time curve of an
medicinal product and the route of administration to the orally administered medicine. It also shows the MEC and
performance in the living organism and to the efficacy and MTC. During the initial phase of the curve the active sub-
safety of the medicinal product. The biopharmaceutical stance is being absorbed from the intestinal lumen into the
blood. At time Tmax the maximum blood concentration It is the major objective of any medicinal product to yield
(Cmax) is reached. At that time the absorption rate has blood levels of the active substance within the therapeutic
reduced (due to depletion of the active substance from the window for the period during which the therapeutic effect is
site of absorption) to such an extent that the elimination rate desired. At the same time the Cmax should not exceed the
of the active from the body exceeds the absorption rate. MTC and the medicine administration frequency should
From this moment on the blood drug concentration will remain reasonable, preferably not more than two to three
therefore decrease. This process is characterised by the times a day. However, this objective is often not easily
elimination half-life of the active substance (t½). The dura- reached, since the degree of absorption, the absorption and
tion of drug action is determined by the period during which elimination rates, the therapeutic window as well as the
the blood concentration exceeds the MEC. The total amount intrinsic pharmacological and toxicological activities of an
of absorbed active substance (bioavailability) is active substance are varying and interactions may occur.
characterised by the area under the curve of the blood con- For example, an active substance with a longer elimination
centration versus time curve, relative to the total half-life may have the advantage of a lower dosing frequency.
administered dose. However, due to the lower elimination rate significant
amounts of active substance may still be present in the body
when the next dose is administered. Therefore the prescribed
dose must be low and it may take several subsequent
MTC administrations before the pharmacokinetic equilibrium (the
Cmax
‘steady state’) is reached and both peak and trough concentra-
tion levels will be within the therapeutic window. For
medicines that are administered once daily this may even
Blood concentration
Absorption phase
take several days and a booster dose may be needed to obtain
a faster therapeutic effect. Active substances possessing a
Elimination phase (t½) narrow therapeutic window often require therapeutic drug
monitoring (TDM). Alternatively, their rate of absorption
may need to be regulated through the use of technologically
MEC advanced controlled release products. If an active substance
AUC has to be administered frequently, because of fast elimination,
the use of a slow release product may be considered. This
technology may also be considered when toxic effects occur
Tmax due to peak concentration levels above the MTC.
Time
Concentration versus time relationships (Fig. 16.1) can be
Fig. 16.1 Blood concentration (log-scale) versus time curve of an translated into concentration versus effect relationships, both
orally administered medicine for desired and for adverse drug effects (Fig. 16.2). Within
Response to medicine
Therapeutic effect
Therapeutic effect
Adverse effect Adverse effect
1 10 100 1 10 100
Concentration of active substance in blood Concentration of active substance in blood
Fig. 16.2 Concentration versus effect relationship of different active substances. On the left hand side an active substance with a steep dose
response and a large therapeutic window is shown and on the right hand side an active with a less steep response curve and a smaller safety margin
Effect of variations in bioavailability on drug efficacy leading to an increased occupancy of those receptors
and safety and the relevance of variations in drug that are causing the adverse effects.
sensitivity. In Fig. 16.3 (right panel) the effect of a change in
Figure 16.3 (left panel) shows the effects of an bioavailability is shown in relation to individual
increased bioavailability of an active substance on differences in drug sensitivity. The drug blood con-
safety and efficacy. This may happen when a given centration versus effect relationships of the same
active substance (‘drug A’) interacts with another active substance in two different patients are given in
active substance (‘drug B’) on the level of transporting this figure. Patient A is more sensitive to the active
enzymes. If, for instance, drug B has a P-glycoprotein substance than patient B. Due to an interaction
(P-gp) inhibiting effect and drug A is excreted back between the medicine and food less active is absorbed
into the intestinal lumen by P-gp after absorption, this (e.g. the effect of milk on tetracycline) in both
interaction will lead to an increase in the blood con- patients. The bioavailability is reduced and the lower
centration and the bioavailability of drug A. However, blood concentrations are reduced by about 30 %. For
the efficacy of drug A hardly increases as a result of patient A this will not result in a significant change in
PRODUCT DESIGN
this interaction, since the efficacy was already at its efficacy. For the less sensitive patient B however, this
maximum before the interaction with drug B occurred interaction will lead to a more than 50 % reduction in
(already at the lower concentration the occupancy of efficacy. Such a reduction may, for example, lead to
receptors causing the therapeutic effect was com- the emergence of drug resistant bacteria in the case of
plete). Conversely, more adverse effects of drug antibiotic therapy.
A will occur, because of the increased blood levels
Patient B
Therapeutic effect
Patient A
Adverse effect
Concentration of
1 100
active in blood Concentration of
10
Active concentration Active concentration 1 10 100 active in blood
before interaction after interaction Active concentration Active concentration
after interaction before interaction
Fig. 16.3 Relationship between response to a medicine and blood concentration. The left figure shows the effect of an increased absorption on
efficacy and safety. The right figure shows the effect that variation in bioavailability may have in patients with different sensitivity for an active
substance
(continued)
the therapeutic window, a low drug blood concentration will Whether or not a concentration-effect curve is desired to
generally lead to a low efficacy and increasing the blood be steep or flat depends on the drug action and on the
concentration will increase efficacy. Moreover, it is consid- intended therapy. For example, for an antihypertensive med-
ered advantageous when the maximum therapeutic effect is icine it may be desirable to tune the effect and a somewhat
reached already at a concentration that is significantly below flatter profile of the curve is preferred. For other situations,
the MTC since this would yield a broad safety margin for the such as anti-migraine therapy or infections, tuning the effect
patient. This is reflected in an increased margin between the is not or less relevant. A steeper curve may have the advan-
therapeutic and the adverse effect in the curve. tage that the desired effect will be obtained sooner, provided
that the maximum effect is reached at concentrations con- Biological factors may change the solubility or dissolu-
siderably below the MTC. tion rate of the active substance from the medicinal product
The impact of variations in the bioavailability on the as well. The residence time in the stomach may increase the
efficacy and safety of an active substance can be easily dissolution of poorly water-soluble active substances and
understood from these figures. The effect of individual change their bioavailability. The pH in the stomach or the
variations in drug sensitivity in relation to variations in intestine may influence dissolution rates of acidic or basic
drug absorption can also be demonstrated. Examples are active substances whose solubility is pH-dependent. Bile
given in the box. salts may increase the dissolution rate and thereby the
absorption of poorly water-soluble active substances such
as ciclosporine, phenytoin, levothyroxine and tacrolimus.
Though, it has been shown that the association with bile
16.1.4 Solubility, Dissolution and Partition
acids reduces the absorption of the hydrophilic beta-blocker
Coefficient
atenolol.
It is not only the solubility in aqueous solutions that may
For many medicinal products dissolution in an aqueous envi-
affect the biopharmaceutical behaviour of an active sub-
ronment (e.g. the fluids of the gastro-intestinal tract or mucosal
stance. The solubility in non-polar solvents is of impor-
lining fluids in the airways) is the major release mechanism of
tance too. The solubility in a lipid phase is of relevance to
the active substance. The dissolved concentration of the active
the passive transport of the substance over lipid
substance is the driving force for all diffusion-based drug trans-
membranes, a process that plays an important role in the
port mechanisms, since only the dissolved active substance is
absorption of many drugs. In order to quantify the
able to pass the absorbing membranes. Therefore the aqueous
lipophilicity of an active substance in relation to its aque-
solubility of an active substance and the dissolution rate of the
ous solubility the concept of the partition coefficient
active substance from a medicinal product are considered to be
was developed. The partition coefficient is defined as the
highly relevant characteristics. To a large extent they determine
quantitative distribution ratio of a dissolved substance over
the performance of a medicinal product in terms of bioavailabil-
two immiscible liquids at equilibrium. In the pharmaceuti-
ity, efficacy and safety. The fundamentals of solubility and
cal sciences the ratio of the concentrations in an aqueous
dissolution (rate) are described in Sect. 18.1.
phase (water or aqueous buffer solutions) and a lipid
The solubility of an active substance and the dissolution
phase (e.g. n-octanol) is often considered. For this purpose
rate of a medicinal product can be varied by changing either
the so called log P value has been defined. The partition
the characteristics that relate to the active substance (such as
coefficient between an aqueous and a lipid phase (log Po/w
particle size, salt form, crystalline form, the use of a
value) of non-ionised substances is defined according
pro-drug like an ester) or characteristics of the medicinal
to (16.1):
product (such as the use of disintegrants, complex-forming
agents like cyclodextrins or polymers that form highly vis- log Po=w ¼ log ðCso =Csw Þ ð16:1Þ
cous gels, and the application of diffusion limiting coatings).
See the box for examples. In this equation Csw is the saturation concentration of the
active substance in the aqueous phase and Cso is the satura-
There are numerous examples of medicinal products tion concentration in the lipid phase. In general, the partition
in which dissolution rate enhancing technologies are coefficient between an aqueous buffer or water and
applied to increase the bioavailability or absorption n-octanol is determined.
rate of an active substance. Cardiac glycosides should For active substances that can be ionised the distribution
be given as micronised particles in a solid oral dosage coefficient (log D) has been defined. The oil-water distribu-
form because otherwise their dissolution rate and tion coefficient (log Do/w value) for a substance is presented
hence their bioavailability is too low. Piroxicam was in (16.2):
shown to be absorbed faster when given as a cyclo-
dextrin complex, which increases the dissolution rate. log Do=w ¼ log Co = Cw i þCw n ð16:2Þ
Similarly, the bioavailability of albendazole as a
cyclodextrin complex was increased compared to In this equation Co is the concentration of the substance in
crystalline non-complexed albendazole, based on the the lipid phase, Cwi is the concentration of the ionised
same mechanism. And finally, the bioavailability of substance in the aqueous buffer at a specific pH and Cwn is
amorphous chloramphenicol is higher than that of the concentration of the non-ionised substance at the same
crystalline chloramphenicol. pH. From the definition it follows that the distribution coef-
ficient varies with the pH of the aqueous buffer.
16.1.5 Absorption and Bioavailability substances will be transported faster over the lipophilic
absorption membrane than those with a more hydrophilic
Poor aqueous solubility or a low dissolution rate or both may character. In general, lipophilic active substances will not
be the cause of poor bioavailability. For poorly water- accumulate into the lipid parts of the absorption membrane
soluble active substances, the amount and composition of because the continuous blood flow in combination with
endogenous aqueous fluid, present at the site of absorption protein binding of the active substance will keep the internal
will play an important role. In the stomach and in the small concentration low. They will also maintain the concentration
intestine there is ample aqueous fluid available, but in the gradient at a maximum causing rapid uptake of the substance
mouth, the nose or the rectum a volume of only a few into the systemic circulation.
millilitres is available. The lipophilicity of an active substance, and thereby its
tendency to pass lipophilic membranes, can be described in
16.1.5.1 Absorption terms of the octanol-water partition coefficient and the polar
After being dissolved the next step is the absorption, so surface area. The octanol-water partition coefficient, the log
passing the biological membrane. The surface area and P value, should be within the 0.4–5.6 range and preferably
type of membrane are major determinants for the extent below 3. The polar surface area of a compound is the total
PRODUCT DESIGN
and rate of absorption. Active substances may be transported sum of the surface of the polar atoms in the molecule. In
over the membrane passively or actively. Absorption via general this will refer to the oxygen and nitrogen atoms in
passive transport may occur as paracellular transport through the molecules and include the hydrogen atoms attached.
the interstitial spaces between the cells lining the absorptive Co-inclusion of sulfur and phosphor atoms in the
membrane. For absorption by passive diffusion across a calculations was shown to add little to the predictive value
biological membrane, the concentration gradient is the of the results. When the polar surface area of a molecule
driving force according to Fick’s diffusion law. A high exceeds 140 Å2 the molecule is too hydrophilic and consid-
external (or luminal) concentration (dissolved active sub- ered to be unsuitable for absorption after oral administration.
stance at the site of absorption), will increase the absorption For special barriers such as the highly lipophilic blood brain
rate over the biological membrane. The continuous blood barrier the threshold is 60 Å2.
flow in combination with protein binding of the active sub- Apart from the partition coefficient and the polar surface
stance will keep the internal concentration low and maintain area, several other molecular characteristics predict mem-
the concentration gradient. brane permeation; major determinants are:
This transport mechanism is typical for the absorption via • Molecular weight, which is preferably below
mucosal membranes such as the intestinal tract, the intra- 300–500 Da
oral (sublingual or buccal), nasal or pulmonary membranes. • Number of H-bond donors and H-bond acceptors, not
The size of the interstitial spaces in mucosal membranes more than 3 donors and not more than 3 acceptors
may vary in size between around 0.4 nm for the duodenum • Number of rotatable bond bonds, not more than 3
up to about 4 nm for the alveolar membranes in the lung. In • Number of non-hydrogen atoms
general the absorption through the interstitial space is lim- Furthermore, a limited number of active substances are
ited to small hydrophilic molecules such as nitroglycerin absorbed by active transcellular transport mechanisms, a
after sublingual administration. The absorption of smaller process that may even occur opposing a concentration gra-
proteins (up to a molecular weight of 20 kDa) via the alveo- dient. This mechanism is characterised by the involvement
lar membrane in the lung is an exception to this rule. The of transporter enzymes able to transport the molecules of the
larger interstitial spaces between the alveolar type I cells active substance over the intestinal membrane. An example
(covering 93 % of the alveolar surface) enable what may be is the absorption of angiotensin converting enzyme
the only non-parenteral route for the administration of inhibitors such as lisinopril and enalapril, which is mediated
proteins. by the di/tri-peptide transporter protein (PepT1). Competi-
Passive transport of lipophilic substances may occur via tion for or induction of transport enzymes may have a
the fluid bilayer membrane of the cells lining the significant effect on the absorption of these active
membranes. This transcellular route is the most important substances. This makes them sensitive for drug-drug or
route for membrane passage of active substances. This trans- drug-food interactions that may significantly affect the
port mechanism is not only driven by the concentration drug absorption, and thereby drug efficacy and safety.
gradient over the absorptive membrane, but also by the oil
to water partition coefficient of the active substance 16.1.5.2 Bioavailability
(expressed as the octanol-water partition coefficient, which The bioavailability of an active substance is defined as the
describes the ratio of the substance’s solubility in aqueous fraction of the administered active substance that enters the
and fatty phases, see Sect. 16.1.9). More lipophilic systemic circulation (for oral administration the circulation
beyond the liver) in unchanged form. The absolute bioavail- investigated, to find out whether the bioavailability is
ability of an active substance is calculated from the area affected by the dissolution behaviour.
under the curve (AUC) of the blood concentration of The corticosteroid dexamethasone has a poor aqueous
unchanged drug versus time profile found following intrave- solubility of 89 microgram/mL. It is given by the oral route
nous administration (by definition 100 % bioavailability) for different diseases. When the medicine is given with a
and the AUC found following the chosen administration glass of water the oral route offers a dissolution volume of
route, corrected for the dose (D). The bioavailability after, about 500 mL in the stomach. When the 4 mg dose used in
for example, oral administration (For) is thus calculated rheumatic diseases is given by the oral route the dose num-
from (16.3): ber will be 0.09 and no major dissolution problems are to be
expected. However, when dexamethasone is used in
For ¼ ½ðAUCor : Div Þ=ðAUCiv : Dor Þ : 100% ð16:3Þ pyodermia gangrenosum the dose has to be 300 mg. At this
dose, the dose number will be 6.7. This is close to 10 and the
Differences in bioavailability of different medicinal dissolution behaviour of the medicinal product has to be
products or after administration via different routes can investigated in order to prevent incomplete absorption of
also be deduced from the ratio of the AUCs of the blood the dexamethasone.
concentration versus time curves. The biopharmaceutical classification system (BCS) not
As well as the total absorbed fraction, the absorption rate only considers solubility but also considers the permeability
is also an important aspect of bioavailability. The absorption of the absorbing membrane. This system classifies active
rate is characterised from the maximum blood concentration substances based on their water-solubility in relation to
and the time at which the maximum concentration occurs in their dose and the route of administration and to their per-
the concentration versus time curve. meability over the absorptive membranes. The BCS divides
The absorption rate of an active substance is relevant to active substances into four classes:
the therapeutic effect for various reasons. If an active sub- • Class I: high solubility, high permeability
stance is used in an acute situation (e.g. epileptic insult, • Class II: low solubility, high permeability
asthmatic attack, sleep induction, pain killing), a high • Class III: high solubility, low permeability
absorption rate is preferred. A formulation design in which • Class IV: low solubility, low permeability
the active substance is already dissolved, may be useful in This classification system is used to characterise potential
such case. A prolonged effect can be achieved however by a problems related to bioavailability and bioequivalence of an
dosage form from which an active substance is released active substance [1].
slowly (sustained release). Finally, if an active substance The variable solubility is determined by the intrinsic
has a longer residence time in the absorbing organs, the solubility of the active substance in the aqueous fluids avail-
bioavailability may be negatively influenced by, for exam- able for dissolution, the dose at which the medicine is given
ple, enzymatic or chemical degradation. and the volume of liquid that is available for a certain route
of administration. A medicine that is administered orally
16.1.5.3 Dose Number and Biopharmaceutical will have a larger volume of liquid available
Classification System (250–750 mL) for dissolution than a medicine that is
The solubility of an active substance in the different body administered via the sublingual or rectal route (5–15 mL)
fluids and the efficacy of the absorption process, together and the composition of the different fluids varies. As a result,
with the dose determine the bioavailability of a medicine. dissolution problems are to be expected for the sublingual or
The dose number (DN) is a dimensionless parameter that rectal route at lower doses than for the oral route. In general
links solubility (Cs) to dose (D) and volume available for an active substance is considered to be highly soluble when
dissolution (V) during the absorption process. The dose the highest dose applied dissolves in about one third of the
number can be calculated from (16.4): total available volume for dissolution. For the oral route, for
example, an active substance is considered highly soluble
DN ¼ D : ðCs : VÞ‐1 ð16:4Þ when the highest dose dissolves in 250 mL of an aqueous
liquid with a pH between 1.0 and 7.5.
When the dose number is less than 0.1 dissolution is not The variable permeability is determined by the absorption
expected to affect the absorption process, whereas at a dose of the dissolved active substance over the membrane. This
number above 10 dissolution is most likely to decrease the may be measured by the direct assessment of the mass
absorption (rate) of an active substance. In general, transfer (rate) over the human intestinal membrane or
solubilisation technology has to be applied for such predicted from relevant animal models or in vitro epithelial
compounds. When the dose number is between 0.1 and cell culture models. An active substance is considered highly
10 the effect of dissolution on drug absorption should be permeable when the extent of absorption is 90 % or higher.
Knowledge of the bioavailability and absorption rate of

an active substance is important because these are important product and its performance may result in signifi-
determinants of efficacy and safety. Large variations in cant fluctuations in effect or safety. Examples of
bioavailability or absorption rate may, in the case of such active substances include: ciclosporin,
decreased absorption (rate), result in insufficient efficacy. tacrolimus, digoxin, ergotamine, levothyroxine,
In the case of unexpectedly high absorption it may lead to capecitabine and phenytoin.
toxicity or serious adverse effects. Quantitative data on the • Safety issues to be considered are the exact equiva-
bioavailability and absorption rate are necessary to evaluate lence of the products (especially for ‘biologicals’
the equivalence or non-equivalence between different this may pose a problem) and the risk of allergy or
medicinal products with the same active substance. These intolerance for a specific excipient (e.g. colouring
data may be used as surrogate parameters to establish effi- agents).
cacy and safety of a (generic) product. • When specific administration devices (affecting
parameters of relevance to the performance
characteristics such as efficacy and safety of a
According to the EMA two products are considered
medicinal product) are used substitution should
to be bioequivalent when they contain the same active
PRODUCT DESIGN
not occur. Different dry powder inhalers, for exam-
substance and when their respective bioavailabilities
ple, generate aerosols of significantly different par-
(rate and extent) after administration in the same molar
ticle size. As a result, relevant variations may occur
dose and via the same route, lie within acceptable
in lung deposition of the active substance. There-
predefined limits. These limits are set to ensure com-
fore substitution of these types of products (e.g. dry
parable in vivo performance, i.e. similarity in terms of
powder inhalers) should not occur.
safety and efficacy. The design and number of studies
• The appearance of the product. When large
that is to be carried out to establish bioequivalence
differences in appearance between both products
depends on the physico-chemical and pharmacokinetic
exist, substitution may confuse the patient.
properties of the active substance. In this respect ref-
• The performance characteristics and handling of
erence is made to the BCS classification of the active
both medicinal products should be similar (e.g. for
substance. For BCS class I active substances it may
auto-injectors, or the occurrence of a score on the
even be possible to obtain a waiver for the in vivo
tablet that allows for dividing a dose).
studies (a so-called biowaiver), whereas for the active
substances showing more complex pharmacokinetic
behaviour extensive studies are to be carried out. In
general bioequivalence will be determined from the Medicinal products administered at a specific site to
parameters Cmax and AUC. Two products are consid- obtain a local effect should preferably not be absorbed
ered to be bioequivalent when the 90 % confidence systemically. However, significant amounts of active sub-
interval of the ratio of test and reference product falls stance can be absorbed, e.g. after application on the skin.
within the 85–125 % acceptance interval. However, Removal of locally acting active substances from the site of
for the required design of the bioequivalence study and action by systemic absorption may result in systemic effects
statistical evaluation details for a specific active sub- that can be considered as adverse effects. After nasal, ocular,
stance reference is made to the appropriate (most pulmonary and rectal administration of active substances for
recent) guideline on this subject [2, 3]. a local effect, absorption into the systemic circulation is
When in daily practice substitution (e.g. by a likely to occur. This may cause adverse effects and limit
generic product) is considered, bioequivalence is of the duration of the desired drug effect. Conversely it should
course the first parameter to evaluate. However, other be realised that the systemic route is often also the main
aspects of medicine’s use related to both the product route for clearance of the active substance from the site of
and the condition of the patient are to be taken into administration. The bioavailability of locally acting
consideration as well. Among these are: medicines is, of course, not determined by the amount of
• For active substances that have a narrow therapeu- active substance that reaches the systemic circulation. As an
tic window or non-linear kinetics substitution is not alternative the fraction of the active substance that is
advised since even the smallest variations in the dissolved in the aqueous fluids at the site of application is
usually taken as a measure for the bioavailability.
(continued)
16.1.6 Excipient and Food Interactions the form of a more stable salt, for example erythromycin
ethylsuccinate.
An active substance, although initially released from its Enteric coated products exist in various presentation
dosage form (and dissolved), may become unavailable for forms. They include tablets surrounded with the coating,
absorption due to reactions with other medicines or food coated pellets in a capsule or coated pellets compressed
components [4]. An example is the formation of insoluble into a tablet (see Sect. 4.10). This last form sets specific
complexes of tetracycline with calcium or aluminium ions requirements to the quality of the coating around the pellets
from antacids or milk products. Interaction (chelation or since the integrity of this coating must not be compromised
binding) with iron ions leads to a reduced absorption for a during the tablet compaction process. Depending on the
variety of active substances such as doxycycline, penicilla- presentation form, tablet breaking may or may not be
mine, methyldopa and ciprofloxacin. The absorption of allowed. Tablets covered with an enteric coating may
active substances showing pH-dependent dissolution never be broken, whereas controlled release tablets produced
behaviour may be influenced by medicines that influence from coated pellets may be divided or sometimes even
the gastric pH, such as H2-antagonists, proton pump dispersed for a short period of time in liquids or semisolid
inhibitors and antacids. Antimycotic active substances such food (custard, yoghurt). The same can be done with capsules
as ketoconazole or itraconazole dissolve better in acidic containing coated pellets. However, coated products should
fluids. Therefore their bioavailability may be increased by never be longer than 5 min in drinks or food before use.
the concomitant use of an acidic drink like cola, whereas the Crushing is not allowed for any controlled release
concomitant use of antacids or proton pump inhibitors is formulation.
likely to reduce the bioavailability. Concomitant use of Metabolic instability of the active substance in the physi-
milk may increase the dissolution of acidic active ological environment may reduce bioavailability especially
substances, whereas fats from food may increase the bio- after oral administration. Enzymatic degradation of an active
availability of lipophilic active substances like albendazole substance in the lumen of the stomach or intestine may
and griseofulvin. reduce the amount of active substance available for absorp-
In dermal preparations ion-pair formation between ionic tion, whereas after absorption enzymes in the intestinal wall
surfactants and an active substance may reduce the local and the liver may reduce the bioavailability. This is called
availability of the active substance. An example is the inter- the first-pass effect.
action between the anion laurylsulfate (from the surfactant After intramuscular or subcutaneous injection, bioavail-
sodium laurylsulfate) and the cationic neomycine or tetracy- ability may become reduced because of enzymatic break-
cline in creams. down of the active substance at the site of injection.
It is important that the (clinical) pharmacist always
provides appropriate advice to the patient about how to
take a medicine and warns against the concomitant use of 16.1.8 First-Pass Effect
other medicines or certain foods, in cases where interactions
may occur. The potential risk of interactions may even be of Following oral administration and absorption from the intes-
greater clinical importance when they occur at the level of tine, an active substance passes the intestinal wall and the
the metabolism of the active substance. This issue is liver. During uptake from the gastro-intestinal tract,
discussed in Sect. 16.1.13. enzymes present in the intestinal lumen or in cells of the
intestinal wall can metabolise an active substance. Subse-
quently the absorbed active substance is transported to the
16.1.7 Stability of the Active Substance liver by the portal vein system. During the first passage
in the Physiological Environment through the liver, liver enzymes may metabolise another
part of the active substance. The metabolic degradation
Several active substances are unstable in an acidic environ- during the first passage of intestine and liver may signifi-
ment and will degrade when in contact with gastric juice. cantly reduce the bioavailability since it occurs before the
Examples are omeprazole, pantoprazole, erythromycin and active substance is distributed over the entire body. This
pancreatic enzymes. Such active substances are formulated particular loss of active substance, after absorption but
in a tablet or pellets covered with an acid-resistant layer, a before distribution, is called the first-pass effect.
so-called enteric coating. The acidic nature of the polymers The extent of a first-pass effect of an active substance
used in these coatings prevents dissolution in the gastric depends on the dose and absorption rate in relation to the
environment. The coating will dissolve in the small intestine enzymatic capacity. Moreover, the first-pass effect can be
(with higher pH values), after which the active substance is influenced by the concomitant use of food, which may affect
released. Alternatively, the active substance may be used in the absorption rate or induce or inhibit the enzymatic
degradation of certain active substances. From this perspec- Transformation

tive it is clear that the bioavailability of an active substance rate ((v))
can be optimised by taking a medicine at the appropriate Vmax
time, e.g. before, during or after a meal. Examples of active
substances that undergo a high first-pass effect after oral
administration include: amiodarone, ciclosporin,
6-mercaptopurin, metoprolol, midazolam, morphine, nifedi-
pine, propranolol, saquinavir, tacrolimus, terbutaline and ½ Vmax
verapamil.
The hepatic first-pass effect can be circumvented by
giving a medicine through a route of administration that
does not primarily absorb the active substance via the portal
vein system, such as an intramuscular or subcutaneous injec-
Km
tion, sublingual or nasal administration or via the pulmonary Concentration [S]
route. The rectal route is often mentioned as an option too.
PRODUCT DESIGN
However, since two of the three rectal veins do end up in the Fig. 16.4 Relationship between the substrate concentration [S] and
portal vein, the maximum effect of this route will be a rate of transformation [ν]
reduction of the first-pass affect by only about 30 %.
16.1.8.1 First-pass metabolism and controlled transformation rate and thereby the (relative) amount of
release products active substance that will escape the metabolism and will
In order to understand the relevance of first-pass metabolism become bioavailable. At lower concentrations the enzymatic
for the formulation of controlled release products, one system will be far from saturated and bioavailability will
should have a basic understanding of enzyme kinetics. thus be low. If, in contrast, higher doses are given,
Enzyme kinetics are described using the Michaelis-Menten concentrations levels far beyond the Km may be present in
equation (16.5). This equation describes the rate of transfor- the portal blood and a dose-dependent increase in bioavail-
mation of a substrate (the active substance) by an enzyme. ability may occur (non-linear absorption kinetics).
When an active substance at a specific dose already
ν ¼ Vmax :½S= ðKm þ ½SÞ ð16:5Þ generates portal blood concentrations around or even some-
what beyond the Km even a minor increase in dose may
In this equation ν is the enzymatic reaction rate, Vmax already cause a significant increase in bioavailability. But
represents the maximum transformation rate (the rate even a new formulation with the same dose that dissolves
achieved at complete saturation of the enzymes), [S] is the somewhat faster may result in a faster absorption and thus in
substrate concentration and Km the substrate concentration higher concentrations in the portal blood, which may lead to
at ½Vmax. Figure 16.4 shows the relationship between the an increased bioavailability.
substrate (active substance) concentration and the transfor- Conversely, if an immediate release product with a given
mation rate. dose yields a reasonable bioavailability (in spite of a signifi-
At low concentrations an enzymatic system is able to cant hepatic first-pass metabolism) because the portal
efficiently break down the presented active substance. concentrations generated by the immediate release product
When the concentration of active substance (substrate) are far beyond the Km, one can easily image what the effect
rises, the transformation rate will increase proportionally to of a slow release formulation would be. Even although the
the increase in concentration of active substance. As a result dose may be higher, the release of the active substance and
the relative amount of active that is metabolised will remain the subsequent absorption are slower. Consequently, signifi-
the same. However, as the concentration increases further cantly lower concentrations will occur in the portal blood,
(significantly beyond the Km) the enzymatic system will get the enzymatic system will be less saturated and lower
saturated and the increase in rate of transformation will no amounts of active substance will escape from the enzymatic
longer be proportional to the increase in concentration. As a degradation in the liver. At the end this may result in signifi-
result relatively more active substance will escape from cant reductions in the bioavailability. It is for this reason that
transformation by the metabolic enzymes. caution should be exercised during the development of slow
This is exactly what happens when an active substance release products of active substances that exhibit a signifi-
that suffers from high first-pass metabolism is given orally. cant first-pass effect.
After absorption from the intestinal tract the active substance In Fig. 16.5 the effect of a variable dose on the relative
is transported with the hepatic blood flow to the liver. The bioavailability of an active substance with a high first-pass
concentration in the hepatic blood determines the metabolism is presented as well as the effect of absorption
Relative Relative
bioavailability bioavailability
Dose Absorption rate
Fig. 16.5 Effect of the dose (left) and the absorption rate (right) on the relative bioavailability
Absolute Absolute
bioavailability bioavailability
Dose Absorption rate
Fig. 16.6 Effect of the dose (left) and the absorption rate (right) on the absolute bioavailability
rate of a certain dose on the bioavailability of an active substances with a high partition coefficient will be absorbed
substance with a high first-pass metabolism. It is assumed rapidly once they are dissolved. Weak acids and weak bases
that the dissolution rate of the active substance is not are usually absorbed in their non-ionised form since this
affected by the dose. form has a much higher partition coefficient than the ionised
The effects of dose and absorption rate on the absolute form as follows from the distribution coefficient. The driving
bioavailability are presented in Fig. 16.6. force of the passive absorption process is the concentration
The phenomena described above clearly illustrate the gradient of the non-ionised active substance. The pH parti-
significant effects on bioavailability that even small tion theory states that the non-ionised fraction of a weak acid
variations in absorption rate may cause. It should be realised or a weak base is determined by the pKa of the active
that such small variations may easily occur upon formulation substance and the pH of the surrounding environment. The
changes or due to food effects on dissolution and/or non-ionised fraction of an active substance can be calculated
absorption rate. using the Henderson-Hasselbalch equation, which after
rearrangement looks for an acid as:
‐1
16.1.9 Charge and the pH Partition Theory Non‐ionised fraction ¼ 1 þ 10 pH‐ pKa ð16:6Þ
Since the absorptive membrane is a lipophilic barrier, active For a base the equation is:
substances are generally absorbed in a form that is able to ‐1
pass lipophilic barriers. Therefore the difference in partition Non‐ionised fraction ¼ 1 þ 10 pKa‐ pH ð16:7Þ
between the oil and water phase is a major driving force for
the absorption process. Often the octanol-water partition The equations 16.6 and 16.7 show that for a weak acid the
coefficient is used to quantitate this (see Sect. 16.1.4). Active highest non-ionised fractions exist in an acid environment,
whereas a more alkaline environment will result in a higher

non-ionised fraction of basic active substances. However,
one should realise that the water-solubility of the ionised
from is significantly higher than of the non-ionised form.
This contradiction causes one of the major problems in
medicine formulation and bioavailability. An environment
in which the majority of the active substance is ionised is
required in order to obtain a fast dissolution, whereas an
environment in which the active substance is largely
non-ionised is required for rapid membrane passage.
Fully ionised active substances, for which no specific
carrier is available in the membrane, are generally too Fig. 16.7 Chemical structure of eprosartan
hydrophilic to be absorbed from the gastro-intestinal tract.
Not many quaternary ammonium compounds are available
in a non-ionised form in the gastro-intestinal tract after oral blood, keeping the concentration difference at a maximum,
and by the binding of the active substances to proteins and
PRODUCT DESIGN
administration due to their high pKa. These active
substances are therefore only administered as an injection. cells in the blood. Therefore transport of active substances
Other active substances for which ionisation may hamper from the absorption membrane into the blood will in general
absorption after oral administration are those active not be the rate-limiting step in the absorption process.
substances that contain multiple H-bond acceptors and
H-bond donors with varying pKa values. Some of these
active substances may not exist in a non-ionised form at 16.1.10 Distribution
any of the pH values that occur in the gastro-intestinal
tract, which may significantly reduce their bioavailability Active substances are often distributed over the body and
after oral administration. An example is the angiotensin II tissues via the blood. Interactions at the level of protein
inhibitor eprosartan (chemical structure shown in Fig. 16.7): binding in blood are possible, for instance with another
an active substance with two carboxylic acid and two amine active substance competing for binding sites on the protein.
functions. The oral bioavailability of eprosartan is only This may result in different drug concentrations in various
13–15 %. The limited oral bioavailability is explained by tissues since the free concentration in the blood determines
both the pH dependent dissolution behaviour of eprosartan the transport into the tissue (or to the site of action). If the
in combination with the degree of ionisation of the dissolved free concentration increases the therapeutic efficacy may
active substance at the different pH values encountered in increase but it may also lead to toxic side effects. However,
the gastro-intestinal tract. clearance may also be increased when the free drug concen-
It is also important to know that the acid-base equilib- tration is increased. For active substances with a narrow
rium adjusts rapidly. If a non-ionised form of an active therapeutic window such as valproic acid or carbamazepine,
substance has a high partition coefficient, this may com- this type of interaction must be taken into account. However,
pensate for the presence of lower fractions of non-ionised after having gained a newly established equilibrium, the
active substance at the absorption site. Due to the fast concentration of free active substance, responsible for the
absorption of the small fraction of non-ionised active sub- activity and subject to biotransformation, usually, hardly
stance in the vicinity of the absorbing membrane a contin- changes (as a result of the increased clearance). Most
uous de-ionisation of ionised active substance will occur as interactions on the metabolic level are caused by enzyme
a result of the continuous equilibrium adjustment. In this inhibition or induction (see Sect. 16.1.13).
way even active substances with somewhat lower
non-ionised fractions at the absorption site (active
substances possessing only a single ionisable group) may 16.1.11 Clearance
still show a considerable absorption rate.
After being taken up over the membrane the second step Many active substances are eliminated from the body after
in the active substance absorption process is the transport of biotransformation. The metabolites are subsequently cleared
the active substance into the blood. Again the concentration via one of the excretion routes or further metabolised to
gradient and partition coefficient will be the rate determining products that can be excreted. The major routes of excretion
factors for passive transport. However, even for lipophilic encompass glomerular filtration followed by excretion into
active substances the transport to the blood will be rather the urine, excretion of the active substance or its metabolites
fast. This is caused by the continuous refreshment of the into the faeces (via the liver and bile, biliary excretion) or via
the exhaled breath. Biotransformation and glomular filtra- 16.1.13 Drug Metabolising Enzymes
tion are the major routes of elimination for most active
substances. The bioavailability of an active substance can Biotransformation of active substances largely occurs
therefore be influenced by interaction with other active through the action of cytochrome P450 enzymes, a large
substances (or food components) that inhibit biotransforma- group of mono-oxygenases located primarily in the liver
tion enzymes, change the glomerular filtration rate or by and the intestine. They are responsible for oxidative
genetic polymorphisms. metabolising steps, often preceding glucuronidation
When an active substance is excreted via the biliary route followed by urinary or biliary excretion. These enzymes
a so-called enterohepatic circulation may occur. This means can be inhibited by active substances (or by food
that the active substance that is removed from the circulation substances). Conversely several active substances are able
by the liver and (after glucuronidation) excreted via the bile to induce them. Enzyme inhibition will increase the bio-
into the lumen of the intestinal tract. In the intestinal tract availability of active substances that are metabolised by
(after deglucuronidation) the active substance can be these enzymes, which may cause toxicity. However, enzyme
absorbed again into the systemic circulation via the intesti- induction will reduce bioavailability and increase systemic
nal membrane. This effect will usually be seen as a second clearance, which in turn may reduce the therapeutic efficacy.
peak in the blood concentration versus time curve. The effect Especially the inhibition or induction of cytochrome
that this phenomenon could have on the AUC of a medicine P450 subtype 3A4 (CYP 3A4) is clinically relevant, because
should be taken into account when the bioavailability is a variety of active substances and food substances
determined since these effects may seriously compromise (e.g. grapefruit juice) are able to affect this enzyme.
the outcome of the calculations. Substances inhibiting CYP 3A4 include: ciclosporin,
dihydropyridines, verapamil, midazolam, paclitaxel, simva-
statin, lovastatin, atorvastatin, cimetidine, erythromycin,
troleandomycin, ketoconazole (and other azoles).
16.1.12 P-glycoproteins
Substances inducing CYP 3A4 include: steroids, rifampicin,
phenobarbital and St John’s wort.
P-glycoproteins (P-gp) are membrane-bound transporters
Drug metabolising enzymes can be over- or underactive
that are able to actively remove active substances and
in different individuals and between populations of different
other xenobiotics from the cell. P-glycoproteins are
ethnic background. Genetic polymorphism may be the
energy-dependent and present in many tissues, including
underlying feature. Polymorphisms with relevance for drug
the blood-brain barrier, the intestinal wall, the liver and the
metabolism are found for N-acetyltransferases and for cyto-
kidney, and responsible for the active removal of among
chrome P450 subtypes 2D6 and 2C19.
others, antineoplastics [5]. Typical substrates for
P-glycoproteins are digoxin, metronidazole, saquinavir,
talinol and calcium antagonists. P-glycoproteins may Herb-Drug Interactions
actively add to the absorption process of active substances, Herb-drug interactions may be clinically relevant
but they are mainly known for their capacity to remove [6, 7]. The dosage and the duration of treatment with
active substances once they are absorbed. Many active herbal preparations should be taken into account to
substances are known to be excreted again by P-gp assess the possible interaction risks with regular phar-
mediated transport into the intestinal lumen after being macotherapy. Special attention should be given to
absorbed first. This may significantly reduce the bioavail- active substances with a narrow therapeutic window
ability of these active substances. The bioavailability of when combined with herbal medicines.
such active substances may be significantly increased Pharmacokinetic herb-drug interactions occur
when they are administered together with other compounds when an herbal preparation changes absorption, distri-
(active substances) that are a substrate for P-gp bution, metabolism or excretion of a medicine.
transporters. For example the bioavailability of the anti- Interactions at the level of metabolism, comprise the
retroviral medicine saquinavir is largely enhanced when it inhibition or induction of different cytochrome P450
is administered together with a P-gp inhibitor such as enzymes, glucuronosyltransferases (UGTs) and
ritonavir, also being a substrate for P-gp and competing P-glycoproteins. Herbal drugs rich in saponins and
for its binding places. Furthermore, ritonavir increases the herbal products that alter the gastric pH or influence
saquinavir tissue concentrations in the central nervous sys- intestinal motility may influence dissolution and
tem, since it also inhibits the effects of the P-gp in the absorption.
blood-brain barrier.
(continued)
substance. This phenomenon is known as ‘flip-flop

Furthermore, pharmacodynamic herb-drug inter- pharmacokinetics’ [8].
actions may occur. They can be the result of a similar When the occurrence of flip-flop kinetics is not recognised
or antagonistic action of an herbal preparation and a it may compromise the interpretation of results from studies
medicine. Knowledge of the pharmacological on the pharmacokinetic behaviour of slow release dosage
properties may help to predict such interaction. forms. Flip-flop pharmacokinetics may occur with any
Active substances that are considered to be most extravascularly administered parenteral slow release dosage
sensitive to interaction with herbal preparations include form. Intramuscular depot injections of antipsychotics such
oral anticoagulants, cardiac glycosides, oral as fluphenazine decanoate, haloperidol decanoate or
contraceptives, antidepressants and antihypertensives. flupenthixol decanoate show this behaviour. It also occurs
Typical herbal products that may influence their activity after the administration of oral slow release products of
are St John’s wort, ginkgo, ginseng, garlic and laxatives active substances such as isoxuprine, carbamazepine,
(bulk formers and anthraquinones). Note that the com- diclofenac, valproic acid, morphine and theophylline.
position of the particular herbal preparation should
always be considered as the profiles of different extracts
PRODUCT DESIGN
from the same plant may vary considerably.
16.2 Dosage Forms and Routes
of Administration
For the administration of medicines, various routes and

16.1.14 Slow Release and Flip-Flop
dosage forms are available. The choice for the most suitable
Pharmacokinetics
route and dosage form is complex and affected by a large
number of interacting factors. Among these factors are
Slow release technology is generally applied to active
aspects related to the physico-chemical characteristics of
substances that are connected with:
the active substance, the pharmacodynamics and pharmaco-
• Long-term or chronic therapies.
kinetic characteristics of the active substance and various
• Large and undesired differences in peak and trough blood
patient related aspects. This section gives, per route of
levels, leading to adverse effects or periods with no or
administration, the basics for handling of the interacting
suboptimal therapy, respectively.
factors. Chaps. 4–14 discuss the practical consequences for
• Non-linear pharmacokinetic behaviour, meaning that the
the formulations.
blood concentration increases are not proportional to
increasing dose. This may lead to toxic blood levels.
Examples of active substances with non-linear pharma-
cokinetics include: nitrates, nifedipine, fentanyl, theo- 16.2.1 Parenteral Administration
phylline, paclitaxel and lithium carbonate. Non-linear
pharmacokinetic behaviour may be due to saturation of Intravenous administration delivers an active substance
pre systemic enzymatic elimination mechanisms at immediately into the systemic circulation. It is often consid-
increasing concentrations of the substrate. ered the fastest way to get a therapeutic effect. By definition,
• High dosing frequency (three or more times daily) due to the bioavailability of an active substance given intrave-
their rapid elimination or excretion. Under normal nously is 100 %. A typical characteristic of the blood con-
circumstances the elimination will be slower than the centration (as measured in whole blood, in serum or in
absorption rate of the active substance. As a result of plasma) versus time curve of intravenously administered
this difference, the elimination is reflected in the active substances is the absence of the absorption phase
descending part of the blood concentration versus time (Fig. 16.8). Any other route of administration would show
curve. A fast elimination rate however would require it to an absorption phase (see Fig. 16.1) but immediately after
be administered several (more than three to four) times a intravenous injection the blood concentration is at its maxi-
day. Slow release of the active substance from the dosage mum and is usually followed by a short distribution phase
form (e.g. a slow release tablet) will cause the absorption and the elimination phase of the active substance, both
rate to become slower than the elimination rate. As a processes will reduce the blood concentration of the active
consequence the elimination phase in the blood concen- substances.
tration versus time curve no longer reflects the elimina- The duration of the action depends on the dose, the
tion rate, but rather the absorption rate of the active duration of administration (in case of an intravenous drip
substance, whereas the initial rising phase in the curve or infusion), the distribution, metabolism and excretion of
is a reflection of the elimination rate of the active the active substance. Constant blood levels can be achieved
By subcutaneous administration, the medicine is injected

32 into the subcutaneous connective tissue. These injections are
experienced as more painful than intramuscular ones. Suit-
Distribution phase
able places are the thigh and the belly pleat. The absorption
Blood concentration of active
16 after subcutaneous injection varies in rate and extent

depending on the site of injection and on patient specific
factors such as the amount of subcutaneous fat and physical
8
C0 Elimination phase activity. When a solution is injected the diffusion of the
active substance through the tissue to the blood vessel will
be the rate determining step for the absorption. When a
suspension is injected the dissolution rate of the active
4 substance may become rate determining for the absorption
process, whereas for lipophilic active substances formulated
as an oily solution or an oil-in-water emulsion the transport
2 over the oil-water interphase may become rate determining.
With suspensions and emulsions the absorption rate can be
t½
slowed down to such an extent that it will become rate
1 limiting for the elimination rate of the medicine. In this
2 4 6 8 10 12 way slow release injections can be formulated.
Time [hr] The bioavailability of an intramuscularly or subcutane-
ously administered active substance is determined by:
Fig. 16.8 Blood concentration versus time curve obtained after intra- • Site and depth of the injection
venous injection. Extrapolation of the elimination phase to the inter- • Physical form of the active substance in the injection
section with the y-axis gives the virtual C0 value. This is the theoretical
concentration of the active substance immediately after administration
(solution, suspension, emulsion)
assuming that it is distributed over the full volume of distribution for • Physico-chemical properties of the active substance (sol-
the particular active substance. The C0 can, together with the dose, be ubility, charge, aggregation)
used to calculate the volume of distribution (Vd ¼ D/C0) • Injected volume
• Thickness of the fat layer in relation to the depth of the
by a constant infusion. By regulating the speed of infusion, injection
the height of a blood level can be adjusted and maintained at • Muscle activity
a constant level without fluctuations. This may be important • Excipients used and composition of the injection (formu-
for active substances with a narrow therapeutic window. lation: solvent or vehicle, osmotic value, viscosity, pH,
The blood concentration versus time profile shown in surfactants, etc.)
Fig. 16.8 is typically found after the injection of an aqueous Section 13.3 discusses the practical consequences for the
solution of the active substance. When lipophilic compounds formulations.
are administered as an oil-in-water emulsion the profile may
be significantly altered, since the transport of the active
substance over the oil-water interface may limit the distribu- 16.2.2 Oromucosal Administration
tion or elimination rate.
By intramuscular administration, the medicine is injected The mucosal membranes in the mouth can be used to admin-
into muscle tissue, through the skin and subcutaneous fat ister active substances. The sublingual and buccal
layer. Suitable muscles for intramuscular injection are the membranes are especially suitable for systemic absorption
upper arm and shoulder muscle (musculus deltoideus), thigh of an active substance. The rate of absorption of the active
muscle (musculus vastus lateralis) and bottom muscle substance is determined by its size and lipophilicity. A high
(musculus glutaeus maximus). The blood flow in these lipophilicity and a small size of the molecule are favourable
muscles differ from each other and hence also the extent for rapid penetration of the sublingual membrane. The thin
and rate in which an active substance is absorbed from these and highly vascularised membrane under the tongue is espe-
sites. Activity of the muscle and physical movements cially suitable for a fast absorption. But before the active
(e.g. horse riding after an injection in the bottom muscle) substances can be absorbed they should be dissolved. Spe-
will also strongly affect the absorption of the active sub- cially designed oromucosal dosage forms have to provide
stance from the injection site. Unlike the intravenous injec- dissolution of the active substance in the limited amount of
tion, oily liquids and aqueous or oily suspensions can be saliva available. Since many persons experience difficulties
injected intramuscularly. keeping a product in the mouth for about 2 min, dissolution
must be rapid as well [9]. When given in a rapidly dissolving lower parts of the small intestine significant absorption can
dosage form, lipophilic hormones like testosterone or estra- still occur.
diol can be absorbed efficiently via the sublingual route In the colon the pH drops a little, to 6.4–7.4, due to the
(circumventing the hepatic first-pass effect). Nitroglycerin metabolic activity of the intestinal flora. The residence time
is an example of a small slightly lipophilic compound that is in the colon varies between 6 and 12 h. Absorption from the
effectively administered (showing a fast absorption within colon is generally of minor importance for orally
minutes) as a sublingual tablet or spray in acute cardiac administered active substances.
insufficiency. The significant variations in pH and residence time in the
gastro-intestinal tract strongly affect the solubility and the
dissolution rate of many active substances as well as the
16.2.3 Oral Administration transport over the intestinal membranes during the absorp-
tion process.
For orally administered medicinal products the pharmaceu- Interactions with food in the gastro-intestinal tract can
tical availability, the rate of absorption and the bioavailabil- influence the bioavailability of active substances at various
ity strongly depend on the design and formulation of the levels (see also Sect. 16.1.6). Examples are:
PRODUCT DESIGN
dosage form. During the transit through the gastro-intestinal • Food components (or active substances) that delay stom-
tract, the active substance is exposed to varying conditions. ach emptying will delay the absorption of active
Of importance are the variations in pH, residence time in substances that are only absorbed from the small
different parts of the gastro-intestinal tract and digestive intestine.
(metabolising) enzymes. The gastro-intestinal tract covers • Food (and active substances) that change the pH in the
the mouth, oesophagus, stomach, small intestine (duode- gastro-intestinal tract may influence the absorption of
num, jejunum, ileum) and large intestine (colon). active substances of which the absorption process is pH
The oesophagus has only a transport function for active dependent.
substances. It is important, however, that corroding and • Food components may form insoluble complexes with
irritating active substances, like doxycycline and active substances, hampering their absorption.
bisphosphonates, do not stick in the oesophagus as they • Swallowing a lot of fluid will increase the amount of
can damage the tissue and cause ulcerations. Ample water liquid in the gastro-intestinal tract available for dissolu-
should be taken when swallowing such medicinal products. tion. As a consequence, larger fractions of poorly soluble
Within the stomach an acidic environment exists, with a active substances may dissolve and the bioavailability
pH between 1.5 and 3.0 (with extremes between 1.0 and 5.0). may increase.
In addition, digestive enzymes are present. The residence • Fat in food stimulates the excretion of bile into the intes-
time in the stomach depends on the nutritional status and on tinal lumen. Bile contains effective emulsifiers that can
the physical form of the medicine and may be highly vari- increase the solubility of lipophilic active substances.
able. An active substance in solution, taken on an empty • Food components (fibres) that increase the motility of the
stomach, will pass the stomach quickly, usually within intestine may decrease the absorption of active
30 min. A non-disintegrating large tablet, taken after a substances due to a shorter residence time.
high-fat meal, may remain in the stomach for several • Food increases the blood flow to the intestinal tract. The
hours. Absorption from the stomach plays a minor role in absorption of active substances will increase, leading to
the total absorption, because of the relatively small surface higher portal drug concentrations. The first-pass effect
of the gastric wall in relation to the stomach volume and the decreases as a result of less effective extraction by the
thickness of mucus layer and membrane. liver.
In the duodenum, the first part of the small intestine, the • Certain food substances and herbal preparations may
pH of the acid gastric content rises to values between 6.4 and inhibit enzymes that play a role in drug metabolism;
6.8, after pancreatic juice is added. This pH is maintained in e.g. cytochrome P450 3A4 enzymes by grapefruit juice.
the jejunum and the proximal part of the ileum. In the Sections 4.3 and 5.3 discuss the practical consequences for
terminal part of the ileum, the pH rises to 7.1–7.5. The transit the formulations.
time through the small intestine is about 4.5–6 h. For many
active substances the duodenum is the principal site of
absorption. This is because of its large surface and the 16.2.4 Rectal Administration
relatively large variation in luminal pH, as a result of
which many active substances are present in the duodenum Rectal administration of medicines aims at a local or a
as a non-ionised molecule for some time. However, also in systemic effect. Suppositories and (micro-)enemas
(3–10 mL) are mainly used for a systemic effect, enemas substance (the solubility in the fat basis), the volume of the
with a larger volume (up to 100 mL) for a local effect (in the suppository (usually 2–3 mL for adults), the nature of the
rectum and lower colon). suppository basis (lipid or aqueous, the viscosity of the
The rectum is the lowest part of the large intestine. It is molten lipid basis, the solubility for the aqueous basis) and
15–20 cm long with a diameter of about 5 cm. In the rectum the particle size of the active substance. To improve the
1–5 mL of viscous fluid with a pH between 6.4 and 7.4 and a absorption rate of less soluble substances, active substances
small buffer capacity is present. The temperature (under can be formulated as a cyclodextrin complex in
physiological conditions) is 36.2–37.6 C. The rectum is a suppositories. For example, piroxicam is formulated as a
flat tube, because of the pressure of the bowels. After admin- beta-cyclodextrin (betadex) complex and cisapride is used
istration of a fluid into the rectum the liquid will spread due as an hydroxypropyl beta-cyclodextrin (hydroxypro-
to this pressure. Larger volumes (enemas) are spread into the pylbetadex) complex in fatty suppositories.
colon as well. A defecation reflex will occur when volumes Rectal solutions have water or oil as a vehicle. If neces-
exceeding 100 mL are applied, which limits the volume of sary to enhance the solubility of poorly soluble active
enemas. substances, aqueous rectal solutions may contain cosolvents,
In older literature the circumvention of the hepatic first- such as ethanol and propylene glycol. However, cosolvents
pass effect is mentioned as an advantage for rectal adminis- and surfactants should only be used in limited amounts
tration of medicines. This is now known to be an invalid because of the potential irritation and the defecation reflex
argument, since two out of three rectal veins end up in the they may cause. For the rectal absorption of active
portal vein. Rectal administration can be useful when a substances from enemas the same mechanisms as for
patient is vomiting, has swallowing problems, is uncon- suppositories apply. A major advantage of a rectal solution
scious, experiences severe gastro-intestinal complaints over a suppository may be the fact that the active substance
when taking the medicine orally (e.g. indomethacin), or for is already in a dissolved state which may increase the
active substances with an unpleasant taste (especially for absorption rate. Increasing the volume of a rectal solution
children). to dissolve a poorly water-soluble active substance will
The most commonly used basis for suppositories is hard enhance the dissolution rate and thereby increase the absorp-
fat, which melts when brought into the rectum. Most active tion rate. Because of the higher volume more active sub-
substances are suspended into the base, but some lipophilic stance will be dissolved and the membrane surface over
active substances are dissolved. The first step after adminis- which absorption occurs, is increased as well.
tration is melting of the base, followed by sedimentation of Section 11.3 discusses the practical consequences for the
the suspended active substance particles to the fat-aqueous formulations.
interface where the active substance is to dissolve in the
aqueous rectal fluid. Subsequently, the active substance is
absorbed by the rectum membrane after which it enters the 16.2.5 Dermal and Transdermal Administration
systemic circulation. It should be known that due to the
viscous nature of the mucus covering the rectal membrane Medicinal products can be applied on the skin to treat local
direct transport from the molten fat to the membrane is not skin diseases (topical application) or to systemically admin-
possible, the active substance always has to pass the aqueous ister an active substance (transdermal application). In the
mucus layer. Therefore, highly lipophilic active substances first case, the active substance should accumulate in or even
should not be formulated into a lipid suppository basis or an on the skin and display its effect there. When transdermal
oily enema. Since the transport from the lipophilic base into administration is intended, the active substance should be
the aqueous rectal fluids is an inevitable step in the drug transported through the skin followed by absorption into the
absorption process, the high octanol-water partition coeffi- systemic circulation. In the skin the stratum corneum (the
cient of these lipophilic active substances will make this most outer layer of 5–50 layers of dead cells, a horned layer
process inefficient and absorption slow and incomplete. As of corneocytes, see Fig. 12.1 and Sect. 12.3.1) forms the
an alternative to fat, a water-soluble basis (macrogol (poly- major barrier for absorption of active substances. The layer
ethylene glycol)) can be used for the preparation of is highly lipophilic in nature and is fully impermeable for
suppositories. The aqueous suppository basis should espe- hydrophilic active substances. Lipophilic active substances,
cially be applied to those active substances that are highly when adequately formulated, may be absorbed via the skin.
lipid soluble and will not partition from the molten fat base Typical characteristics which make an active substance suit-
into the aqueous rectal fluid. able for transdermal transport are: an octanol-water partition
The release of an active substance from a suppository coefficient (expressed as log Po/w) between 1 and 3 and a
depends on the pH and the buffer capacity in the rectum, molecular mass below 500 Da [10, 11]. Moreover the dose
the solubility in water and the lipophilicity of the active should not exceed 20 mg per day. Hydrophilic active
substances can be absorbed via the transdermal route The rate of penetration through a damaged skin is higher
when the stratum corneum is damaged, for example by than that through an intact skin. The state of hydration of the
the use of microneedles [11]. However, such action also skin is also important. The rate of penetration is usually
compromises the natural protective function of the skin. higher in a well-hydrated skin. Occlusion (e.g., by covering
The layers of the skin under the stratum corneum are the part of the skin where the dermatological preparation has
permeable to both hydrophilic and lipophilic substances. been applied) enhances hydration and hence enhances drug
Lipophilic substances may form a depot in the lipid parts penetration of more hydrophilic active substances into
of the skin before they are transported into the systemic the skin.
circulation. The major route of penetration over the stra- Technical factors, like rubbing and massage, also
tum corneum is the intercellular route. The transcellular enhance the penetration of medicines. Several excipients
route through the corneocytes is less relevant. Penetration may act as penetration enhancers, by reducing the thickness
may also occur via hair follicles, sebum glands and sweat of the skin (salicylic acid or urea), or by changing the
glands, but because of the smaller surface these routes are coherent structure of the stratum corneum, such as dimethyl
of minor importance. sulfoxide, propylene glycol, or several surfactants. Whether
For a good therapeutic effect the choice of the active the active substance is present in the inner or outer phase of
PRODUCT DESIGN
substance and the choice of the vehicle are important. Phys- an oil in water or a water in oil cream affects the extent and
ical and chemical factors play an important role. The solu- rate of transdermal absorption of an active substance. When
bility of the active substance in the vehicle and the present in the inner phase transport is generally slower, due
concentration, the size of the molecule of the active sub- to the fact that the active substance at first has to pass the
stance, the partition between vehicle and skin, the particle outer phase before reaching the skin. When the partition
size (in case of suspensions) and the nature of the vehicle between inner and outer phase is highly in favour of the
(aqueous or lipid) determine the penetration speed and inner phase only small amounts of active substance will
depth. Hydrocortisone, for example, is more lipid soluble enter the outer phase and transport will be slow. Conversely,
in the ester form (hydrocortisone acetate). The latter will when the inner phase consists of small droplets a large
penetrate into the skin faster and more complete. interface exists between the inner and outer phase and drug
Hydrocarbons, such as soft and liquid paraffin, release transport may still be relatively fast. As a consequence,
lipophilic active substances only very slowly and substances active substances that are dissolved in the inner phase may
formulated in these bases will penetrate only in limited still be faster and more completely absorbed into the skin
amounts into the skin. Fatty oils (vegetable oils, compared to a suspension-type formulation. This is, for
triglycerides) are able to pass into the upper layers of the example, the reason why lipophilic corticosteroids are
skin. Penetration enhancers (salicylic acid, dimethyl sulfox- often formulated in oil-in-water creams.
ide, propylene glycol, urea) increase the penetration of Iontophoresis (see also Sect. 12.7.11), finally, is a
active substances into the skin. means to enhance the penetration of charged active
The pH of the vehicle in relation to the skin pH (around substances. When positively charged molecules are
5.5) is very important. Many active substances, also in administered at the site of an anode and negatively
dermal preparations, are weak acids or bases. The pH parti- charged active substances under the cathode, electric
tion theory (see 16.1.9) plays a role here as well and affects repulsion will increase the driving force for transport of
the effective partition of the active substance between the the active substance into the skin. Variation of the electric
vehicle and the skin. charge that is applied will change the rate of transdermal
Physiological factors also determine the effectiveness of drug transport. This can be used to rapidly adjust the dose
dermal preparations. The thickness of the skin varies across for example in pain management: iontophoresis is used for
the body. The penetration rate is higher when applied on thin example to control the delivery of lidocaine for local
skin (e.g. behind the ear, on the eyelid or scrotum) than anaesthesia or of fentanyl.
when applied on thick skin (e.g., palm of the hand, sole of Dermatological preparations for local use may exert a
the foot). Comparing the skin of babies and adults, the ratio systemic effect as well. Especially for corticosteroids this
between body surface (skin) and body volume is larger for can be a problem. The patient should be informed not to use
babies. In addition, skin absorption in term and in preterm such preparations for too long, and not more frequently than
new-borns is increased because their stratum corneum is prescribed. Furthermore, the surface on which the prepara-
thinner and the epidermis of children is better perfused and tion is applied and the thickness of the film should be
hydrated compared to adults. As a result, the toxicity of limited.
active substances applied on a baby’s skin can be much Section 12.3 discusses the practical consequences for the
higher than on an adult’s skin. formulations.
16.2.6 Nasal Administration may be unable to pass the throat or subsequent bifurcations
of the airways. Inertial impaction, especially in the throat,
The application of medicines in the nose usually aims at a may significantly reduce the overall efficacy of the drug
local effect (e.g., for decongestion of the mucous membrane deposition in the lung. Throat depositions varying between
of the nose, or to administer anti-allergic medicines). In 70 % and 90 % of the dose are not exceptional for widely
recent years, it has become clear that the nose can be used used inhalation devices, such as nebulisers, metered dose
as a route for systemic therapy as well. Nose drops and nose inhalers or dry powder inhalers. Since the drug loss by throat
sprays are the most commonly used nasal preparations. deposition of aerosols is a mechanical phenomenon this
Many active substances, solvents and excipients possess problem should also be solved in a mechanical way. This
ciliotoxic properties, meaning that they (irreversibly) dam- can be done by reducing the particle size of the aerosol
age the cilia. Cilia are hair-like projections of the nasal particles to a size between 1.5 and 3.0 μm, reducing the
epithelium cells. They facilitate the movement of mucus inhalation airflow rate and prolonging the breath-hold. In
from the nasal cavity to the nasopharynx. From there it is this way, throat and upper airway deposition can be
swallowed into the gastro-intestinal tract. The cilia play an decreased while optimising the lung deposition. It is for
important role in keeping the nose clean from particles and this reason that for pulmonary drug administration the
pathogens. In order not to damage this defence mechanism, device and the way it is used by the patient are considered
special attention should be given to the constituents of nasal to be as important as the choice of the active substance. Once
preparations, including the active substance, antimicrobial particles have passed the upper airways particles in the size
preservatives, antioxidants, salts for adjusting pH and tonic- range between 1.5 and 3.0 μm will deposit by settling on the
ity, solvents and viscosity increasing agents. Also the pH and airways wall and a small fraction will deposit in the alveoli.
tonicity of nasal preparations lie within narrow limits. Most of the particles smaller than 0.5–1.0 μm may penetrate
As a consequence of the mucociliary clearance of the deeply into the lung but sedimentation on the airway wall
nasal cavity active substances that are unable to pass the will be limited due to the limited effect of gravity on these
nasal membrane will end up in the oropharynx and are particles. They will therefore to a large extend be exhaled
swallowed into the gastro-intestinal tract, from where they again. This is discussed in more detail in Sect. 6.3.
may be absorbed. This gastro-intestinal absorption after The lungs can be considered to consist of two different
nasal administration may erroneously be considered as organs: the airways and the alveoli. These two parts of the
nasal absorption. Such a phenomenon may, for example, lung are physiologically different and the barrier function of
occur when the nasal spray of the anti-migraine medicine their mucosal membranes differs completely. The airways
sumatriptan is used. are covered by a ciliated mucosal membrane covered with a
The nasal administration was shown to be an effective mucus layer that is transported to the throat. The airway
administration route for lipophilic active substances like membrane is not permeable to hydrophilic molecules with
fentanyl. Moreover, the nasal route has also been used for a molecular weight over 1,400 Da. The alveoli on the other
the systemic administration of small peptides like buserelin hand, have a completely different structure: their membrane
acetate, nafarelin acetate and desmopressin, all of them consists for over 93 % of the alveolar type I cell. This is a
containing ten or less amino acid residues. However, for non-ciliated cell type that is covered with the alveolar lining
these molecules the nasal route forms only a poor fluid, an aqueous fluid that contains huge amounts of the
non-invasive alternative to injection, since the nasal bio- surfactant dipalmitoylphosphatidylcholine. Between the
availability of these peptides is less than 3–5 %. alveolar type I cells intercellular spaces occur with sizes up
Section 8.3.2 discusses nasal absorption, mainly the to 4 nm. Because of these large interstitial spaces proteins
enhancement, in more detail and the practical consequences with a molecular weight up to 20 kDa can be absorbed into
for the formulations are dealt with in Sect. 8.5. the systemic circulation after inhalation. This fact, and the
low activity of proteolytic enzymes in the alveolar lining
fluid, makes the pulmonary route probably the most suitable
16.2.7 Pulmonary Administration route of administration for small and medium size therapeu-
tic proteins as an alternative to the parenteral route. How-
The human lungs consist of a branching system of airways ever, it should be kept in mind that for proteins with a
with 23 bifurcations between the mouth and the alveoli. The molecular weight over 1,400 Da absorption will only occur
transport of drug-containing aerosol particles by the airflow via the alveoli. Unfortunately the alveoli are found only at
into the lung is one of the major obstacles in pulmonary drug the end of the branching airway system and only a fraction of
administration. Due to their inertia (meaning that due to their 10–15 % of the particles of 1.5–3.0 μm will reach the alveo-
mass and velocity the particles show the tendency to ‘fly out lar region. This limits the final bioavailability of inhaled
of the bend’) the particles that are transported by the airflow proteins.
corticosteroids the smaller airways should be the primary

The Pulmonary Route for the Systemic Adminis- target. Long acting muscarinic antagonists should be targeted
tration of Medicines at the entire bronchial tree, whereas antibiotics should prefer-
The systemic administration of medicines via the pul- ably be directed at the infectious loci in the lung.
monary route has attracted significant interest over the Pulmonary drug administration can be considered as the
past decades. The development of an insulin formula- most successful application of the drug targeting concept so
tion for inhalation is an example. A few years after the far. Locally at the site of action, much higher active sub-
discovery of insulin in the 1920s, it was described that stance concentrations can be attained and the onset of action
after inhalation in dogs systemic blood levels of insu- is faster than after systemic administration. Following inha-
lin were obtained. Considering the fact that proteins lation, blood levels are usually lower and thus the occurrence
with a molecular weight of up to 20 kDa can pass the of adverse effects is limited compared to systemic adminis-
alveolar membrane, it is not surprising that the less tration. When a patient is short of breath, he will experience
than 6 kDa insulin is systemically absorbed after inha- the effect of pulmonary administered medicines fast, within
lation as well. However, it took more than 60 years a few minutes. This is of paramount importance when
before inhalation systems and protein formulation exacerbations are treated.
technology had developed to a level that could guar-
PRODUCT DESIGN
As described above, the pulmonary route can also be used
antee a well-controlled and reproducible alveolar for systemic administration of active substances. Smaller
deposition of the insulin containing aerosol particles. molecules (<1,400 Da) can already be absorbed via the
In 2006 the first insulin dry powder inhaler was airways and bioavailabilities of over 30 % can be reached.
launched (Exubera™). This product had a low bio- For the larger molecules penetration can only occur over the
availability of about 12 % and was available in two alveolar membrane and their bioavailability will be much
dose strengths only. After less than 2 years the product smaller. However, no such products are on the market yet.
was withdrawn from the market because of safety
concerns and poor sales performance. Following this
withdrawal most other developments regarding 16.2.8 Ocular Administration
inhaled insulin were also stopped.
In spite of this failure, the lungs seem to be a The ocular administration of medicines is only used for a
suitable port of entry for active substances that cannot local effect in, on or around the eye. The local application
be systemically administered by other routes such as results in high local concentrations of the active substance.
the oral or transdermal route. Also for active Pharmaceutical dosage forms for the eye encompass eye
substances that suffer from a high first-pass metabo- drops, eye washings, eye ointments, inserts and intra-ocular
lism or a highly variable absorption behaviour after injections. In all cases, it is important that the preparations
oral administration, the pulmonary route could poten- do not cause irritation of the eye. If they do, the medicine
tially be a better route of administration. For a wide will be washed out quickly due to tear production, which
variety of active substances ranging from the thera- may reduce the effect and limit its duration. In addition,
peutic peptides such as somatropine or gonadoreline- small sharp particles can damage the eye. Strict limits exist
agonists to small organic molecules such as fentanyl or for pH and tonicity of ocular preparations.
ciclosporin, the systemic availability after inhalation Active substances administered via the ocular route (with
has been proved. Furthermore, the lungs seem to offer the exception of an intra-ocular injection) may be absorbed
a suitable organ for needle-free vaccine administra- via the different membranes of the eye. When an active
tion. For several vaccines such as the measles and substance is active in the eye it should be able to pass the
influenza vaccine successful vaccination, eliciting an cornea. The epithelial and endothelial layers of the cornea
adequate (protective) immune response, has already are of a highly lipophilic nature as a result of which only
been shown in humans [12, 13]. lipophilic and non-charged active substances can pass the
epithelium of the cornea. For active substances with a parti-
tion coefficient below 0.3 or active substances that are
Pulmonary administration of active substances is com- charged at the physiological pH of the eye the driving
mon in the treatment of lung diseases such as asthma and force for transport over the corneal epithelium (the first
COPD and infectious lung diseases. For these indications step of the absorption process) will be insufficient and
different levels of the airways are targeted with different absorption will generally be low. To obtain sufficient trans-
medicines. For the beta-agonists such as formoterol the port of the active substance over the corneal epithelium it is
higher airways (generation 4 to 11, see Fig. 16.2) are the therefore necessary to administer the active substance in a
primary target, whereas for the anti-inflammatory formulation that has a pH at which a significant part of the
active substance is unionised. Examples are carbonic delivery systems have been developed to open new (mostly
anhydrase inhibitors and beta adrenergic antagonists, used non-parenteral) routes of administration in order to improve
in the treatment of glaucoma. the ease and comfort of drug administration for the patient.
Absorption into the systemic circulation of active Certainly, the development of advanced drug delivery
substances administered to the eye may occur to a limited forms is not new. Oral slow release products and pro-drugs
extent, via the conjunctival membrane and the nasal mucosa that target mesalazine to the lower part of the intestinal
(after being washed from the eye the active substance may tract have been available for decades. However, the rapid
enter the basal cavity via the nasolacrimal duct). The resi- developments in biotechnology as well as the development
dence time of medicines in the eye may be prolonged by of new active substances that require site-specific delivery
increasing the viscosity of the eye drops (which reduces the has propelled the development of more advanced drug deliv-
efficacy of lacrimation to wash out the medicine from the ery systems. Without these systems therapeutically success-
eye) or via the application of polymeric ocular inserts which ful administration of these new active substances will be
slowly release the active substance. It should be realised that impossible.
many ocular inserts are placed in the conjunctival sac, as a A common denominator of all advanced drug delivery
results of which a significant fraction of the active substance systems is their aim to change the intrinsic pharmacokinetic
will not be absorbed via the cornea but rather end up in the behaviour of the active substance they contain. This may
systemic circulation due to absorption via the membrane of either be at the level of absorption or absorption rate, at the
the conjunctival sac. level of metabolism or distribution, or by changing the
The intraocular injection of active substances that are elimination. From a biopharmaceutical point of view these
active in the eye leads to a bioavailability of 100 %. How- changes may have significant implications, since they may
ever, this route of administration is a serious burden to the alter bioavailability, efficacy and safety as well as the dura-
patient and formulation related safety aspects are of para- tion of action. It is for this reason that in the development
mount importance since elimination from the site of injec- these advanced drug delivery systems should be considered
tion is generally slow. However, this route may be the only as completely new medicines, requiring an almost full devel-
way to get an active substance to the site of action, or to get it opment program before they can reach the market. So far the
in a sufficiently high concentration at the site of action (e.g., number of advanced drug delivery systems that reached the
an antibiotic). Larger molecules such as monoclonal market is limited. Obviously many of the concepts designed
antibodies (e.g., bevacizumab or ranibizumab used against for improved bioavailability or drug targeting appeared to be
macular degeneration) are administered in this way to the not successful in real life, in the complex in vivo situation
eye. A further advantage of the intraocular route is that the in man.
large molecules are cleared slowly from the intraocular Among the advanced drug delivery systems that did reach
fluids and effects may last for days (or even weeks). the market are liposomal formulations of active substances
Section 10.4 discusses the practical consequences for the like doxorubicin and amphotericin B. Recently trastuzumab
formulations. emtansine which is a conjugate of the monoclonal antibody
trastuzumab and the antineoplastic mertansine was
introduced on the market [14]. Since the HER2-receptor is
16.3 New Developments and Advanced Drug overexpressed in tumour cells a dual action will be obtained
Delivery Systems from this conjugate. Trastuzumab itself can already stop the
growth of tumour cells whereas the antineoplastic
Over the past years a range of new developments in the field mertansine is specifically targeted to the tumour cells by
of drug delivery has emerged. Advanced drug delivery the antibody, which increases efficacy and reduces side-
systems have been designed and a few of them made it to effects. The active substance is used in HER2-positive met-
the market. Examples of such advanced drug delivery astatic breast cancer. Using this product for the first time
systems are liposomal medicinal products, nanocapsules, monoclonal antibody-based drug targeting has been applied
antibody-drugs conjugates, polymer-drug conjugates successfully.
(e.g. pegylated proteins) and higher drug excipient (poly- Another interesting innovation is the registration of
mer) associated medicines. Many of these delivery systems alipogene tiparvovec, it represents the first gene therapy
have been developed for active substances that suffer from treatment that has reached the market [15]. The medicinal
intrinsic difficulties from a biopharmaceutical point of view product consists of the human lipoprotein lipase gene that is
such as therapeutic proteins, DNA or RNA and small encapsulated in a vector derived from adeno-associated virus
organic molecules that require drug targeting because of (AAV), serotype 1. The viral vector will deliver the gene
their intrinsic toxicity when distributed over the entire into the cell, in this case a muscle cell, where the gene can be
body (e.g. antineoplastic medicines). Furthermore, advanced expressed after which the lipoprotein lipase is produced. In
this way lipoprotein lipase deficiency can be treated. Taking • Quantitative data on bioavailability and safety data are
into account the considerable efforts that are still being made required when two different pharmaceutical products
in the development of the advanced drug delivery systems, with the same active substance are compared to deter-
several new advanced drug delivery systems may reach the mine bioequivalence (e.g., a branded product versus a
market in the coming years. generic product or two different generic products).
• Comprehensive information on the physico-chemical
background and biopharmaceutics can be found in
16.4 Essentials Chap. 19 of this book and in general textbooks covering
(parts of) the subject, specifically:
• Pharmacotherapy can only be optimal if the pharmaceu- – Aulton ME, Taylor KMG. Aulton’s pharmaceutics:
tical formulation (the medicinal product) and its The design and manufacture of medicines, 4th edition.
functionalities are appropriate for the chosen route of Edinburgh: Churchill Livingstone Elsevier, 2013.
administration and intended therapeutic objective. – Felton LA, ed. Remington: Essentials of
• The technical and biopharmaceutical functionalities of a pharmaceutics. London: Pharmaceutical Press, 2013.
medicinal product are determined by its qualitative and – Sinko PJ. Martin’s physical pharmacy and pharmaceu-
tical sciences, 6th edition. Philadelphia: Lippincott
PRODUCT DESIGN
quantitative composition, as well as by the structure of
the different components in the product. Williams & Wilkins, 2011.
• From a biopharmaceutical point of view, a pharmaceuti- – Florence AT, Attwood D. Physico-chemical principles
cal formulation should be tailored to the route of admin- of pharmacy, 5th edition. London: Pharmaceutical
istration, the physico-chemical properties of the active Press, 2011.
substance, the desired mode of action, the onset and – Rowland M, Tozer TN. Clinical pharmacokinetics and
duration of the therapeutic effect, the site of action, and pharmacodynamics: concepts and applications.
the pharmacokinetic and pharmacodynamic properties of Philadelphia: Lippincott Williams & Wilkins, 2011.
the active substance. – Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson
• Active substances can only pass the absorptive G. Rang and Dale’s pharmacology, 8th edition.
membranes when they are dissolved in the aqueous fluids Edinburgh: Elsevier Churchill Livingstone, 2015.
adjacent to these membranes.
• The bioavailability of an active substance is defined as the
fraction of the active substance that reaches the systemic
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show a limited bioavailability, often with large intra- and Medicines Agency, London. www.ema.europa.eu. Most recent
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Product Design
17
Herman Vromans and Giovanni Pauletti
Contents Abstract
Pharmaceutical companies, hospital and community
17.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
pharmacies prepare medicines. Although batch sizes
17.2 Quality by Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 vary greatly, the underlying principles of product devel-
17.3 Target Product Quality Profile . . . . . . . . . . . . . . . . . . . . . . . . 348 opment are comparable and driven by physical chemistry,
17.4 Administration Route and Bioavailability . . . . . . . . . . . . 349 physiology and pharmacokinetics. When the medication
17.4.1 Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 is meant for only a small group of patients or even for
17.4.2 Permeability; Membrane Passage . . . . . . . . . . . . . . . . . . . . . . . . 351 individual use, these principles cannot be fully elaborated
17.4.3 Liver Passage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 and formulation becomes more and more based on risk
17.5 Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 assessment.
17.6 Method of Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 The design phase encompasses all aspects of
converting an idea into a safe and efficacious product.
17.7 Control Strategy: Critical Quality Attributes,
Process Parameters and Sources of Variability . . . . . . 352 To ensure quality, all factors affecting product perfor-
mance have to be identified and critical limits or
17.8 Product Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
specifications defined. Medicines can be designed
17.9 Product Documentation and Design in Pharmacy according to the concept of Quality by Design (QbD),
Preparation Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
using its elements of defined target product quality profile,
17.9.1 Extemporaneous Preparation, Not Standard . . . . . . . . . . . . . 354
17.9.2 Extemporaneous Preparation, Standard . . . . . . . . . . . . . . . . . . 355 robust product and preparation processes, critical quality
17.9.3 Stock Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 attributes, process parameters, sources of variability, and
17.10 Product Life Cycle Management . . . . . . . . . . . . . . . . . . . . . . 355 controlled preparation processes.
The QbD concept is essential for large scale produc-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
tion but also assists in effective design of pharmacy
preparations. Starting with an active substance, the prod-
uct profile and biopharmaceutical and pharmacokinetic
qualities, the administration route and a specific dosage
form are chosen. Physico-chemical properties of the
active substance limit these options. Formulation and
preparation method have to be designed. Based on critical
product and process characteristics, the ‘design space’
Based upon the chapter Ontwerpen by Herman Vromans en Reinout
Schellekens in the 2009 edition of ‘Recepteerkunde’.
can be defined. A robust process is associated with a
large design space. Proper documentation of the design
H. Vromans (*)
Department Pharmaceutical Technology and Biopharmacy, Utrecht
process assists in troubleshooting or when modifications
University, Academic Hospital Utrecht, Universiteitsweg 99, occur. Successful life cycle management is underpinned
3584 CG Utrecht, The Netherlands by an active attitude towards improving the design qual-
e-mail: [email protected] ity of the product.
G.M. Pauletti
Department Biopharmaceutics and Pharmacokinetics, University of
Cincinnati, James L. Winkle College of Pharmacy, 3225 Eden Avenue,
Cincinnati, OH 45267, USA

348 H. Vromans and G.M. Pauletti
Keywords The design process guided by the QbD concept generally

Quality by design Product validation Critical quality includes the following actions [2]:
attributes Process parameters Product life cycle Tar- • Define target product quality profile
get product quality profile Formulation • Establish robust product and manufacturing processes
• Identify critical quality attributes, process parameters,
and sources of variability
• Control manufacturing processes to produce consistent
17.1 Orientation quality over time
These four actions are subsequently discussed in this chapter
The design phase is the first step in the product life cycle (see with an emphasis on pharmacy preparations. In addition
Sect. 35.4) of a medicine and comprises all aspects necessary to pharmaceutical aspects, selection of a suitable admin-
to translate an idea into a product of sufficient technological istration route and specific bioavailability considerations
and therapeutic quality. The philosophy of Quality by Design were recognised as relevant input variables in formulation
(QbD) is the guiding principle not only for the design of design.
large-scale industrial medicinal products (as illustrated in
the Bipolar Depression Case) but also for small-scale phar-
macy preparations as illustrated in several boxes.
17.3 Target Product Quality Profile
Prior to initiating the design phase, feasibility of a prepa-
ration or product has to be assessed. For pharmacy prepara-
The design of a medicine requires clarity about its intended
tion this assessment is discussed in Sect. 2.2. At the end of
use in a target patient population. Commonly asked
the life cycle, a production is discontinued due to an
questions include: “What therapeutic benefit should a patient
unfavourable risk/benefit ratio or economic reasons. For
gain?”, “How large is the patient population?”, “Do patients
pharmacy preparations, loss of feasibility may also be the
have unique pathophysiological or practical situations?”,
reason for discontinuation.
“Where in the body is the desired therapeutic target for the
This chapter represents the foundation for Chaps. 4–14
active substance?”, or “What is the duration of dose admin-
that outline details of administration routes and dosage
istration and where is it performed (e.g. patient self-
forms.
administration at home or in-patient setting at a hospital)?”
Bipolar depression case study #1

17.2 Quality by Design The design specification for the long-term treatment of
patients with bipolar depression is as follow: Self-
Design quality entails both the quality of the formulation as administration of an oral solid dosage form containing
well as the preparation method. The QbD paradigm is cov- x mg of the active substance Y, which has
ered by the CHMP/ICH guideline Q8 [1]. It stresses the demonstrated efficacy in the central nervous system.
importance of a proper and well-understood design,- meeting Considering the known sedative side effect of Y and
the requirements of the patient and physician, and the impor- the absence of an established relationship between
tance of incorporating product quality into the design (see pharmacokinetics and pharmacodynamics (PK/PD),
also Sect. 35.4.3). the medicine is preferably administered at night before
The Q8 guideline emphasises the importance of under- bedtime. Since the active substance has an unpleasant
standing the formulation and the method of preparation, as taste, taste masking is desired. Furthermore, it is
well as preparation process control that is based on scientific established that many patients diagnosed with bipolar
data and risk analysis of the preparation process (see also depression experience (neurotic) difficulties with oral
Chap. 21). Identification of all relevant sources of variability medicines. Therefore, the solid dosage form should be
will result in a window (the design space) for all adjustable of neutral colour and easy to swallow. As rapid absorp-
parameters (particle size, pH, mixing time, etc.). Practically, tion of the active substance results in vertigo, a
the QbD approach will lead to a robust formulation and modified release dosage form is preferred.
preparation process that is still flexible enough to adapt to
necessary modifications. Detailed documentation of the
development research will help limiting time- and resource- For an assessment of the therapeutic rationale and feasi-
intensive follow-up studies in order to explain process bility of requests for pharmacy preparations, reference is
deviations or applying process modifications. made to Chap. 2.
17 Product Design 349
been tested for safety and efficacy when administered via a

17.4 Administration Route different route such as the cutaneous application. Formally,
and Bioavailability at least, local toxicity studies are then required. Furthermore,
excipients that are approved for tablet formulations may not
Chapter 16 Biopharmaceutics discusses bioavailability in be used in parenteral formulations. These examples illustrate
detail. This chapter focuses on the line of thought and on that when a different administration route is chosen there
guidance to enable global decisions about feasibility from a might be a need to reassess the appropriate selection of
biopharmaceutical viewpoint. excipients. In some cases, additional safety studies will be
For all extravascular administration routes, bioavailabil- required.
ity is determined by the following two sequential processes
(see Fig. 17.1):
• Release of the active substance from the dosage form “The European – United States Paediatric Formula-
facilitated by disintegration or dissolution or both (¼ tion Initiative (Eu-US PFI) has established that there is
pharmaceutical availability) a pressing need for a single authoritative comprehen-
• Pre systemic elimination, membrane passage, first-pass sive database of adverse effects of excipients for pae-
metabolism, and appearance of the active substance in the diatrics. Safety and Toxicity of Excipients for
PRODUCT DESIGN
systemic circulation (¼ biological availability) Paediatrics (STEP) Database holds all the animal tox-
An active substance generally exerts its effect through icity and human health data, regulatory information
defined molecular interactions with a receptor. As a prereq- and toxicological reviews of excipients. STEP acts as
uisite, the substance needs to be dissolved and reach the repository for all the scientific communities to share
receptor. For a local effect, the substance is usually the data for better understanding and paediatric
administered in close proximity to the desired target and medicines development” (European Paediatric Formu-
should penetrate into body tissues as little as possible. How- lation Initiative. STEP Database. See [3]).
ever, when a systemic effect is desired, the substance has to
reach the blood circulation system for distribution. For The selection of an adequate dosage form should also
extravascular administration routes, this requires membrane consider limitations associated with the preparation method.
passage and may expose the substance to various pre sys- For instance, if an active substance is harmful to the opera-
temic elimination mechanisms, including metabolism and tor, the pharmacist may decide to prepare a liquid dosage
efflux transporters such as P-glycoprotein. form rather than a solid dosage form to avoid exposure to the
In the request for a pharmacy preparation, the physician harmful agent via inhalation (see Sect. 26.7.1).
often prescribes the administration route. Pharmacists have Physico-chemical properties of the active substance influ-
to critically evaluate whether the proposed route is appropri- ence to a large extent the administration routes and dosage
ate to reach the desired bioavailability. For example, conforms that are feasible. Relevant properties include solubil-
ventional oral medications may not be suitable for patients ity, partition coefficient (log P), pKa, membrane passage,
with a nasogastric feeding tube, children, or nauseous metabolic stability, and half-life. Conversely, the adminis-
patients and alternative routes such as parenteral, rectal, or tration route and formulation influence safety and efficacy of
nasal have to be considered (see also Sect. 37.6.3). When the active substance. This cause-effect relationship implies
adapting a dosage form or administration route to special that formulations designed for different or even the same
needs of a patient, the pharmacist is required to consider route of administration may not be interchangeable.
safety aspects. It is important to recognise that an active Chapters 4–14 discuss these (im)possibilities in more detail,
substance approved for oral administration may never have for different administration routes.
Fig. 17.1 Processes that

determine bioavailability at m
extravascular administration e
routes
m
b
medicinal solution circulation
product r
dissolution permeation
a
n
e
Table 17.1 Estimated physiologically available volumes

Administration route Liquid Volume (mL)
HP LP Oral Intestinal volume/glass of water 250
Rectal Volume rectum 3
Transdermal Patch material 0.2
HS I III
Buccal/sublingual Saliva 0.9
Vaginal Vaginal mucus 1.2
LS II IV Nasal Nose drops 0.2
drug concentrations after oral administration. In [5] the

HP = high permeability LP = low permeability
selection of formulations for substances with poor water
HS = high solubility LS = low solubility solubility is illustrated.
Fig. 17.2 Biopharmaceutics classification system
For the dissolution properties of the active substance, the
volume of liquid available at the site of administration is
Although principally only valid for oral administration, it important. As outlined in Table 17.1, these volumes can vary
may be useful to assess the biopharmaceutical feasibility of significantly depending on the administration route.
any desired route of administration by the Biopharmaceutics A dose of a poorly soluble substance may be able to
Classification System (BCS, see e.g. [4]) (Fig. 17.2). dissolve in the intestinal volume (250 mL). However, the
The BCS classifies active substances into four classes: limited volume of only 200 microlitres of fluid available in
Class I: high solubility, high permeability the nasal cavity will be insufficient to allow complete disso-
Class II: low solubility, high permeability lution of the same dose when administered as a nasal formu-
Class III: high solubility, low permeability lation. It must be noted therefore that literature most often
Class IV: low solubility, low permeability classifies substances into a certain BCS class based on the
oral application of the highest available dose. When the oral
application concerns class l characteristics this would not
necessarily hold for the nasal use since this may be consid-
17.4.1 Solubility ered as class II, as indicated above.
For most pharmacological targets, a medicine has to
The relationship between the fluid volume available at the permeate across a biological membrane (absorption) after
site of administration and the dose administered will deter- dissolution is completed in order to exert its desired thera-
mine whether or not solubility and dissolution rate of the peutic effect. In general, absorption characteristics differ
active substance are adequate. Mathematically, this critical considerably between the various administration routes,
interaction is described by the dimensionless dose number mainly due to anatomical features of individual barriers.
(see also Sect. 16.1.5): For example, the skin differs to a large extent from the
barrier properties of the intestinal mucosa. Physiologically,
D = V x Cs ð17:1Þ
the skin provides protection and, consequently, only
lipophilic substances can passively permeate this barrier. In
where:
contrast, the gastrointestinal tract is specialised for absorp-
• D ¼ dose
tion of nutrients and water to maintain a viable organism. To
• V ¼ (aqueous) volume available for dissolution
effectively accomplish this physiological task, a combina-
• Cs ¼ solubility in water
tion of active and passive transport mechanisms are avail-
If the dose number < 0.1, solubility of the active substance
able for absorption across the gastrointestinal barrier.
is not considered limiting. If the dose number > 10, it is
predicted that limited solubility of the active substance neg-
atively affects oral bioavailability. Bipolar depression case study #2: modification of
When the dose of the active substance does not dissolve administration route
in the approximately 250 mL of liquid that is present in the For the acute phase, a fast acting, sedative preparation
gastrointestinal lumen (a high dose number), the solid frac- is required, such as an injection or fast acting mouth
tion of the substance will be unable to permeate across the spray. However, such preparations may have not only
intestinal mucosa and, consequently, will be eliminated in a different absorption profile, but also a different met-
the faeces. Newly discovered active substances are often abolic profile (e.g. because of enzymatic saturation).
very poorly soluble in water, which requires unique Thus, additional clinical research is required.
formulations in order to achieve therapeutically relevant
Many exceptions to this rule are reported in the literature,

Rectal Absorption of Oxcarbazepine [6] mainly for substances that bind to membrane transporters,
A mentally disabled young woman with status including vitamins and antibiotics.
epilepticus was admitted to the hospital. The parents
had misunderstood that the oral oxcarbazepine
(1,600 mg/day) should not be terminated, after which 17.4.3 Liver Passage
the seizure occurred. The clinical situation did not
allow for administration of oxcarbazepine per feeding Before an active substance enters the systemic circulation, it
tube. Instead, oxcarbazepine was given rectally as may be subjected to metabolic processes in the intestinal
lipid-based suppositories (three times a day 400 mg). wall and the liver (usually to a much larger extent). This
After 40 h, still no therapeutic blood level had been first-pass effect may diminish the availability of the active
obtained, and thus a feeding tube was inserted after all, substance even when all other biopharmaceutical
making enteral therapy possible. Adequate levels were characteristics are adequate. See also Sect. 16.1.8.
obtained within 1–2 days.
The pharmacist should have anticipated the bio-
PRODUCT DESIGN
pharmaceutical consequences of the physico-chemical
properties of oxcarbazepine. The drug is classified as a
17.5 Formulation
Class II substance for oral application. Logically, lack
Before initiating the design of a formulation and method of
of adequate solubility is even more evident for the
preparation, additional physico-chemical properties of the
rectal administration as the volume of rectal fluid is
active substance should be defined such as particle size and
limited (see Table 17.1). With an aqueous solubility of
particle size distribution, salt, polymorphism, aqueous solu-
approximately 300 mg/L, the solubility of the sub-
bility in dependence on pH, hygroscopicity, melting point,
stance in the lipophilic base of the suppositories
sublimation behaviour, water of crystallisation, dehydration
would certainly not be higher than 9.5 mg/mL (being
temperature. The properties of the raw material are also
a direct consequence of the value of the log P ¼ 1.5 of
relevant to the physical and chemical stability and the com-
oxcarbamazepine). This means that oxcarbazepine is
patibility with the excipients and packaging. Furthermore,
not dissolved in the lipid but dispersed as crystals,
compatibility with other active substances has to be
which settle from the molten suppository once
investigated when the new substance is to be administered
introduced in the rectal cavity. The amount of rectal
through the same infusion line.
liquid is limited and therefore a saturated solution will
Requirements for an optimal effect may require a specific
exist which involves only less than 1 mg dissolved
release profile.
oxcarbamazepine. Low solubility yields a low concen-
tration and hence a low driving force for diffusion to
occur. As a consequence, the rate of absorption is Bipolar depression case study # 3. Target product
relatively low. This slow release may lead to hardly quality profile for a tablet
any uptake, due to defecation within several hours The tablet contains x mg of active substance Y. Based
after insertion. on the biopharmaceutical properties, a good absorp-
tion after oral administration is expected. Substance Y
shows a 50 % first-pass metabolism, one of the
17.4.2 Permeability; Membrane Passage metabolites is moderately active. Substance Y has a
half-life of 6 h and no relation between effect and
Transfer of an active substance across a biological mem- plasma kinetics is apparent. However, there is a rela-
brane is influenced by different physico-chemical drug tion between side effects and plasma profile. To be
properties, which are combined in Lipinski’s ([7] ‘Rule-of- effective, a receptor occupancy > 75 % is required,
5’. This rule predicts poor absorption of an orally during at least 5 h a day. It can be concluded from
administered active substance when it: PK/PD modelling that a good balance between effi-
• Has a molecular weight > 500 Da cacy and side effects can be reached when the tablet
• Is lipophilic (octanol-water partition coefficient, log has the following controlled-release profile: after
P > 5) 30 min, the release is >10 % but <30 %, after 1 h
• Has the ability to form multiple hydrogen bonds the release is >30 % but <50 %, etc.
Lipinski’s Rule-of-5 is not a physical law but allows reason- Y is chemically compatible with excipients a, b, and
able prediction of membrane permeation properties of c, but not with d, e, f, and g. Once dissolved in water, Y
molecules that are mainly absorbed by passive diffusion.
(continued)
does not crystallise upon drying, but forms an amor- The preparation process as described in [8] consists
phous matrix that crystallises in time. The amorphous of the following process steps:
phase crystallises more rapidly at a relative humidity • Dissolve the methyl parahydroxybenzoate in 50 mL
(RH) >75 %. That is why, after drying, the granulate boiling purified water.
must be stored for 24 h at 20 C and 90 % RH. • Disperse the colloidal aluminium magnesium sili-
cate in the hot solution.
• Disperse the carmellose sodium in this suspension;
After selecting a suitable dosage form, the chemical, phys- • Mix with the sugar syrup.
ical and microbiological stability (see Chap. 22), the type of • Dissolve the citric acid monohydrate and sodium
packaging (see Chap. 24), the compatibility with administra- citrate in approximately 15 mL purified water, if
tion systems (see Sect. 13.10.4), and the labelling (see Sect. necessary under heating.
37.3) have to be investigated. Formulation design ends with • Mix this solution with the suspension.
the draft of the quality requirements (see Chap. 32). • Disperse the sulfadiazine.
In Chaps. 4–14 for every administration route the relevant • Mix the raspberry essence with the suspension.
principles of formulation design are dealt with. An illustrative • Add with purified water and mix.
example can be found in Sect. 5.4.2 that discusses the choice The preparation process thus consists subsequently of
between an oral solution or suspension (or neither of them). the process steps: dissolving – dispersing – dispersing
– mixing – dissolving – mixing – dispersing – mixing –
complementing/mixing.
A pharmaceutical preparation process usually comprises of a

series of individual processing steps or unit operations to When drafting a batch preparation instruction for a phar-
produce the finished product. Every process step represents a macy preparation, the process steps should be described
discrete activity that includes physical changes such as more extensively. It should be exactly described how to
mixing, dispersing, grinding, granulating, drying, mix, disperse etc. for a given batch size and given equipment
compressing, and coating. Chapter 29 Basic Operations (see Sect. 33.4). Each process step should be coupled to an
discusses several of these operations. in-process control (see Sect. 17.7).
An associated physical, chemical, or biological property
of an input or output material is qualified as an attribute.
Process parameters that influence these critical product 17.7 Control Strategy: Critical Quality
attributes (e.g., batch size, operating conditions, or moisture) Attributes, Process Parameters
are defined as critical parameters. and Sources of Variability
To control the quality of the product, any relationship among

As an illustration of working with process steps (unit the critical raw material attributes, process parameters, and
operations), the preparation method of an oral suspen- quality attributes for each process should be established
sion is described, see Table 17.2: during development. In addition, limits need to be specified
for critical process parameters that define the design space
where the quality of the product is guaranteed.
Table 17.2 Sulfadiazine oral suspension 100 mg/mL [8]
A design space can be defined for process conditions such as
Sulfadiazine 10 g time, temperature, pressure, pH, rate, but also for ambient
Aluminium magnesium silicate 0.54 g conditions such relative humidity. When the window of the
Carmellose sodium M 0.54 g critical parameters is relatively broad, the process is robust. As
a consequence, usual deviations and variations in the conditions
are predicted to affect product quality only insignificantly.
Raspberry essence (local standard) 0.3 g
Since equipment maintenance, training of operators who
are engaged in the process, and standard operating
parahydroxybenzoate 1 mg per g) procedures may directly or indirectly affect product quality
Water, purified 67.2 g as well, risk assessment tools (see Sect. 21.4) are necessary
to reduce the number of variables under investigation.
Total 114 g (¼ 100 mL)
A preparation process such as tableting has many more
process parameters than for example, dissolving. The
(continued)
preparation of a sterile solution has more process parameters Critical product and process parameters need to be
than the preparation of a non-sterile solution. In other words: monitored, preferably during production. Every process
tableting is much more complicated than the preparation of a step can be provided with in-process controls that monitor
solution. With regard to pharmacy preparations, the prepara- whether or not the critical parameters are maintained within
tion of suspension suppositories has many more variables the limits.
than dispersing an active substance in a cream base. Apart from simple in-process controls (visual
Limits are defined within a specific batch size. Deviations observations, recording pH-values, weights, counting, etc.)
of the batch size should be handled as modifications of a it is also possible to perform analyses. For this, large scale
critical parameter and must follow a predefined change production utilises the term Process Analytical Technology
control procedure (see Sect. 35.6.10). (PAT). PAT utilises a diverse array of analytical in-process
Every process step has critical product and process controls such as near-infrared spectroscopy (NIR, see
parameters. Fig. 17.3) to quantify water content, particle size, and homo-
geneity of mixtures.
In-process controls and PAT allow for a more robust
Bipolar depression case study #4
product quality. Both are also used to adjust the process
Once dissolved in water, Y does not crystallise upon
PRODUCT DESIGN
(see Sect. 34.6).
drying, but it forms an amorphous matrix that can
By collecting data on processes and products, the
crystallise in time. The substance is chemically less
tolerances of product and process parameters (design
stable in the amorphous phase than in its crystalline
space) can be determined. According to Q8, design space
phase. Moreover, it dissolves too fast. This is a critical
is: “the multidimensional combination and interaction of
parameter, since the dissolution rate is critical for the
input-variables and process parameters, of which has been
occurrence of adverse effects. The amorphous phase
shown that they guarantee the quality”.
crystallises at a faster rate at a relative humidity
For licensed medicines, regulatory authorities only
>75 %. Therefore, the granulate should be stored
approve a design space that has been defined by the manu-
after drying at 20 C and 90 % RH. This conversion
facturer of the particular medicinal product. Consistent with
should be regarded as a critical process step that
the QbD concept, modifications to the product or process
should thus be validated, and preferably be controlled
within the defined design space do not have to be presented
during the process.
for approval to the regulatory agencies.
0.004
1st derivative signal at 8669 cm-1 (a.u.)
0.003
Fig. 17.3 In-process control: 0.002

in-line control of the mixing with
NIR (Taken from [9]). With NIR,
the mixing of 15 g citric acid and
75 g Avicel PH-101 is measured.
The peak resembles a quantity
unmixed citric acid that passes the
screen of the NIR system. After
300 s, homogeneity is obtained. 0.001
Source: Recepteerkunde 2009, 0 150 300 450 600 750 900
reprinted by permission of the
copyrights holder time(s)
For pharmacy preparations, the process of standardisation

of an individual formulation can be seen as defining its 17.9 Product Documentation and Design
design space. This design space should be large enough to in Pharmacy Preparation Practice
enable different pharmacies to prepare a product following
the formulation and according to the requirements. Ways to A product dossier allows for demonstration and transparency
perform that task are: about the quality of medicines and if it provides all knowledge,
• Using raw materials of different suppliers at the design data and experience used at the design of the product, it can be
phase. very helpful in troubleshooting or when modifications occur.
• Having a number of local and hospital pharmacies A product dossier that accompanies an application for
involved in preparation of test batches. authorisation should comply with the requirements of the
• After publishing the formulation: sampling batches from European Medicines Agency (EMA). The sections and for-
many pharmacies and analyse them, as is done in the mat of this product dossier – Common Technical Document
Netherlands and Germany. These analyses provide data (CTD) – can be found with the accompanying directives in
about the variation in practice and may lead to improve- [10]. The Q8 guideline gives guidance for the elaborating the
ment of the formulation (and the way information about it product design in the CTD.
is given) as well as to proper education of pharmacists. For agents for clinical trials, an Investigational Medicinal
From a different point of view this can be seen as trying to Product Dossier (IMPD) is required [8], see also Sects. 3.4
create as many guarantees as possible to help pharmacies and 35.5.10. In the IMPD, the production and quality of both
to remain with their preparation activities within the the raw materials and the products is described. Further-
design space. more, all known data from preclinical and clinical research
The individual pharmacist should control the design space is summarised in this document.
with a system of professional development and product and Product files for pharmacy preparations are described in
process validation. Sect. 33.8. National formularies such as FNA (see Sect.
39.4.5) and NRF (see Sect. 39.4.2) entail the product and
process design of a large number of standard pharmacy
preparations. These formularies contain the description of
the formulations and method of preparation, as well as
17.8 Product Validation elaborate elucidations on them. Many of these elucidations
reflect the QbD ideas about documentation of the design
Product validation is performed to test whether the limits for
process. Information about product quality, efficacy, and
the parameters have been set correctly. The main purpose of
safety is published in those formularies or in other clearly
this strategy is to investigate which parts of the product and
related sources: information leaflets for the patient or clini-
process design significantly influence the quality of the
cal information booklets for physicians.
product. Such an investigation gives information about the
For the scope and depth of the product file of a pharmacy
robustness of the design. If, for example, the pH should be
preparation, no strict rules exist yet. However, the pharma-
set within certain limits, it should be known outside of which
cist should clearly connect the solidity of the investigation
pH-limits the properties of the product are essentially
and documentation to the extent of the risk of a suboptimal
changed. Other examples are the amount of thickening
design or suboptimal control strategy. A risk based approach
agent required to prevent sedimentation of a suspension
leads for instance to the following practical solutions as they
while taking a dose, or the type of mixing apparatus and
occur in the Netherlands.
the mixing time and its effect on the homogeneity of the
product.
Furthermore, findings from the on-going stability inves- 17.9.1 Extemporaneous Preparation,
tigation are a part of the product validation. This research Not Standard
may, for example, show that a solution would be
better stored in a glass or plastic bottle. Information that When a pharmacist is to prepare an extemporaneous prepa-
is obtained during the validation research can later be ration for which no standard formulation exists, there is
used for the assessment of deviations during routine usually not much time for experiments and pilot batches.
productions. The risk assessment of the prescription should however be
Product validation is independent of process validation, performed carefully (see Sect. 2.2). The preparation process
since it is independent of the location where the product is should be validated on the level of dosage form and the
made. A validated product design subsequently requires a preparation documentation (see Sect. 33.5), including the
validated process (see Sect. 34.14) to allow for preparation results of in-process controls, should be evaluated by the
of the product with a constant quality. pharmacist before dispensing for use by the patient.
testing. The analytical test methods are developed and

Preparation of Ivabradine Capsules (Low Dose) validated.
A woman with persistent cardiac arrhythmia consults a Information for patient and caregiver is drafted and, if
cardiologist. Administration of flecainide, atenolol, necessary, substantiated with research, for example about
and metoprolol for some weeks did not lead to the compatibility with other medicines in case of a
improvement due to the sinus tachycardia. Having multiple-use infusion line (so-called Y-site compatibility).
the patient’s consent, the physician decides to start The first batch that is prepared and analysed, is placed in
treatment with ivabradine (Procoralan®). Since the quarantine until evaluation of the preparation and analysis
patient showed a hypotensive response to two doses has been performed. Preferably, the batch size is always the
of 5 mg, it is decided to start with a very low dose of same, since batch size is a critical variable, and thus a
0.625 mg twice daily. modification requires a change control procedure. In case
The raw material is not available. Therefore the of a suspected short shelf life, the results of the first time
pharmacist decides to prepare capsules from points of the shelf-life analysis should be awaited before the
Procoralan® tablets. These tablets have a coating, product can be used.
but one without modified-release properties.
PRODUCT DESIGN
Ivabradine has a high aqueous solubility and high
membrane permeability (BCS class I), and thus the
pharmacist disregards the coating. He mixes the 17.10 Product Life Cycle Management
ground tablets with lactose monohydrate and fills
capsules with the powder blend. Product control Life cycle management could support an active attitude
shows that the preparation complies with requirements towards improving the design quality of the product, as a
for uniformity of mass and deviation of the theoretical contrast with just reacting to events, see also Sect. 35.4.1. In
weight. Post-preparation analysis by HPLC with diode contrast to licensed medicinal products for instance, phar-
array detection shows a mean content within the macy preparations are usually not tested on efficacy and
acceptable limits (90–100 %) and a proper content safety before use in patient care. Their safety is based upon
uniformity. literature. Therefore, it is important to evaluate the outcomes
of a treatment (pharmacovigilance, see also Sect. 35.4.2) and
to relate this knowledge to the continuation, modification, or
17.9.2 Extemporaneous Preparation, Standard discontinuation of the product. The treatment outcomes gen-
erally consist of observations by the physicians, case reports,
When a pharmacist regularly produces a specific preparation or retrospective analysis of patient dossiers.
for an individual patient, a better substantiation of the design
quality is necessary. Both literature and experimental Midazolam Oral Solution Becomes Enema
research may provide extra information about the pharma- For pre-operative sedation of children, the anaesthesi-
cotherapy and about pharmaceutical properties such as ologist applies midazolam (0.5–0.8 mg/kg, maximally
homogeneity, stability microbiological quality, compatibil- 15 mg orally or rectally). Midazolam has a beneficial
ity, tolerability, and taste. For this, the pharmacist may use profile for small surgical procedures because it has a
data from other pharmacies as well. Furthermore, more fast onset of action, gives retrograde amnesia, and has
specific in-process controls may be added to the preparation a short half-life, which causes the patient to wake up
process. An end control (usually non-destructive) by the quickly. However, the midazolam oral solution that is
operator is required for every batch, as well as a more used in many hospitals has a very unpleasant taste.
specific validation of the preparation method. Especially during second and subsequent treatments,
the oral administration of midazolam may stress the
children. In some cases, children refuse to take the
17.9.3 Stock Preparation mixture or spit it out.
The physician requests the hospital pharmacy to
Before a stock preparation is added to the range of products develop and prepare an enema. At first, the pharmacist
of a pharmacy, the design quality needs to be substantiated. attempts to improve the taste of the oral solution. After
The pharmacotherapy is evaluated and for the choice of testing and rejecting various possibilities, the pharma-
dosage form and concentration, feedback from the users is cist assesses the request for an enema as justified. The
highly valued. Production batch scaling may influence the tolerability of the formulation of midazolam in the
preparation process. A strategy is set to control product rectum is evaluated by adding a dye to the first batch.
quality by a combination of in-process controls (generally
off-line), the testing of intermediate products, and end (continued)
3. European Paediatric Formulation Initiative. STEP Database, http://

The nurses assess the amount of leakage by a pharmacyapp-a.ucl.ac.uk:8080/eupfi
4. Amidon GL, Lennernäs H, Shah VP, Crison JR (1995) A theoretical
pre-operative check of the underpants of the patient. basis for a biopharmaceutic drug classification: the correlation of
Administration of the midazolam enema followed by a in vitro drug product dissolution and in vivo bioavailability. Pharm
suppository results in no leakage. The entire dose can Res 12(3):413–20
be administered, which is often not possible for the 5. Branchu S, Rogueda PG, Plumb AP et al (2007) A decision support
tool for the formulation of orally active, poorly soluble compounds.
oral solution. The physicians are content with the Eur J Pharm Sci 32:128–39
sedation. Based on this experiment, the hospital phar- 6. van der Kuy PHM, Koppejan EH, Wirtz JJJM (2000) Rectal absorp-
macist and physician decide to introduce the treatment tion of oxcarbazepine. Pharm Weekbl Sci Ed 22:165–6
to the entire hospital. 7. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experi-
mental and computational approaches to estimate solubility and
permeability in drug discovery and development setting. Adv
Drug Deliv Rev 46(1–3):3–26
8. Sulfadiazinesuspensie 100 mg/ml FNA. Formularium der
Nederlandse Apothekers. Jaar 2013. Den Haag: Koninklijke
References 9. Bellamy LJ, Nordon A, Littlejohn D (2008) Effects of particle size
and cohesive properties on mixing studied by non-contact NIR. Int J
1. CHMP/ICH-Q8 Pharmaceutical Development 2008. www.ich.org Pharm 361(1–2):87–91
2. Yu LX (2007) Pharmaceutical quality by design: product and 10. Notice to applicants and regulatory guidelines medicinal products
process development, understanding and control. Pharm Res for human use. Volume 2B – Presentation and content of the
25:781–91 dossier. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex
Physical Chemistry
18
Wouter Hinrichs and Suzy Dreijer - van der Glas
Contents Abstract
Many pharmaceutical dosage forms are liquids or semi-
18.1 Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
18.1.1 Solubility and pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 liquids such as solutions, colloidal systems, suspensions
18.1.2 Solubility and Salt Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 and emulsions. This chapter deals with the physico-
18.1.3 Solubility in Non-aqueous Solvents . . . . . . . . . . . . . . . . . . . . . 361 chemical backgrounds that are important for the prepa-
18.1.4 Solubility and Complex Formation . . . . . . . . . . . . . . . . . . . . . . 363
ration of these types of dosage forms. Successively
18.1.5 Solubility of Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
18.1.6 Solubility and Supersaturation . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 solubility, rheology, interfaces, surface active agents,
disperse systems and osmosis are addressed. Physical
18.2 Rheology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
18.2.1 Rheograms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 chemistry plays an important role in the design of liquid
18.2.2 Measurement Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 or semi-liquid pharmaceutical dosage forms. By chang-
18.3 Interfaces and Surface Active Agents . . . . . . . . . . . . . . . . . 367
ing physico-chemical parameters intentionally or unin-
18.3.1 Surface and Interfacial Tension . . . . . . . . . . . . . . . . . . . . . . . . . . 367 tentionally, the biopharmaceutical properties and thus
18.3.2 Wetting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 the therapeutic activity of an active substance can dras-
18.3.3 Micelle Formation and Solubilisation . . . . . . . . . . . . . . . . . . . 368 tically change. Many physico-chemical properties are
18.4 Disperse Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 related to each other. For example, changing the com-
18.4.1 Colloidal Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 position of a solvent mixture does not only affect its
18.4.2 Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
solubility for an active substance but also its surface
18.4.3 Emulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
tension, osmotic value, etc. The chapter is primarily
18.5 Osmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 intended to explain physico-chemical aspects described
18.5.1 Osmotic Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
18.5.2 Iso-osmotic and Isotonic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 in other chapters. Many examples of the design of
18.5.3 Non-ideal Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 pharmaceutical preparations are described to clarify
18.5.4 Calculation of Osmotic Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380 and illustrate the concepts, considering excipients as
18.5.5 Importance of Osmotic Value in Dosage Forms . . . . . . . . 381 well as active substances, and small molecules as well
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382 as proteins.
Keywords
Solubility Viscosity Suspensions Osmotic value
Surface activity pH Rheology Disperse systems
Colloidal systems
Based upon the chapter Fysische Chemie, by Wouter Hinrichs, Suzy

Dreijer, Herman Vromans in the 2009 edition of Recepteerkunde.
18.1 Solubility
W.L.J. Hinrichs (*)
Aqueous solubility is an important property of active
University of Groningen, Groningen, The Netherlands substances. For example, incompatibility reactions leading
e-mail: [email protected] to undesired precipitation in parental formulations can be
S.M. Dreijer - van der Glas avoided with a good knowledge of solubility properties
Royal Dutch Pharmacists’ Association KNMP, The Hague, [1–3]. Furthermore, there can be several reasons to influence
The Netherlands

358 W.L.J. Hinrichs and S.M. Dreijer - van der Glas
the aqueous solubility of an active substance. It may be Table 18.2 Explanation of the Definitions for the Solubility in Water
required to increase the solubility to be able to prepare as specified in the Ph. Eur.
dosage forms in which the active substance is dissolved or Solubilitya
it may be more useful to disperse an active substance as Very soluble Less than 1
particles in a suspension, thus in the undissolved form. Freely soluble From 1 to 10
Bringing active substances into solution can have impor- Soluble From 10 to 30
tant advantages: Sparingly soluble From 30 to 100
• The preparation method is much simpler than that of Slightly soluble From 100 to 1,000
disperse systems. Very slightly soluble From 1,000 to 10,000
Practically insoluble More than 10,000
• The dosage accuracy is much better than of disperse
a
systems. Amount of water in millilitres required to dissolve 1 g of an active
substance
• The rate of absorption and the bioavailability will be
higher than those of disperse systems (see Sect. 16.1.5).
• Solutions in certain dosage forms are much better
tolerated than suspensions. Suspensions (except for
nanosuspensions) are not suitable for parenteral infusion Although the terms in Table 18.2 to describe the
for instance. solubility of an active substance are still used in
In a number of cases however, suspensions are preferable: many handbooks, from a clinical view they are no
• If an active substance is unpalatable, the undissolved longer used. The principle of solubility in perspective
form can mask the taste. is now used. That is, the solubility of an active sub-
• If the active substance is unstable in solution. stance is connected to the dose that should be
• If a reduction of the dissolution rate of an active sub- administered to the patient. Thus, solubility in per-
stance is desired in order to slow down the absorption. spective is not a pure physico-chemical characteristic
of the active substance. For example, the solubility
will not cause any problems when an active substance
The pH of Tetracycline Mouthwash 5 % FNA
with a low solubility has to be given to a patient as a
(Table 18.1) is adjusted to 5.0–5.5 with sodium citrate
solution at a very low concentration. In Chap. 17
to minimise the solubility of tetracycline hydrochloride.
Product design and in Chap. 16 Biopharmaceutics
Tetracycline hydrochloride solutions are unstable.
this concept will be explained in more detail.
Table 18.1 Tetracycline Mouthwash 5 % [4]
Tetracycline hydrochloride 5.0 g
Methyl parahydroxybenzoate 0.1 g The rate at which an active substance dissolves does not
Sodium citrate 6.5 g only depend on the solubility of the active substance. The
Sorbitol, liquid (crystallising) 65.5 g dissolution of an active substance is described by the Noyes-
Tragacanth 0.5 g Whitney equation:
dm D A
Total 118.2 g (¼ 100 mL) ¼ ðCs CÞ ð18:1Þ
dt h
where dm/dt is the dissolution rate, D the diffusion coeffi-

Chloramphenicol has an extremely bitter taste. When this cient of the active substance in solution, A the contact
antibiotic is used orally, it should be formulated as a suspen- surface area of the active substance with the solvent, h the
sion, using the insoluble chloramphenicol palmitate. thickness of the diffusion layer, Cs the solubility of the active
In the European Pharmacopoeia (Ph. Eur.) various substance and C the concentration of the active substance in
definitions for solubilities in water are described, i.e. from the bulk of the solution.
“very soluble” to “practically insoluble” (Table 18.2) Amongst other strategies, the solubility of a substance
[1]. The solubility is also indicated by the amount of water, can be influenced by variation of the pH, salt formation,
in millilitres, necessary to dissolve 1 g of the substance at variation of the solvent, complex formation, or derivatisa-
room temperature. The solubility of a substance can also be tion. These concepts, with pharmaceutical preparations as
specified in grams per Litre. examples, are explained below.
18 Physical Chemistry 359
18.1.1 Solubility and pH
Most substances are more easily dissolved in water when

they are ionised. The degree of ionisation for many
substances depends on the pH. Many active substances are
weak acids or weak bases. The degree of ionisation, and thus
the solubility, can be influenced by adjusting the pH of the
medium. The solubility of a non-ionised weak acid can be
increased by raising the pH, while the solubility of a
non-ionised weak base can be increased by lowering the pH.
The pKa value of an acid indicates how weak the acid is:
the higher the pKa value, the weaker the acid. Thus when a
weak acid is dissolved in pure water, the decrease of the pH
and the extent of dissociation of the acid will be less when
the pKa value increases. The relationship of the pH, pKa, and
Fig. 18.1 Titration of a weak monovalent acid with a strong base
PRODUCT DESIGN
the concentrations of a non-ionised acid [HA] and its salt
[A-] is given by the Henderson-Hasselbalch equation:
pH of the initially acidic solution (λ ¼ 0) is dependent on
½ A
pH ¼ pKa þ log ð18:2Þ the concentration and the degree of dissociation of the acid.
½HA
When the pH is around the pKa, the solutions acts as a buffer
because the addition of a small amount of acid or base will
When the pKa of a substance is known, the fraction ionised
hardly affect the pH. When λ ¼ 0.5, the pH equal to the pKa,
active substance as a function of the pH can be calculated
there is an equal amount of acid and salt present. In this
using the following derivatives of this equation:
situation, the buffer capacity is maximal. The equivalence
1 point of the titration is found when λ ¼ 1.
fraction ionised 1 10 pH‐ pKa þ 1 ð for a weak acidÞ
A salt composed of a weak base and a strong acid lowers
ð18:3Þ the pH in aqueous solution. Conversely, a salt composed of a
weak acid and a strong base raises the pH in aqueous solu-
1
fraction ionised 1 10 pKa ‐ pH þ 1 ð for a weak baseÞ tion. Examples are lidocaine hydrochloride (acid reaction)
and sodium phenobarbital (alkaline reaction), respectively.
ð18:4Þ
When the pH of aqueous solutions of these substances is
The pKa of phenobarbital is 7.4. When the pH is adjusted adjusted to pH ¼ 7, lidocaine and phenobarbital, respec-
to 5.4, 7.4 or 9.4, the fraction ionised active substance will be: tively, are partially formed again and precipitate.
1 1 The so-called pHp equations (18.5 and 18.6) can be used
1 105:47:4 þ 1 ¼ 0:01 ; 1 107:47:4 þ 1 ¼ 0:5 to calculate the solubility of a weak acid or a weak base as a
9:47:4 1
or 1 10 þ1 ¼ 0:99, respectively. This example function of the pH [2, 5]. pHp is an abbreviation for pH
emphasises that by varying the pH around the pKa, the precipitation, the pH at which just no precipitation occurs.
fraction of ionised active substance can be strongly affected: At a given concentration, the weak acid will precipitate
up to 2 pH units below the pKa, only 1 % is ionised, whereas when the pH is lower than the pHp and the weak base will
at 2 pH units above the pKa 99 % is ionised. precipitate when the pH is higher than the pHp.
For a further understanding of the dissolution of a sub-
stance by salt formation, some basic concepts of analytical S S0
pHp ¼ pKa þ log ð for a weak acidÞ ð18:5Þ
chemistry are summarised (Fig. 18.1). S0
When an aqueous solution of a weak monovalent acid in
water is titrated with NaOH, the pH strongly increases with S0
pHp ¼ pKa þ log ð for a weak baseÞ ð18:6Þ
the first amounts of added NaOH, but when the pH almost S S0
reaches the proteolytic constant or the pKa value of the acid,
the pH changes to a lesser extent. When the pH is one to two where S0 is the solubility of the undissociated acid or base
units above the pKa, the pH again rises sharply upon adding and S the concentration of the acid or base which has been
more NaOH. For a titration, the amount of added reagent added initially (both in mole/L).
(in this case NaOH) divided by the quantity of the substance The pHp equation can be illustrated in more detail with an
to be determined (both in moles) has been defined as λ. The example of a calculation. Suppose a 1 % w/v solution of
Table 18.3 Furosemide Oral Solution 2 mg/mL [7] Table 18.5 Tetracycline Hydrochloride Eye Drops Solution 0.5 % [9]
Furosemide 0.2 g Tetracycline hydrochloride 0.5 g
Methyl parahydroxybenzoate 0.075 g Borax 0.5 g
Propyl parahydroxybenzoate 0.025 g Sodium chloride 0.7 g
Saccharin sodium 0.1 g Water, purified ad 100 mL
Trometamol 0.1 g
Water, purified ad 100 mL
Examples of pharmaceutical preparations in which the
active substance is dissolved by influencing the pH are
infusion or inhalation solutions with acetylcysteine and a
Table 18.4 Tetracycline Hydrochloride Cream 3 % [8] furosemide oral solution (Table 18.3). In both cases, a
Tetracycline hydrochloride 3g
weak acid is brought into solution by raising the
Sodium citrate 4g pH. Usually sodium hydroxide is used for acetylcysteine
Water, purified 11 g and in the formulation of Table 18.3 the primary amine
Cetomacrogol cream FNAa 82 g trometamol is used for furosemide.
Tetracycline hydrochloride easily dissolves in water, to
Total 100 g
give an acidic solution. In Tetracycline hydrochloride cream
a
Cetomacrogol emulsifying wax (BP) 15 g, Sorbic acid 200 mg, Decyl 3 % FNA, the pH is adjusted to about 5.5 by adding sodium
oleate 20 g, Sorbitol, liquid (crystallising) 4 g, Water, purified 60,8 g.
citrate to a tetracycline hydrochloride solution (Table 18.4).
Total 100 g
At this pH, tetracycline is insoluble and therefore a suspen-
sion is formed. In undissolved state tetracycline is chemi-
sodium phenobarbital should be prepared. The following cally more stable than in the dissolved state. Moreover, a pH
information can be obtained from the Merck Index [6]: of 5.5 is only slightly lower than the third proteolytic con-
MW phenobarbital ¼ 232.32 g/mol; stant of citrate (pKa ¼ 6.4 at 25 C), so a citrate buffer is
MW sodium phenobarbital ¼ 254.22 g/mol; formed. This saves tetracycline from dissolving again due to
Solubility phenobarbital in water ¼ 1 g/L; slight pH decrease.
pKa (phenobarbital) ¼ 7.4. Tetracycline is an amphoteric substance which forms
It follows: salts in both an acidic and an alkaline environment. The
S0 ¼ 1=232:32 ¼ 0:0043 mol=L; substance dissolves at a pH higher than about 8. This was
1 % w/v corresponds to 10 g/L; thus: made use of in the preparation of a solution of tetracycline
S ¼ 10=254:22 ¼ 0:0393 mol=L; for eye drops (Table 18.5). By the addition of borax, a pH of
Thus the pHp becomes: about 8.2 is reached. As a consequence, tetracycline readily

pHp ¼ 7:4 þ log 0:03930:0043
0:0043 ¼ 8:3. dissolves.
It follows that in order to obtain a 1 % w/v sodium Is a bumetanide infusion solution 5 mg in 50 mL (syringe
phenobarbital solution, the pH must be at least 8.3. At a for a pump) possible as a solution? The pH of the licensed
pH lower than 8.3, phenobarbital will remain partially product (injection solution 0.5 mg/mL) is 7.0. According
undissolved. to information from the manufacturer, the concentration
However, the choice of pH cannot be unlimited. In par- should be maximally 0.1 mg/mL when mixed with infusion
ticular at a high or a low pH, the active substance can for fluids. The reason is that when the concentration is higher
example be chemically unstable. In addition, an extreme pH than 0.1 mg/mL bumetanide will precipitate unless the
can be incompatible with other components in the solution, pH of the preparation is maintained. The solubility of
for example, preservatives. In addition, the selected pH (non-ionised) bumetanide is 0.1 mg/mL or even lower. The
should also be compatible with the route of administration. licensed product contains alkaline additives in order to reach
Thus with the correct setting of the pH, either a solution a concentration of 0.5 mg/mL. If these additives are diluted,
or a suspension can be obtained. The preparation of solutions the pH becomes too low, which may cause precipitation of
and suspensions by manipulation of the pH will be illustrated non-ionised bumetanide.
with a number of examples. Theophylline can be dissolved by salt formation with
There are several ways to adjust the pH to a certain value, ethylenediamine or other amines. Previously, ethylene-
which are essentially not different. Either NaOH or HCl can diamine theofyllinate (aminophylline) was used in oral
be added to obtain a suitable pH at which the salt is soluble, preparations. Soluble double salts of theophylline can be
or the pHp equation can be used to calculate the amount of prepared using sodium acetate and sodium glycinate. How-
an acid or a base with its corresponding salt that will be ever, excellent absorption is achieved after oral administra-
soluble. tion of theophylline as such, for example in capsules, so
Table 18.6 Solubility of some Mineral Salts in Water in grams per Litre Table 18.7 Solubility Product of some Mineral Salts in Water

22 C 38 C Solubility product (S)a pS (¼ – logS)
CaSO4.2H20 2.41 2.22 CaSO4 7.1 105 4.15
CaCO3 0.014 0.018 CaCO3 5.0 109 8.30
Ca3(PO4)2 0.02 Not available Ca3(PO4)2 2.1 1033 32.7
CaHPO4.2H2O 0.316 Not available MgCO3 6.8 106 5.17
Ca(H2PO4)2.H2O 18 Not available Mg3(PO4)2 6.5 105 4.18
MgSO4.7H2O 710 910 Mg3(PO4)2 3.5 105 b 4.46
MgCO3 0.106 Not available a
Room temperature
MgHPO4.7H2O 3 2a 38 C
b
a
Magnesium and phosphate ions can co-exist in mineral infusions.
As can be seen in the table, the solubility of magnesium hydrogen phosphate is 18 g/L and that of calcium monohydrogen
phosphate decreases when the temperature is increased. As a result,
phosphate 0.3 g/L.
during sterilisation a precipitate can be formed in a solution that was
originally clear. After cooling, however, this precipitate will dissolve As long as the pH of the mixture remains below 6.4,
again precipitation is not likely to occur. But for instance at a pH
of 7.4, 60 % of the phosphate will be present in the form of
PRODUCT DESIGN
monohydrogen phosphate, with an increasing risk of precip-
administration as a solution does not seem to be necessary itation. Therefore, it is always best to check the solubility of
from a biopharmaceutical viewpoint. After absorption, at a the product.
physiological pH of approximately 7.4 there is obviously no Solubilities of many active substances are listed in Merck
difference in the degree of ionisation of the substance Index [6] and in Martindale [11]. When a pharmaceutical
whether it was administered as such or as a salt. Therefore, preparation contains various salts there may be (multiple)
no differences in physiological activity between an active combinations of ions that are incompatible and may result in
substance and its salt are expected. However differences in the formation of a precipitate. For example, after addition of
solubility and dissolution rate and differences in absorption a chloride salt to a chlorhexidine digluconate solution, the
and absorption rate may generally influence the earlier insoluble salt chlorhexidine chloride is formed resulting in
stages of administration and lead to a difference in bioavail- precipitation. Exact data on this are hard to find. In general,
ability. In addition, the counter ion may induce (undesirable) the risks of precipitation are high for combinations of large
side-effects. The use of ethylenediamine was abandoned positive and negative ions. Examples are carmellose anion
because of the sensitising properties, even after oral use and lauryl sulfate, which is a component of Lanette wax.
[10]. In addition, it might be toxic, being a secondary amine. Insoluble salts can be made to mask an unpleasant taste or
to prevent local irritation of the gastrointestinal tract. Well-
known examples are ferrous fumarate suspension and potas-
18.1.2 Solubility and Salt Formation sium hydrogen tartrate suspension. In Sect. 5.4.10 more
examples of insoluble salts to mask unpleasant tastes are
Not all salts exhibit a good aqueous solubility. A number of discussed.
inorganic salts having a relatively low molecular weight and
a low water solubility are listed in Table 18.6. Also the
solubility product often is given (Table 18.7). This allows 18.1.3 Solubility in Non-aqueous Solvents
us to determine the effect of other ions in the solution on
the solubility of a given substance, for example, when When the aqueous solubility of an active substance is too
sodium carbonate is added to a solution of magnesium low, it can be dissolved in a different solvent or mixture of
chloride. Also the reduction of the solubility of the poorly solvents, which is compatible with the route of administra-
soluble calcium carbonate can be calculated when a certain tion. The solubility of a lipophilic substance (a substance
amount of the readily soluble sodium carbonate or calcium which dissolves well in the oil or fat but poorly in water) can
chloride is added. This reduction in the solubility of, in this be increased by making the dissolution medium (water)
case, calcium carbonate is also known as the common less polar by the addition of less polar but water-miscible
ion effect. solvents. Often mixtures of water, ethanol and
An example of this can be found in solutions for paren- propylene glycol are used. Also glycerol and macrogol
teral nutrition that contain calcium and phosphate ions (see (polyethylene glycol) can be used. The polarity of a solvent
Sect. 13.9.2). At the pH of parenteral nutrition mixtures can be expressed by its dielectric constant, ε (for examples
dihydrogen phosphate and monohydrogen phosphate will see Table 18.8, the higher the dielectric constant, the higher
both be present. The solubility of calcium dihydrogen the polarity).
Table 18.8 Dielectric Constants of Some Solvents Table 18.9 Digoxin Solution for Injection 1 mL ¼ 0.25 mg [12]

Solvent: Dielectrical constant, ε (25 C) Digoxin 0.025 g
Water 79 Citric acid monohydrate 0.075 g
Glycerol 43 Disodium phosphate dodecahydrate 0.450 g
Propylene glycol 32 Ethanol (96 %) 10 g
Ethanol 24 Propylene glycol 40 g
Macrogol 400 12 Water for injections ad 100 mL
Table 18.10 Paracetamol Oral Solution 24 mg/mL [13]

The dielectric constant of a mixture of solvents can be Paracetamol (500-90) 2.4 g
calculated as the sum of the dielectric constants of its Ethanol (96 per cent) 8.1 g
components, each multiplied by the volume fraction of that Glycerol (85 per cent) 74 g
solvent. The dielectric constant of a mixture of solvents A, Raspberry flavouring (local standard) 0.1 g
B, . . . is thus: Sodium (S)-lactate solution 600 g/kg 6.65 g
Sorbitol, liquid (crystallising) 30.75 g
εmixture ¼ f A εA þ f B εB þ . . . ð18:7Þ Total 122 g (= 100 mL)
where fA, fB . . . are the volume fractions of the solvents A,

B, respectively, and εA, εB, . . . the dielectric constants of the Table 18.11 Phenobarbital Solution for Injection 50 mg/mL [14]
solvents A, B, . . ., respectively. Phenobarbital 5.0 g
This equation can be used when the composition of a Ethanol (96 %) 31.5 mL
liquid mixture is to be changed, while keeping the dielectric Propylene glycol 35.0 mL
constant the same. For example, assume that an active sub- Sodium hydroxide solution 2 M (local standard) q.s.
stance dissolves in a mixture of 20 % v/v water and 80 % v/v Water for injections ad 100 mL
ethanol. As such a large volume percentage of ethanol is not
desirable for many pharmaceutical applications; it has to be
The relationship between the solvent medium, the pH and
reduced to 20 % v/v. In order to maintain the dielectric
the pKa can be clearly illustrated using barbiturates as
constant, macrogol 400 can be used to replace a large part
examples. Phenobarbital can be dissolved in water as its
of the ethanol. The volume percentages of water and
sodium salt. This requires a pH of 10 or higher. At this pH
macrogol 400 can be calculated as follows:
(it appears that) barbiturates decompose by ring-opening
Original mixture:
under the formation of malonylurea derivatives. The shelf
εmixture ¼ f water εwater þ f ethanol εethanol life of such aqueous barbiturate solutions for oral adminis-
¼ 0:2 79 þ 0:8 24 ¼ 35 tration is therefore limited to approximately 1 week. In
addition, heat sterilisation of an aqueous solution for injec-
Adjusted mixture: tion is not possible at this pH. In the formulation of
injections, this problem has been solved by improving the
εmixture ¼ f water εwater þ f ethanol εethanol þ f PEG εPEG solubility at slightly alkaline pH through the addition of a
¼ y 79 þ 0:2 24 þ ð0:8 yÞ 12 ¼ 35 less polar solvent mixture e.g. a mixture of propylene glycol
and ethanol.
It follows that the volume fraction of water, y, is 0.31 and the In a mixture of 35 % v/v water, 35 % v/v propylene
volume fraction of the macrogol 400, (0.8 – y), 0.49. The glycol and 30 % v/v ethanol at a pH of 8.9, the solubility
composition of the adjusted mixture by volume percentage is of phenobarbital at room temperature is approximately
thus: water/ethanol/ macrogol 400 ¼ 31/20/49. 11 % w/v. An example of a formula for a phenobarbital
Pharmaceutical examples of solutions where a relatively injection of 50 mg/mL is given in Table 18.11. The pH is
poorly water soluble substance is dissolved in a mixture of usually adjusted to a value between 7 and 8. Phenobarbital in
solvents are injections with diazepam or digoxin these injections is thus partially in the ionised form. The
(Table 18.9). In both of these preparations a mixture of non-ionised form is dissolved by the organic solvents.
ethanol, propylene glycol and water is used as the solvent. An alternative way to prepare solutions of lipophilic
Paracetamol in an oral solution could at first be dissolved substances is to use solvents that are not miscible with
in 85 % glycerol (Table 18.10) water such as oils or esters of wax alcohols.
OH HO
HO OH
O
O
O O O
HO OH
HO
HO O
OH
HO O OH
HO
OH
O O
OH HO O
O
HO OH
O
O O
OH
PRODUCT DESIGN
HO
Fig. 18.3 Schematic representation of a betadex–prednisolone
complex
HO OH
Fig. 18.2 Chemical structure formula of betadex (betacyclodextrin) Ph. Eur.) for example dissolves much better in water
than the non-derivatised betadex (betacyclodextrin). Thus,
the aqueous solubility of lipophilic molecules increases
18.1.4 Solubility and Complex Formation after complexation with cyclodextrins. By selecting the
right combination of active substance and cyclodextrin,
Sometimes two substances strongly interact (non-covalent) the solubility of poorly water-soluble substances can be
with each other in solution. In these cases complexes are increased.
formed whose solubility is different from that of the individ- Amongst other applications, cyclodextrins are used for
ual components. For example, iodine is only soluble in water the oral administration of lipophilic active substances. By
in the form of a complex with iodide ions or with povidone. complexing piroxicam with cyclodextrin a product is formed
Iodinated povidone has the additional advantage that its which shows an enhanced dissolution rate and therefore a
solutions do not irritate the skin, as is the case for solutions more rapid absorption. An itraconazole oral mixture
where iodine is dissolved by complexation with potassium containing cyclodextrin has been developed to guarantee
iodide. sufficient absorption of the active substance. Cyclodextrins
Cyclodextrins are another category of substances that are are also used in parenteral preparations. Fluasteron is an
used for complex formation. Cyclodextrins are ring-shaped antineoplastic agent which is preferably administered by
oligosaccharides consisting of six, seven or eight glucose injection to the patient at a concentration of 1,000
units referred to as alpha-, beta-, and gammacyclodextrin, micrograms per millilitre. Its aqueous solubility, however,
respectively (see Fig. 18.2 for the chemical structure of is only 0.045 microgram per millilitre. With a 20 % w/v
betacyclodextrin) [15]. hydroxypropylbetacyclodextrin solution, the desired con-
The Ph. Eur. has a monograph for betacyclodextrin: centration can be achieved [16].
Betadex. Cyclodextrin forms a hollow truncated cone struc-
ture which is hydrophilic at the outside and contains a
non-polar cavity into which lipophilic molecules fit 18.1.5 Solubility of Derivatives
(Fig. 18.3).
The diameter of the non-polar cavity increases when Derivatisation is a method of changing the properties of a
cyclodextrin contains more glucose units. As a consequence, molecule by means of a chemical reaction where an addi-
small lipophilic substances form better complexes with tional group is covalently coupled. By derivatisation, the
cyclodextrins having a small non-polar cavity and large solubility of substances can be either decreased or increased.
lipophilic substances better with cyclodextrins having a In pharmacy, esters are important derivatives. This will be
large non-polar cavity. On the outside, cyclodextrins are explained in greater detail on the basis of corticosteroids of
polar by which they are fairly soluble in water. The aqueous which the C21-alcohol group can be esterified. These esters
solubility of cyclodextrins can be affected by derivatisation. are not effective but should first be hydrolysed in the body.
Hydroxypropylbetacyclodextrin (Hydroxypropylbetadex The rate of hydrolysis of esters in solution is strongly pH
hydrocortisone hydrocortisone acetate
O
O
O H CH3
OH O
CH3 OH HO CH3
HO OH
CH3 H
CH3 H
H H H H
O O
triamcinolone triamcinolone acetonide

OH
O O
OH CH3
CH3 OH CH3 O
HO HO CH3
CH3 H OH O
CH3 H
H
F H
F H
O
O
Fig. 18.4 Chemical structure formulas of hydrocortisone, hydrocortisone acetate, triamcinolone and triamcinolone acetonide
dependent. In a strongly acid or alkaline environment hydro- In order to increase their lipid solubility, corticosteroids
lysis rapidly occurs. In vivo, the hydrolysis is catalysed by have been esterified with monocarboxylic (fatty) acids.
esterases. Examples include hydrocortisone acetate, beclomethasone
Esters of corticosteroids with a polyvalent acid group, for dipropionate and betamethasone isovalerate. For triamcino-
example succinic acid or phosphoric acid, are soluble in their lone, the following method has been developed to make the
salt form. This is because most of the non-esterified acid substance lipophilic: the hydroxyl groups at the C16 and
groups are deprotonated when sufficiently high pH is cho- C17-position of triamcinolone are used to form a cyclic
sen. Examples of corticosteroids which are esterified with acetal (Fig. 18.4). Although the formed substance, triamcin-
polybasic acids are hydrocortisone sodium succinate, pred- olone acetonide, is not a fatty acid ester, with regard to lipid
nisolone sodium phosphate and dexamethasone sodium solubility it behaves as such.
phosphate. In an aqueous medium with a pH of about 7 or Fatty acid esters of corticosteroids may be used for the
higher, hydrocortisone sodium succinate is largely ionised preparation of depot injections, either as oily solutions or
and thus fairly soluble. At this pH, however, the hydrolysis aqueous suspensions. The nature of the fatty acid, in partic-
of the ester is quite fast (this ester is most stable at a pH of ular the length of the carbon chain, determines, to a large
about 4.5). As a result, dissolved in water, this substance is extent, its solubility and therefore its release and absorption
unstable and therefore its shelf life is limited. rate into the bloodstream. In addition, in the case of
In aqueous solution, prednisolone sodium phosphate and corticosteroids, solutions or microcrystalline suspensions in
dexamethasone sodium phosphate are more stable than either oil or water are used for intra- or periarticular
hydrocortisone sodium succinate. At a pH of about 8, the injection.
acid groups are sufficiently ionised to make the substance Dermatology is another important field where fatty acid
very soluble, while the phosphate ester is reasonably stable esters of corticosteroids are applied. Examples are creams
at this pH. Water soluble corticosteroids are mainly used in with hydrocortisone acetate and triamcinolone acetonide,
parenteral preparations, eye drops, oral mixtures and respectively. These fat-soluble derivatives are used because
enemas. Examples are prednisolone oral mixtures and dexa- they show better penetration into the lipophilic stratum
methasone injections. corneum of the skin.
Table 18.12 Hydrocortisone Eye Drops 1 % [17] Table 18.14 Magnesium Citrate Oral Solution 80 mg/mL [19]
Hydrocortisone acetate (micronised) 1g Magnesium carbonate, light 3.00 g
Benzalkonium chloride 0.001 g Citric acid monohydrate 8.33 g
Disodium edetate 0.1 g Lemon Spirit BP 0.40 g
Disodium phosphate dodecahydrate 0.04 g Syrup B.P. 10 g
Povidone 2.5 g Water, purified ad 100 mL
Sodium dihydrogen phosphate dihydrate 0.03 g
are present in the solution. These solid particles may act as
crystallisation nuclei and so initiate the crystallisation
process.
The rate of crystallisation increases when the difference
Table 18.13 Acid Ear Drops with Hydrocortisone 1 % [18]
between the temperature at which the solution is prepared
Hydrocortisone (micronised) 1g and the storage temperature increases. This is because the
Acetic Acid (30 %) DAC 2.4 g driving force for crystallisation will increase when the tem-
PRODUCT DESIGN
Propylene glycol 96.6 g perature difference increases. Supersaturation can occur in
Total 100 g starting materials or intermediates, but supersaturated
compositions are also used in therapy. Some relevant
examples will be briefly discussed below.
Liquid Sorbitol 70 % (crystallising) is a supersaturated
Lipophilic esters of corticosteroids either suspended in
starting material. Before using/processing this product in
water or dissolved in ethanol, propylene glycol, or macrogol
preparations the operator should check whether
300 are applied in eye and ear drops, respectively.
crystallisation has occurred. Crystals can be dissolved by
Table 18.12 gives an example of an aqueous suspension
heating and cooling again. Using a crystallised solution in
containing 1 % micronised hydrocortisone acetate.
several portions at different times will lead to a too low
Flumetasone pivalate and fludrocortisone acetate are
sorbitol concentration in the first portions, while in
commercially available as solutions in macrogol and a mix-
subsequent portions the concentration will be too high if
ture of glycerol and propylene glycol, respectively.
the crystals have been dissolved again. Thus, when using a
The aqueous solubility of free, not esterified,
crystallised material in preparations, there is a risk that the
corticosteroids and their lipophilic esters do not differ sub-
content in the final product will not be correct.
stantially. However, their solubility in ethanol is better.
Calcium gluconate 100 mg/mL is an example of a super-
Examples are: hydrocortisone, prednisolone and dexameth-
saturated injection solution.
asone. These free corticosteroids are mainly used in solid
Mannitol 20 % w/v is an example of a supersaturated
oral dosage forms. Hydrocortisone is applied in Acid Ear
solution for infusion. The solution should be inspected for
Drops with Hydrocortisone 1 % FNA (Table 18.13), because
the presence of crystals. As said, the crystals can be
the underivatised steroid dissolves in propylene glycol, in
dissolved by heating and cooling again.
contrast to its acetylated derivative. Although the lipophilic
Magnesium Citrate Oral Solution 80 mg/mL FNA
versions/variants are preferred in dermatological prepara-
(Table 18.14) is a supersaturated solution of magnesium
tions, the free corticosteroids may also be applied.
citrate. The patient should be warned that crystallisation
can take place after about 2 weeks, or earlier when the
preparation is stored in the refrigerator. Magnesium citrate
18.1.6 Solubility and Supersaturation mixture USP has a similar formula.
Given the risks of crystallised products, the use of super-
If the solubility of a substance increases with temperature, its saturated solutions in pharmaceutical preparations should be
dissolution rate can be enhanced by heating. When a avoided as much as possible.
saturated solution is obtained at an elevated temperature, it
will be supersaturated after cooling. Also solutions that are
prepared at room temperature can become supersaturated
when they have to be stored in the refrigerator because of 18.2 Rheology
their chemical instability. It may happen that supersaturation
does not immediately result in crystallisation. Such a solu- The rheology describes the flow behaviour of fluids. When a
tion is called metastable and sooner or later crystallisation force is exerted on a liquid, it will start to flow. The resis-
will occur. This process can proceed faster if solid particles tance to flow is called dynamic viscosity but in practice it is
Shear stress a b
immobilised
shear rate
shear rate
Fig. 18.5 Effect of shear stress on a cube of liquid
shear stress shear stress

Newtonian flow Plastic flow
usually simply referred to as viscosity. Consider a cube of
liquid composed of slices like a stack of cards (Fig. 18.5). c d
When the bottom of the cube is immobilised and a shear
force is applied at the top, the upper slice will get the
maximum speed, the slice underneath a little less speed,
and so on, until the bottom slice which does not move.
Consequently, there is a velocity gradient, D (shear rate).
shear rate
shear rate
According to the Newton’s law (18.8), viscosity (η) is
defined as the force exerted per unit area (τ) (shear stress)
divided by the shear rate (D). The dimension of viscosity is
shear stress shear stress
Pascal.second (Pa.s), but in practice the derived dimension
Pseudo-plastic flow Dilatant flow
millipascal.second (mPa.s) is generally used.
Fig. 18.6 Rheograms of liquids with Newtonian, plastic, pseudo-
τ
η¼ ð18:8Þ plastic and dilatant flow behaviour. Source: Recepteerkunde 2009,
D #KNMP
Rheology and viscosity are important for a proper under-

because viscosity is shear stress divided by shear rate
standing of the stability of disperse systems and for the
(τ/D), and not the change of the shear stress divided by the
accuracy of the dosage of liquid preparations.
change of the shear rate (dτ/dD). Pseudo-plastic flow
strongly resembles plastic flow. The difference is that
pseudo-plastic fluids do not exhibit a yield stress. The con-
18.2.1 Rheograms sequence of this is that the fluid never exhibits solid state
behaviour because even at a very low shear stress flow takes
Two types of flow behaviour can be distinguished, namely place.
Newtonian and non-Newtonian flow. Non-Newtonian flow Gels and emulsions show plastic and pseudo-plastic
is further divided into plastic, pseudo-plastic and behaviour. At rest, these systems are more viscous than
dilatant flow. when they flow. Creams and ointments should be easily
When the shear rate of a Newtonian fluid is plotted as a spreadable, but they should not drip from the skin.
function of the shear stress, a straight line is obtained that Emulsions and suspensions should be as stable as possible
passes through the origin (Fig. 18.6a). This means that at any and pouring should be easy.
shear stress, the viscosity of the fluid is the same, since shear This aim is even better achieved if, after a temporary high
stress divided by shear rate is constant. In this case, one may shear stress, the recovery of the higher viscosity is delayed.
speak of the viscosity of a Newtonian fluid. This phenomenon is called thixotropy. This phenomenon
Conversely, the viscosity of non-Newtonian fluids is can often be seen in daily practice. For example, highly
dependent on the applied shear stress and is referred to as viscous emulsions like tomato ketchup and other cooking
apparent viscosity. When a fluid exhibits plastic flow, a sauces temporarily have a lower viscosity after vigorous
certain minimum shear stress must be applied, called yield shaking. Also cutaneous emulsions often exhibit thixotropic
stress, before the fluid starts to flow (Fig. 18.6b). At a shear behaviour.
stress of less than the yield stress, the viscosity is thus Finally, if the viscosity increases with increasing shear
infinitely large and the liquid behaves like a solid. Above stress, the flow behaviour is called dilatant (Fig. 18.6d). It is
the yield stress, the viscosity decreases with increasing shear characteristic for pastes with a high content of solids. The
stress. Also in the straight part of the curve in Fig. 18.6c, the pharmaceutical applicability of fluids with this flow
viscosity decreases with increasing shear stress. This is behaviour is limited because they are often poorly
spreadable. Only in a few cases this may be an advantage, of materials can be achieved. In an extensometer, an oint-
namely when the paste must possess abrasive properties, as ment or cream is allowed to spread between two glass plates
in cases where chalk is the main component. During rubbing, which yields the spreading capacity. With a penetrometer,
the skin is vigorously massaged due to the increasing vis- the resistance during the penetration of a pin connected to a
cosity of the paste. cone into a product is measured. This method can be used to
characterise highly viscous preparations, e.g. ointments.
18.2.2 Measurement Methods

18.3 Interfaces and Surface Active Agents
The techniques to measure viscosity can be subdivided into
two groups. Many pharmaceutical preparations consist of several phases.
In the first group of methods, the relationship between the For example, a suspension consists of solid particles dis-
shear stress, τ, and the velocity gradient, D, is measured. The persed in a liquid and an emulsion is composed of drops of a
main device within this group is the rotational viscometer. liquid dispersed in a second liquid which is immiscible with
The method is described in the European Pharmacopoeia the first. Interfaces exist between the different phases. In this
PRODUCT DESIGN
[1]. In a vessel, a measuring body (spindle) is rotated in the section the properties of interfaces are discussed.
test sample. The resistance to the rotation speed is measured
as torque in the shaft. Because several combinations of
vessel and spindle can be chosen for this equipment, the 18.3.1 Surface and Interfacial Tension
torque of both fluids with a very high and very a low
viscosity can be measured accurately. For each combination, Molecules exert attractive (Van der Waals) forces to each
the manufacturer supplies a table or often computer soft- other. In the bulk of a liquid, this force is equal in all
ware, which can be used to derive the viscosity from the directions. Because fewer molecules per unit of volume are
torque and the rotational speed. Thus, with this method the present in the air than in a fluid, the Van der Waals forces at
viscosity can be calculated directly. The method is applica- the interface of liquid and air are smaller in the direction of
ble to both Newtonian and non-Newtonian fluids. By vary- air than in the direction of liquid. As a result, there is a net
ing the rotational speed, complete rheograms can be force (or pressure if force per unit area is considered) per-
obtained. This provides information about both pendicular to the liquid surface in the direction of the bulk of
non-Newtonian behaviour and thixotropy. The method is the liquid. Due to this pressure, which is called surface
especially useful in the investigation of the stability of vis- tension, the molecules located at the surface are in a higher
cous systems. Gibbs free energy state than in the bulk of the liquid. This
In the second group of methods, gravity is used as a force implies that if a new surface is created, molecules are in a
to bring the fluid in motion. The suspended level viscometer higher Gibbs free energy state. In other words, it takes Gibbs
as described in [20] is based on this principle. The Ford cup, free energy to create a new surface. A similar situation
a sort of funnel through which the fluid flows, is another occurs at the interface of two non-miscible liquids and the
example. The flow rate of a fluid per unit area of the outlet interface between a liquid and a solid. In these cases one
opening of, for example a capillary tube or cup is propor- speaks of interfacial tension. The terms surface tension and
tional to the viscosity, η, but inversely proportional to the interfacial tension are often used interchangeably. The
relative density, ρ, of the fluid. The rate at which the fluid dimension of surface and interfacial tension is J/m2 [5, 21].
level decreases thus depends on η/ρ. Viscosity divided by Molecules consisting of a highly water soluble or hydro-
density, η/ρ, we call kinematic viscosity, with m2/s as philic moiety and a highly oil soluble or lipophilic moiety
dimension. By calibrating the device with a fluid having a are called amphiphilic. These molecules accumulate at
known kinematic viscosity, the kinematic viscosity of the interfaces in such a way that the water soluble or hydrophilic
fluid can be calculated. The equipment used for these part is oriented to the hydrophilic (aqueous) phase and the oil
methods are usually much cheaper than those in the first soluble part to the lipophilic (oil) phase. This causes lower-
group. Moreover, they are useful for designing preparations. ing of the surface or interfacial tension. Therefore, the Gibbs
The disadvantage of these viscometers is that they are only free energy required to create a new surface or interface can
suitable for measuring the viscosity of Newtonian fluids. be reduced by using amphiphilic substances. In the context
However, with these viscometers information about the of this application, these substances are referred to as surface
pouring behaviour can be achieved which is, for example, active agents or surfactants. An overview of surfactants used
relevant to emptying a bottle. in pharmaceutical preparations can be found in Sect. 23.6.
With an extensometer and a penetrometer, the viscosity is In order to make a proper choice of a surfactant for a
not directly measured but information about the flowability specific preparation, a system has been developed in which
Fig. 18.7 Equilibrium of forces

at the point P due to surface and
a γI-III b γI-III
interfacial tensions. The force
vectors are shown as arrows for γI-II θ Air γI-II θ Air
explanation see Sect. 18.3.2.
P γII-III P γII-III
Source Recepteerkunde 2009, Solid Solid
#KNMP
Good wetting (θ < 90) Poor wetting (θ > 90)
the relative contribution of the hydrophilic and the lipophilic When an aqueous suspension is prepared, the air at the
part of the molecule is expressed as a number. This system is surface of the particles should be replaced by the aqueous
called hydrophilic-lipophilic balance, abbreviated as HLB. phase. When a poorly wettable substance is used (θ > 90 )
Surfactants that are equally soluble in oil and in water have this will not happen. The particles can float when the air is
an HLB value of 7. Surfactants which are more soluble in oil not replaced. This phenomenon is called flotation. Poorly
have a HLB-value < 7 and surfactants which are more sol- wettable and floating particles often adhere to the wall of the
uble in water have an HLB-value > 7. Surfactants may have bottle neck. As a result, dosing is difficult with such systems.
an HLB value of 1-40. In designing of a formula, the HLB Pharmaceutical examples of poorly wettable substances are:
value is generally used as a number to characterise phenytoin, sulfur, zinc oxide and barium sulfate. By adding a
surfactants. surfactant, the interfacial pressure can be reduced by which
wetting is improved.
To reduce the risk of foaming, surfactants that lower the
18.3.2 Wetting interfacial pressure only moderately are mostly used.
To improve wetting, surfactants with an HLB larger than
Wetting means bringing a solid in close contact with a 15 are used, such as sodium dioctyl sulfosuccinate (Aerosol
liquid. This process is of importance for example for the OT ®), ethoxylated castor oil, poloxamer, sodium salts of
preparation of suspensions and the disintegration of a tablet higher alcohol sulfates (sodium lauryl sulfate) and
in the gastrointestinal tract. polysorbates, but also polymers with interfacial activity as,
When a drop of liquid is placed on a solid (smooth) for example hydrogel formers as methylcellulose,
surface, the drop will spread depending on the properties hypromellose, etcetera. A further discussion of these
of the liquid and of the solid. For example, a drop of water substances can be found in Sects. 23.6 and 23.7. In practice,
completely spreads out on a (clean, grease-free) glass but propylene glycol or a thickening agent will lower the inter-
hardly at all on a Teflon® surface. The angle formed by a facial tension to a sufficient extent.
liquid at the three phase boundary where a liquid, air and
solid intersect as shown in Fig. 18.7, is called the contact
angle θ. Young’s law describes the relationship between the
18.3.3 Micelle Formation and Solubilisation
surface and interfacial tension of the three phases: air (I),
solid (II) and liquid (III) and contact angle (θ). In equilib-
Surfactants are not only applied to reduce the surface or
rium, the forces will compensate each other at the point P,
interfacial tension. They can also be used to increase the
so:
solubility of substances. When dissolved in water above a
γ III ¼ γ IIIII þ γ IIII cos θ ð18:9Þ certain minimum concentration, aggregates of surfactants
are formed, also called micelles. Lipophilic substances can
or be brought into solution (solubilised) using these micellar
solutions. Micelles can be prepared as follows.
cos θ ¼ γ III γ IIIII =γ IIII ð18:10Þ Consider an aqueous solution of which the surfactant
concentration is gradually increased. At low concentration
When the contact angle θ is larger than 90 it is called poor of the surfactant, the molecules are predominantly located at
wetting and when it is smaller than 90 it is called good the surface. If the concentration is increased, more of the
wetting. Wetting can be improved by the addition of surfactant molecules will be present at the surface and the
surfactants to the aqueous phase. As a result, the contact surface tension will decrease. Above a certain concentration,
angle θ becomes smaller (thus cos θ becomes larger) and however, the surface will be full and the extra molecules will
finally approaches to 0. In complete wetting (θ ¼ 0 ) the migrate into the bulk of the solution. When this occurs, the
droplet spreads out completely on the surface. surface tension will not further decrease.
The surfactants molecules that migrate into the bulk of

the solution form micelles. The structure of the micelles is 18.4 Disperse Systems
such that the lipophilic part of the surfactant molecules is at
the inside of the micelle, so that the thermodynamically Many liquid and semi-liquid pharmaceutical preparations are
unfavourable contact of the lipophilic part of the surfactant disperse systems. Disperse systems are defined as systems in
molecules with the water molecules is minimal. The mini- which a substance is distributed as particles (discontinuous)
mum concentration at which micelles are formed is called into a dispersion medium (continuous). Three types of disperse
the critical micelle concentration (CMC). The exact shape of systems will be discussed which are pharmaceutically rele-
the micelles and the CMC differ from substance to sub- vant: colloidal systems, suspensions and emulsions. In both
stance. Micelles have the size of colloids and also behave colloidal systems and suspensions, solid particles are dis-
physico-chemically as such. This behaviour will be persed in a liquid. The difference is that in colloidal systems
discussed in more detail in Sect. 18.4.1. the particles do not settle, while they do in suspensions. This
In an oil phase, micelles with the inverted structure can be difference is caused by the size of the particles. In colloidal
formed, i.e. the hydrophilic part of the surfactant molecules systems, the particles are so small (1 nm – 1 μm) that the
is oriented towards the inside. These micelles are also called Brownian motion (diffusion caused by thermal energy) is
stronger than the force of gravity so that they remain
PRODUCT DESIGN
reverse micelles.
Many poorly water soluble substances can, molecularly suspended in the liquid and do not settle. In suspensions, the
disperse, adsorb or absorb on or into micelles. These micel- particles are larger (>1 μm) and as a consequence the force of
lar solutions are optically clear. This is called solubilisation. gravity is stronger than the Brownian motion which makes
Examples from the Dutch formulary FNA are oral aqueous them settle (if the density of the particles is larger than that of
preparations with vitamin A (retinol palmitate) or D (chole- the dispersion medium). Emulsions consist of non-miscible
calciferol (Table 18.15)). Another example is a licensed oral liquids. Two types of emulsions will be discussed: oil drops
mixture with ciclosporin. dispersed in water (oil-in-water emulsion or o/w emulsion)
and water drops dispersed in oil (water-in-oil emulsion or w/o
emulsion). There are also more complex structures such as
w/o/w emulsions and bi-continuous systems. However, these
Table 18.15 Cholecalciferol Oral Solutiona 50.000 IU/mL [22] systems will not be discussed.
Cholecalciferol concentrate (oily form) 2.5 g
2,000,000 IU/g
Polysorbate 80 12.5 g 18.4.1 Colloidal Systems
Star anise oil 0.22 g 18.4.1.1 Lyophilic and Lyophobic Systems
Syrup BP 12.5 g Colloidal systems can be divided into lyophilic and
Water, purified 75.7 g lyophobic systems. Lyophilic colloids have a strong affinity
Total 104 g (¼ 100 mL)
with the dispersion medium by which a solvation shell
around the particle is formed. This process is called solva-
a
This solution is actually a solubilisate tion and if the dispersion medium is water it is called hydra-
tion. A polysaccharide dissolved in water is an example of a
The order of mixing the components in this prepa-
lyophilic colloidal system. The solvation shell is formed by
ration is important in order to achieve solubilisation:
hydrogen bonds between the hydroxyl groups of the polymer
first polysorbate to cover the flask with a layer, then
molecules and the water molecules. Pharmaceutical
carefully adding and mixing the cholecalciferol con-
examples are solutions of dextran, used as plasma
centrate and star anise oil. The ratio between the
expanders. Micelles are also lyophilic colloids. Example of
amount of polysorbate and the cholecalciferol concen-
such a system is the aqueous cholecalciferol oral mixture
trate is also important.
(Table 18.15). In these preparations, a lipophilic fluid is
dissolved in an aqueous medium by incorporating it in
micelles. Because this type of colloids falls apart on dilution
Solubilisation may also be undesirable. Solutions containing to concentrations below the CMC, they are also known as
polysorbate cannot be preserved with for example methyl or association colloids. Lyophobic colloids have no affinity
propyl parahydroxybenzoate. The preservative effect of these with the dispersion medium. Thus, in this type of colloids
substances is inhibited by solubilisation or even nullified. With no solvation shell is formed around the particles. An exam-
sorbic acid/sorbate, preservation is possible, provided that a ple of lyophobic particles are colloidal gold particles (with a
higher than conventional concentration is used. diameter of 1 nm – 1 μm) dispersed in water. There are no
hydrogen bonds or other interactions between the gold onto lyophilic particles. However, by covalently linking
particles and the water molecules, so the solvation shell is hydrophilic polymers to their surface, we can also achieve
missing. If the dispersion medium is water, lyophilic steric stabilisation of lyophilic colloidal particles. A detailed
colloids and lyophobic are also referred to as hydrophilic description of the forces of attraction and repulsion can be
and hydrophobic colloids, respectively. found in literature [5, 21].
So a lyophilic colloidal system can be stabilised by two
mechanisms, namely by a solvation shell and by electrostatic
18.4.1.2 Stabilisation of Colloidal Systems
repulsion. This implies that a lyophilic colloidal system with
Basically, colloidal systems are not thermodynamically sta-
a zero zeta-potential does not necessarily have to be unsta-
ble. The particles have the tendency to attract each other by
ble. This is because the stabilising effects of the solvation
Van der Waals forces and aggregation can take place. Yet
shell may be sufficient. A lyophobic colloidal system, how-
there are many colloidal systems that can be stored for
ever, lacks a solvation shell. A lyophobic colloidal system
extended periods of time without this happening. This is
can therefore only be stable if the zeta-potential is suffi-
because two stabilising mechanisms may play a role.
ciently high (positive or negative).
Around lyophilic colloids a solvation shell is formed,
which acts as a protective layer around the particles. This
protective layer prevents the two particles from approaching 18.4.1.3 Destabilisation of Colloidal Systems
each other too closely. In addition, the particles repel each A sol is a colloidal system in which the repulsion forces
other when they are electrostatically charged. This repulsion between the colloidal particles dominate in such a way that
is not fully determined by the charge at the surface of the they can move freely with respect to each other. Lyophilic
particle (Nernst potential) but by the charge at a small colloidal particles can be destabilised either by making the
distance from the particle which is called zeta or particles more lyophobic or by reducing the zeta-potential or
ζ-potential. During the diffusion of the particle through the both. Lyophobic colloidal particles, however, can only be
dispersion medium a layer of the dispersion medium around destabilised by reducing the zeta-potential. Lyophilic colloidal
the particle is dragged along with it. Therefore, it is not the particles can be rendered more lyophobic by adding a fluid
charge of the particle, but the charge of the particle together which is miscible with the dispersion medium but in which the
with this layer of dispersion medium that is relevant for the colloidal particles are lyophobic (for example, ethanol when
stability of the system. If the particle is charged and when the dispersion medium is water). The zeta-potential of colloi-
ions are present in the dispersion medium, there will be more dal particles (lyophilic or lyophobic) can be reduced by adding
ions of opposite charge (counter ions) in the near vicinity of an electrolyte to the system. When a sol is partially
the particle than ions of the same charge due to electrostatic destabilised, the forces of attraction are stronger than the
attraction. The charge of the particles is therefore neutralised forces of repulsion. As a result, the particles will no longer
to a certain extent. This neutralisation increases with be able to move freely with respect to each other, but they will
increasing ionic strength. This implies that the zeta-potential form a continuous three-dimensional network extending
is smaller than the Nernst potential and decreases with throughout the dispersion medium. Such a structure is called
increasing ionic strength. If the dispersing medium contains a gel and it is called a hydrogel if the dispersion medium is
polyvalent counter-ions, the zeta-potential and the Nernst water. This sol-gel transition can be observed by the flow
potential can even have opposite charges. behaviour. Because the colloidal particles in sols move more
The zeta-potential can also be influenced by the absorp- or less freely with respect to each other, Newtonian or pseudo-
tion of specific ions from the dispersion medium onto the plastic flow behaviour can be observed. Gels exhibit a yield
surface of the colloidal particle. For example, if a positively stress because first the continuous three-dimensional structure
charged surfactant adsorbs onto a positively charged colloi- must be broken down before flow can occur. In this case plastic
dal lyophobic particle, the zeta-potential becomes larger flow behaviour can be observed. Because the colloidal
than the Nernst potential. particles in a gel cannot move freely with respect to each
Moreover, the adsorption of surfactants onto lyophobic other, a gel can be considered as a partially or controlled
particles has a second effect. Because only the lyophobic destabilised sol. However, when sols are extensively
part of the surfactant adsorbs onto the lyophobic particle, its destabilised a compact aggregate will be formed, which will
lyophilic part is oriented towards the dispersion medium. start to float or sediment depending on the density difference
This lyophilic part forms a protective layer by which the with the dispersion medium. They are no longer considered as
particles can approach each other less easily. This effect is colloidal systems. This process is called salting-out when it is
called steric stabilisation. Surfactants usually do not adsorb induced by the addition of an electrolyte.
Carbomer is a special hydrogel former. The chemical Repulsion

name for carbomer is polyacrylic acid. As such the
polymer is poorly soluble in water. However, when
monovalent bases (e.g. NaOH) are added, the carbox-
2
ylic acid groups are deprotonated. By deprotonation
a
the polymer becomes negatively charged and thereby
hydrophilised and forms a hydrogel. c
Carbomer in combination with monovalent bases,
however, is not extremely hydrophilic as it also forms 3 Distance
a gel in ethanol.
Addition of salts may have two effects: b
1. Divalent ions such as calcium and magnesium form
cross-links between deprotonated carboxylic acid
1
groups by which the negative charge is neutralised
PRODUCT DESIGN
and the hydrophilisation is counteracted. To pre- Attraction
vent this, disodium edetate is added in (aqueous)
carbomer gel pH 6.5 NRF (Table 18.16). Fig. 18.8 Potential energy between two particles as a function of
their distance. (a): repulsion due to zeta-potential; (b): attraction
Table 18.16 Carbomer Gel pH 6.5 [23] as a result of Van der Waals forces; (c): net potential energy
curve; primary minimum, maximum and secondary minimum are
Carbomer 35000 1g indicated by 1, 2 and 3, respectively. Source: Recepteerkunde
Disodium edetate 0.1 g 2009, reprinted by permission of the copyrights holder
Trometamol 1g This curve is established by adding the potential
Water, purified 87.9 g energies resulting from the attraction and repulsion
Total 100 g forces to each other (with a negative potential energy
meaning attraction and a positive potential energy
2. At high ionic strength the (absolute) zeta-potential repulsion). Suppose that two particles approaching
of carbomer will decrease, which may result in each other have too little thermal energy to pass the
precipitation and is an example of salting-out of a maximum. In this situation they approach each other
colloid. to a distance where the secondary minimum is located
and thus attract each other. Now two situations can
occur:
Carbomer, carmellose sodium, hydroxypropylcellulose
1. The particles have sufficient thermal energy and
and other cellulose derivatives are examples of well-known
they spontaneously diffuse away from each other.
polymers that form hydrogels. An overview of different gel
This kind of system is a sol. Such a situation is also
formers can be found in Sect. 23.7.
called deflocculation.
2. The particles have insufficient thermal energy and
DLVO-Theory remain at the same distance. This kind of system is
The destabilisation of colloidal systems can also be a gel, because external energy (in the form of yield
described with the DLVO (Deryagin-Landau-Verwey- stress) is needed to bring the particles at a greater
Overbeek) theory. This theory has been proposed for distance from each other. This is called reversible
lyophobic colloidal systems but can also be applied aggregation or flocculation.
qualitatively to lyophilic colloidal systems. If the poten- Suppose a lyophobic colloidal system that behaves
tial energy is plotted as a function of the distance of two like a sol and it is destabilised by decreasing the zeta-
particles, a curve is obtained as shown in Fig. 18.8.
(continued)
(continued)
CH3
potential. At a certain point, a sol-gel transition will
take place. The reduction of the zeta-potential by the O O
addition of electrolyte is expressed in the energy curve HO O H
by a lowering of the potential energy in the secondary a a
minimum. The addition of a certain amount of electro- b
lyte will result in such a lowering of the potential
Fig. 18.9 Chemical structure of poloxamer
energy in the secondary minimum that the particles
have insufficient thermal energy to spontaneously dif-
fuse away from each other. However, addition of elec-
trolyte also results in a lowering of the maximum of temperature. Because the gel slowly erodes in vivo, the
the potential energy curve. Therefore, when a huge active substance is slowly released. In principle, different
amount of electrolyte is added, it is possible that the routes of administration for this delivery system are possible.
particles have sufficient thermal energy to pass the Preparations based on poloxamers have been studied for
maximum. The particles approach each other now to e.g. parenteral (subcutaneous and intramuscular injection),
a distance where the primary minimum is located. rectal, vaginal, nasal, ocular, and dermal administration.
Compact aggregates are formed and there is no longer E.g. a poloxamer based morphine-containing hydrogel for
a colloidal system. Because the attractive forces are so the treatment of large-scale skin wounds has been
high, the original colloidal system cannot be restored developed [25].
by adding external energy. This process is called irre-
versible aggregation or coagulation.
18.4.1.4 Protein Solutions as an Example
of Colloidal Systems
A great deal of research has been performed into the use Until the beginning of the twenty-first century, in pharmacy,
of poloxamers for the controlled release of active substances the particles in a colloidal system usually did not consist of
[24]. Poloxamers, also referred to as Pluronics or Lutrols, active substances but of excipients, such as viscosity
consist of triblock copolymers having a central hydrophobic enhancers. The number of publications in the pharmaceuti-
polypropylene oxide block and on both sides a hydrophilic cal literature on colloidal systems in which the dispersed
polyethylene oxide block (Fig. 18.9). particles solely consist of a drug substance or consist of
By varying the length of the blocks, polymers with dif- carrier systems in which an active substance has been
ferent physical properties can be achieved. At low incorporated, however, has increased dramatically in recent
temperatures, these polymers are generally soluble in water years.
and form sols. When the temperature is increased, however, Important medicines within this so-called nanotechnol-
a sol-gel transition may take place. This is caused because, ogy are therapeutic proteins. Protein solutions are becoming
with increasing temperature, the thermal energy and thus ever more popular within pharmacy. This is due to the fact
also the Brownian motion of the molecules increases. As a that the unravelling of the human genome and the recent
result, the hydrogen bonds between the water molecules and developments in the field of biotechnology offer access to a
the polymer become weaker. The stabilising effects of the growing number of proteins that can be used for the treat-
solvation shell will therefore decrease and the attraction ment of various diseases and disorders. Due to their specific
forces will become dominant, resulting in gelation. The physico-chemical properties, these medicines must be han-
temperature at which the sol-gel transition takes place dled in a different way from the classical drugs, which are
depends on the composition of the polymer (length of the usually relatively small organic molecules. The specific
three blocks) and the concentration. In addition, the sol-gel three-dimensional structure of proteins is essential for their
transition temperature can be influenced by the addition of therapeutic action.
other substances. For example, the sol-gel transition temper- The structure of proteins can be described at four levels:
ature will be greatly reduced by the addition of a small 1. Proteins are polymers built up from amino acids. The
amount of carmellose sodium. This makes it possible to sequence of the amino acids is called the primary
prepare a solution of poloxamer (and an active substance) structure.
that behaves as a sol at a low temperature, for example room 2. Parts of the protein form specific three-dimensional
temperature or lower, but transforms into a gel at body structures, for example alpha-helices (spiral like
temperature. Therefore, the solution can be administered at structures) and beta-sheets (plate like structures), which
low temperature as a free flowing liquid to a patient after are called the secondary structure. The secondary struc-
which a gel is formed in situ by the increase of the ture is mainly stabilised by hydrogen bonds.
3. The relative orientation of the structural elements with the stabilisation and formulation of proteins for pharmaceu-
respect to each other is called the tertiary structure. This tical applications see references [26] and [27].
structure is stabilised by hydrogen bonds, disulfide bonds, Summarising, physical degradation of proteins can be
electrostatic interactions and hydrophobic interactions. caused by:
4. In some cases, several chains of amino acids, also • Aggregation
referred to as polypeptide chains, form complexes. For • Denaturation
example, insulin forms hexamers in the presence of zinc • Adsorption onto surfaces
ions. The relative orientation of the polypeptide chains • Precipitation
with respect to each other in such a complex is called the Chemical degradation can be caused by:
quaternary structure. • Deamidation
Some proteins also contain, besides amino acids, oligo- or • Oxidation
polysaccharides. These substances are called glycoproteins. • Hydrolysis
One of the major problems with proteins is that they are • Racemisation
usually not stable. Physical or chemical changes may lead to • Reduction disulfate bridges/disulfide exchange
changes in the three-dimensional structure. This may not
PRODUCT DESIGN
only cause a loss of efficacy but it can also have dramatic
effects such as the induction of antibodies and severe
18.4.2 Suspensions
immune responses.
Some practical advice to improve the stability of proteins
Suspensions are regularly used as a dosage form. Examples
is given below.
can be found in oral suspensions (co-trimoxazol suspension),
Protein solutions should not be stored at a pH which is
dermatological preparations (zinc oxide or calamine lotions
equal to their iso-electric point. At the iso-electric point, the
like Zinc oxide lotion NRF (Table 18.17)), parenteral
amount of deprotonated carboxylic acid groups and
preparations (corticosteroid injections, medroxyprogesterone
protonated amino groups are equal and thus the net charge
injection) and a suspension in the form of a solid dispersed in
of the particle is zero. In that situation the zeta-potential is
a melted fat base as in the case of suppositories.
zero and irreversible aggregation can easily occur. For the
As with colloidal systems, suspensions consist of
same reason, the electrolyte concentration in the solution
particles dispersed in a liquid. As a result, the physico-
should not be too high. A very low or high pH is not
chemical properties of suspensions are, in principle, similar
recommended because the hydrolysis of proteins is both
to those of colloidal systems. As described in the introduc-
acid and base catalysed. The oxidation of many proteins is
tion to Sect. 18.4, the main difference is that the particles in a
catalysed by the divalent metal ions, in particular Fe2+ and
suspension are larger (>1 μm) than in a colloidal system
Cu2+. Divalent metal ion catalysed oxidation of proteins can
(1 nm – 1 μm). As a result, the particles settle in a suspension
be prevented by the addition of disodium edetate to complex
(if the density of the particles is greater than the density of
these ions. However, certain divalent metal ions can also act
the dispersion medium, which is generally the case) while
as stabilisers for specific proteins.
this is not the case in a colloidal system. Fast sedimentation
Proteins can in particular irreversibly adsorb onto hydro-
of particles in a suspension has major drawbacks. Pouring
phobic surfaces. Storage of a protein solution in polypropyl-
out a partially settled suspension in several portions or at
ene vials is therefore not recommended. In addition, protein
different times leads to too low particle concentrations in the
solutions are sensitive to shear forces. The use of peristaltic
first portions and too high in later portions. In the past this
pumps during the preparation of formulations should there-
has had fatal consequences, when a 4 months old boy got a
fore be avoided. By refrigerated storage and transportation,
threefold dose of spironolactone [29].
the degradation processes of protein solutions can be slowed
down, and thus their shelf life increased. However, freezing
must be prevented since ice formation can damage proteins.
Alternatively, proteins can be stabilised by freeze-drying
them. Sucrose or other sugars are often added to the solution Table 18.17 Zinc oxide Cutaneous Suspension [28]
as a stabiliser during freeze-drying to avoid damage to the Zinc oxide 25 g
protein during the freezing and the drying phase of the Glycerol (85 %) 5g
process. During the reconstitution, by adding water to the Ethanol (90 %) BP 25 g
freeze dried samples, vigorous shaking should be avoided. Water, purified 45 g
During vigorous shaking a large liquid-air surface is created
Total 100 g
at which denaturation can easily occur. For an overview of
18.4.2.1 Sedimentation Behaviour particles are gradually being filled up with the small particles.
The sedimentation rate of the particles in a suspension can be Therefore, a very compact sediment (cake) is slowly built up
calculated using Stokes’ law: from the bottom of the container (Fig. 18.10a).
If the suspension also contains particles smaller than 1 μm
2r 2 ðρ1 ‐ρ2 Þg (the colloidal fraction of the suspension), these particles will
v¼ ð18:11Þ
9η not settle but will continue to be suspended in the liquid so
that the liquid above the sediment remains cloudy. The
where v is the sedimentation rate, r the radius of the particle, ρ1, sediment exhibits dilatant flow behaviour.
the density of the particle, ρ2, the density of the medium, g the In a flocculated system, the particles do attract each other
acceleration due to gravity and, η the viscosity of the medium. and aggregates will be formed anywhere in the fluid. These
From this equation, it can be deduced that the rate of aggregates have very open structures. This is because when a
sedimentation decreases as the particle size decreases, the particle approaches an aggregate, it will be immobilised by
difference in the density of the particles and the medium the attractive forces at the outside of the aggregate. This
decreases and the viscosity increases. makes diffusion of the particle to possible void spaces in the
When applying this equation, the zeta-potential of the inside of the aggregate impossible. As everywhere in the
particles has also to be taken into account. Again the curve fluid aggregates are formed, a large and loose sediment is
can be used in which the potential energy is plotted as a formed (Fig. 18.10b). This typical way of settling of
function of the distance of two particles, as discussed for flocculated suspensions may be called sedimentation, but
colloidal systems (Fig. 18.7). The difference with colloidal more precisely subsidencing as is suggested by [5]. Because
systems is that the maximum in the curve for suspensions is the aggregates rapidly increase in size the subsidencing also
generally higher. As a result, coagulation or irreversible progresses rapidly. Any further settling and compaction of
aggregation almost never occurs in practice. Usual situations the sediment is unlikely to occur. Once the sedimentation
are either reversible flocculation or aggregation when the has been completed, a very open sediment is obtained due to
zeta-potential is small or deflocculation when the zeta- the cavities in the aggregates. As a result, at the same volume
potential is large. The sedimentation behaviour is largely fraction of particles, the volume of the sediment of a
affected by whether or not flocculation or aggregation flocculated suspension will be much larger than in a
occurs, as described below. deflocculated suspension. The liquid above the sediment is
In a deflocculated system the particles will not aggregate clear because particles smaller than 1 μm are included in the
and therefore settle separately from each other. Because, aggregates. The sediment exhibits plastic flow behaviour.
according to Stokes’ law, the sedimentation rate increases Both deflocculated and flocculated systems have
with particle size, large particles will arrive earlier on the advantages and disadvantages. In a deflocculated system
bottom of the container than smaller particles. Because the sedimentation proceeds slowly but once it is completed, it
particles do not attract each other, the voids between the large is very difficult to disperse the very compact sediment. The
Fig. 18.10 Schematic representation of deflocculated (a) and flocculated (b) sedimentation. Source: Recepteerkunde 2009, #KNMP
Table 18.18 Properties of a deflocculated and a flocculated

suspension the rotor-stator mixer. During this process the chlor-
Deflocculated suspension Flocculated suspension amphenicol palmitate crystallises to form
Sediment built up from the bottom Subsidencing sediment microcrystals. The size of these microcrystals is not
Slow sedimentation Fast sedimentation only determined by the intensity of stirring but also by
Compact sediment Open sediment the presence of polysorbate 80, which acts as the
Small volume sediment Large volume sediment surfactant. During storage polysorbate 80 also inhibits
Possibly cloudy fluid above Clear fluid above sediment any crystal growth. In addition, in this suspension
sediment
design, polysorbate 80 acts as a deflocculating agent
Flow behaviour sediment: dilatant Flow behaviour sediment:
plastic and prevents, by wetting chloramphenicol palmitate,
Sediment difficult to disperse Sediment easy to disperse flotation and sticking of the active substance to the
bottleneck.
disadvantage of a flocculated system is the high sedimenta-

tion rate. The sediment, however, is easy to disperse because
PRODUCT DESIGN
18.4.2.2 Influencing Sedimentation Behaviour
it has a very open structure.
Ideally the sedimentation rate of pharmaceutical preparations
In practice, therefore, the objective is to achieve an inter-
is as low as possible. On the basis of the Stokes’ law, it is clear
mediate form by the addition of a controlled amount of
which variables can be varied to accomplish this. The gravi-
electrolyte or surfactant. When the particles strongly repel
tational acceleration cannot be reduced, nor the density of the
each other, an electrolyte can be added. By decreasing the
particles. However, the particle size, the density and the
zeta-potential, the repulsive forces will decrease. When the
viscosity of the dispersion medium may be adjusted.
particles attract each other too strongly a surfactant can be
A first method to reduce the sedimentation rate is particle
added. As the lyophobic part of the surfactant molecule
size reduction. This can be accomplished by milling. On a
adsorbs onto the surface of lyophobic colloids its lyophilic
small scale, this is possible by using a mortar and pestle, if
part will be oriented into the dispersion medium. By steric
electrostatic charging and agglomerating can be managed.
stabilisation, the attraction forces are decreased. The
On a larger scale, high-tech equipment has been developed
properties of flocculated and deflocculated suspensions are
for this (see Sect. 29.2.2). The precipitation method is
summarised in Table 18.18.
another method to reduce the particle size. It is a useful
method when no milling equipment is available or when
A preparation that illustrates the versatile function of electrostatic charging will be a problem. In the precipitation
a surfactant in a suspension is the Chloramphenicol method, at first the active substance is dissolved and then its
Oral Suspension 33 mg/mL FNA (Table 18.19) solution is brought into the supersaturated state. As a result,
the dissolved substance will precipitate. The size of the
Table 18.19 Chloramphenicol Oral Suspension 33 mg/mL [30]
precipitated particles will decrease when the degree of
Chloramphenicol palmitate 5.75 g supersaturation increases or when the rate at which supersat-
Carmellose sodium M 1g uration has been achieved increases, or both. Supersaturation
Polysorbate 80 0.5 g can be created in different ways. The solubility of many
Cacao Syrup (local standard) 15 g active substances is pH dependent. As described in
Syrup B.P. 15 g Sect. 18.1.1, active substances with for example one or
Ethanol (90 %) BP 1 mL
more acid groups are generally poorly soluble at a low pH
Vanillin 0.02 g
but their solubility will be better at a high pH. This property
can be used by preparing a solution of the active substance at
high pH and then adding an acid to the solution by which it
In this preparation, first a gel of carmellose is becomes supersaturated. Obviously, the opposite strategy
prepared in a portion of the cold water using a rotor- can be used for active substances containing one or more
stator mixer. Then chloramphenicol palmitate is amine groups: first the active substance is dissolved at low
dissolved in a mixture of hot polysorbate 80 and pro- pH and then a base is added. Thus in both cases a solution of
pylene glycol. Polysorbate 80 thus functions here as a the active substance in ionised form is prepared. Then, the
part of the solvent mixture. The hot clear solution is active substance in the form of its free acid or base
added to the aqueous gel under intensive stirring with (non-ionised form) is formed by changing the pH and super-
saturation is achieved.
(continued)
In another precipitation method, two different liquids are Ostwald ripening is happening because the solubility of a
used that are miscible with each other, but in which the substance in the near vicinity of small particles is greater
solubility of the active substance substantially varies. Firstly, than in the near vicinity of large particles. The relationship
the active substance is dissolved in the liquid in which the between the solubility and the size of the particles is given
active substance dissolves well. Subsequently, supersatura- by the Ostwald-Freundlich equation:
tion is achieved by adding the second liquid to the solution in
which the active substance is poorly soluble. 2γM
Cs, curved ¼ Cs, flat exp ð18:12Þ
In a third precipitation method, the fact that most RTρr
substances are more soluble at a high than at a low tempera-
ture is to made use of. A saturated solution is made at a high where Cs,curved and Cs,flat is the solubility near a small parti-
temperature after which it is cooled until supersaturation is cle and an infinitely large particle, respectively, γ the inter-
achieved. This last method is the least suitable because in facial tension between the particles and the dissolution
practice it is often difficult to cool rapidly. The chloram- medium, M the molecular weight of the substance, R the
phenicol palmitate suspension as described in Table 18.19 is gas constant, T is the temperature (in K), ρ the density of the
an example of a suspension prepared by precipitation. Chlor- substance, and r the radius of curvature of the particles.
amphenicol palmitate precipitates when the solution in a hot Due to the differences in solubility, differences in concen-
mixture of polysorbate 80 and propylene glycol is mixed tration in the dispersion medium arise and the dissolved
with the cold aqueous gel. By vigorous stirring during the molecules diffuse from the small particles to the large
final step, small particles are obtained. particles. As a consequence, the dispersion medium around
A second method to reduce the sedimentation rate is to the large particles becomes supersaturated and the dissolved
increase the density of the dispersion medium, for example, molecules will precipitate onto these particles. Because the
by the addition of syrups or a solution of sorbitol. dissolved molecules around the small particles are diffusing
A third method to reduce the sedimentation rate is to away, the dispersion medium is no longer saturated and
increase the viscosity of the dispersion medium, which is molecules from the small particles will dissolve. Thus, small
almost always achieved by the application of polymers. But particles become smaller and eventually disappear and large
it must be kept in mind that accurate dosing by the patient of particles are getting bigger. A second effect is that irregularly
a specific amount of the suspension is more difficult when shaped particles in suspensions become spherical.
the viscosity increases. To avoid inadequate dosing the From the above it can be concluded that by both temper-
preparation can be delivered together with a dosing/measur- ature fluctuations and Ostwald ripening the particle size will
ing syringe instead of a measuring cup or spoon. increase faster when the particle size distribution is larger. It
is therefore desirable that the particle size distribution in a
suspension is as small as possible.
Most corticosteroids nasal sprays (licensed
preparations) are suspensions in which croscarmellose 18.4.2.4 Polymorphism, Pseudo-polymorphism,
sodium is used as viscosity enhancer. The inhalation Glassy State
liquids for nebulisation with the same type of active Solids may exhibit polymorphism, which means that they
substances however only contain polysorbate and can exist in different crystal modifications which differ in
sorbitan laureate to stabilise the suspension. For their physical properties [3, 20, 31, 32]. No less than eleven
atomisation in jet nebulisers, the liquid should not be different crystal modifications of phenobarbital are known.
too viscous, in order to prevent clogging of the It depends on the physical conditions such as temperature
nebuliser. which crystal modification is stable. The other modifications
are metastable. For substances that exhibit polymorphism,
the solubility of the metastable form is higher than that of the
stable form. This means that if the metastable modification is
18.4.2.3 Particle Size Stability in equilibrium with the solution (i.e. saturated for the meta-
The size of the particles in suspensions is not stable. During stable form), the solution is supersaturated for the stable
time, the particle size will increase by temperature modification. In other words, the stable form can grow
fluctuations and by the so-called Ostwald ripening. over time at the expense of the metastable form. Some fats
Because most substances are more soluble at a high than also exhibit polymorphism [33]. The preparation method
at a low temperature, small particles present in a suspension and the storage temperature will influence for example the
will dissolve when the temperature increases. When subse- melting behaviour of suppositories, and thereby probably
quently the temperature decreases again the solution will also the release rate.
become supersaturated. The undissolved larger particles Besides polymorphism, pseudo-polymorphism also
will act as nuclei for precipitation and grow. exists. In pseudo-polymorphism, a substance is found in
Table 18.20 Erythromycin Eye Ointment 0.5 % [34] interface. This implies that energy is liberated when the
Erythromycin, anhydrous 0.5 g interfacial area is reduced. Since this is thermodynamically
Cetostearyl alcohol 2.49 g advantageous, the system will attempt to minimize the inter-
Paraffin, liquid 39.8 g facial area. Because liquids are ‘deformable’ the dispersed
Paraffin, white soft 51.2 g drops in emulsions will therefore have a strong tendency to
Wool fat 5.97 g coalesce. This coalescence may eventually result in ‘break-
Total 100 g ing’ of the emulsion. When breaking occurs, the two phases
will be present as two liquid layers. The stability of an
emulsion can be improved by adding surfactants. The
crystal modifications whose hydration or solvation state driving force of the dispersed drops to coalesce becomes
differs. There may therefore be crystal lattices in which smaller because less energy will be liberated.
more or less water or other solvent molecules are included. Specifically applied in emulsions, surfactants are referred
Similar to polymorphism, the substance in the form of one to as emulsifying agents. According to the rule of Bancroft,
pseudo-polymorph is more soluble than in the other. Eryth- the HLB of the emulsifying agent determines which type of
romycin is an example of a substance which exhibits pseudo- emulsion is obtained, water in oil (w/o) or oil in water (o/w).
PRODUCT DESIGN
polymorphism. It exists in an anhydrous form and as a According to this rule, the phase in which the emulsifying
hydrate. In Erythromycin Eye Ointment FNA (Table 18.20) agent dissolves better will be the dispersion medium. An
the anhydrate is used, because this form dissolves faster in emulsifying agent with an HLB < 7 thus gives a w/o emul-
the fatty ointment base. sion, and an emulsifying agent with an HLB > 7 an o/w
Besides in the crystalline form, a substance may also exist emulsion. This can be explained as follows. When an
in the glassy state. In the glassy state, the molecules are not emulsifying agent is more soluble in oil than in water (HLB
oriented in a specific manner towards each other as they are < 7), the lipophilic part of the molecule occupies a larger
in a crystal lattice, but randomly (amorphous). The aqueous volume than the hydrophilic part. Since at the outside of a
solubility and thereby also the dissolution rate of a substance drop there is more space than at the inside, it is sterically
in the glassy state is better and higher than in crystalline more favourable when the (larger) lipophilic part is directed
form [35, 36]. Therefore, the bioavailability of lipophilic towards the outside and (smaller) hydrophilic part to the
active substances after oral administration, which is limited inside of the droplet. In this case a w/o emulsion will be
due to their slow dissolution, can be improved by converting obtained. With an emulsifying agent having an HLB > 7,
them into the glassy state. the hydrophilic part occupies a larger volume and an o/w
emulsion is obtained.
The stability of an emulsion increases when the
emulsifying agent molecules form a more compact layer at
18.4.3 Emulsions the interface. A very compact layer can be achieved by
making use of two different emulsifying agents, one of the
Emulsions can often been found as dermatological o/w-type and one of the w/o-type. One emulsifying agent
preparations, and sometimes as injections and oral occupies the cavities in the interface that the other
preparations. They make combinations of immiscible liquids emulsifying agent cannot fill. Such combinations of
possible, typically of fatty/lipophilic components and water. emulsifying agents are referred to as mixed layer
The fat/lipophilic ingredients can act as an active substance, emulsifying agents or emulsifying agent complexes. The
for example, in creams to keep the skin hydrated. They can HLB of a two emulsifying agents can be calculated by
also serve as a solvent for other substances such as diazepam multiplying the weight fraction of each emulsifying agents
in Diazemuls® injection or for fat soluble vitamins in paren- by its HLB value and adding them together. Thus the HLB of
teral nutrition (see Sect. 13.9.2). a mixture of two emulsifying agents A and B can be calcu-
The physico-chemical properties of emulsions are basi- lated as follows:
cally similar to those of suspensions, with the essential
difference that in emulsions the dispersed phase consists of HLBmixture ¼ f A HLBA þ f B HLBB ð18:13Þ
a liquid instead of a solid. This difference has important
consequences. Similar to a suspension, an emulsion exhibits where fA and fB are the weight fractions of the emulsifying
a large interface between the dispersed phase and the dis- agents A and B, respectively; HLBA and HLBB are the HLB
persing medium. It requires energy input to create an values of the emulsifying agents A and B, respectively.
the fluid levels creates a hydrostatic pressure difference that

When two emulsifying agents are combined, one with leads to a driving force for water transport in the opposite
an HLB of 4.7 and the other with an HLB of 10.3, in a direction, i.e. across the membrane to the compartment
weight ratio of 40/60, the HLB of the whole will containing pure water. At a given moment the driving forces
become 8.1 (HLBmixture ¼ 0:40 4:7 þ 0:60 10:3 ¼ for transport of water from the solution to pure water and
8:1). According to the rule of Bancroft, with this com- from pure water to the solution are equal, and the liquid
bination an o/w emulsion will be obtained. levels in the two compartments do not change anymore.
The process of transport of water through a semiperme-
able membrane due to a concentration difference is called
The Bancroft rule should be interpreted as a general rule.
osmosis and the final pressure difference between both sides
In practice, however, there are many exceptions. In addition,
of the membrane is called osmotic pressure. Basically, the
the type of emulsion that is formed will also depend on the
osmotic pressure should be expressed in Pascal, but in prac-
volume ratio of the two phases, the method of preparation,
tice the words osmolality or osmolarity are used to indicate
the electrolyte concentration, etc.
osmotic pressure, both with osmole as unit.
Osmotic pressure is a colligative property. A colligative
property solely depends on the concentration of the
18.5 Osmosis dissolved molecules or ions and is independent of the nature
of the solute. Freezing point depression is also a colligative
Osmosis is the transport of water through a semi-permeable property and can be indirectly used to determine osmotic
membrane as a result of a difference in the concentration of pressure. In practice, it is much more difficult to determine
solutes on either side of the membrane. A semi-permeable the osmotic pressure of a solution than to measure its freez-
membrane is only permeable to water; dissolved dissociated ing point depression. The freezing point of a solution can be
or undissociated substances cannot pass through it. Living measured and the osmotic pressure can be calculated from it.
cells are provided with a membrane through which water The molar freezing point depression of water is 1.86
transport can take place. This must be taken into consider- C. Blood freezes on average at -0.54 C. Plasma and tear
ation when the envisaged dosage form for an active sub- fluid have the same freezing point. The osmolarity of blood,
stance is a solution. If a solution is administered to a patient, plasma and tear fluid is thus equal to:
water transport across the cell membrane of the cells in the
near vicinity of the site of administration should be avoided 0:54
¼ 0:290 osmole ð290 mosmoleÞ ð18:14Þ
as much as possible. This is because extensive water trans- 1:86
port across cell membranes may lead to irritation and cell
damage. The risks for this are, in particular, present with In literature, also a freezing point depression of blood of
parenteral preparations and irrigations, but also in the case of 0.52 C or 0.56 C has been reported. Based on these values,
preparations for eye, middle ear, and nose. In this section the it can be calculated that the osmolarity of blood, plasma and
water transport across membranes is dealt with in more tears will be 280 or 300 mosmole, respectively.
detail. Methods are given to prevent net water transport
across cell membranes after the administration of solutions. The osmotic pressure has the unit of Pascal (N/m2)
but in clinical practice this unit is not used as such.
Measurements and calculations are performed with
18.5.1 Osmotic Pressure concentrations expressed as osmoles or milliosmoles,
which are abbreviated as “osmole” and “mosmole”,
When an aqueous solution and pure water in two different respectively.
compartments are separated from each other by a semiper- In the clinical setting 1 osmole means a concentra-
meable membrane, a spontaneously transport of water tion of 1 mol of a non-dissociable substance per kg of
molecules across the membrane into the solution will take solvent or per litre of solution. If this concentration is
place. This spontaneous transport is caused by the attractive expressed as mole per kg of solvent (molality) it is
forces between the solute molecules and the water called osmolality. If the concentration is expressed as
molecules. As a result, water molecules are forced through mole per litre of solution (molarity) it is called
the pores of the semi-permeable membrane. By this water osmolarity.
transport, the liquid level in the compartment of the solution Since the concentration of, in particular, parenteral
will rise, while it will fall in the compartment of pure water. preparations is more commonly expressed as mole per
The rise of the liquid level in the solution compartment will,
however, not continue indefinitely because the difference of (continued)
through a cell membrane at a relatively high rate. If an

litre solution than mole per kilo solvent, usually the erythrocyte for example is placed in an iso-osmotic solution
osmolarity of injections and infusions is given. The of ammonium chloride, the transport of ammonium chloride
difference between osmolarity and osmolality in dilute across the cell membrane occurs quickly until its concentra-
aqueous solutions is usually not significant, because tion in- and outside the cell is equal. For this reason,
the density of water is one kilogram per litre, and the solutions containing that type of molecules may be
volume fraction of the solute is usually negligible. In iso-osmotic with the cell content, but nevertheless show
highly concentrated solutions, however, there is a clear water transport when brought into contact with cells. On
difference between osmolality and osmolarity. But the other hand, a net water transport does not necessarily
highly concentrated solutions are clinically hardly rel- occur when the cell content is not iso-osmotic with the
evant (see Sect. 18.5.2). environment. If certain ions or molecules do not stay at
one side of the (cell) membrane, their contribution to the
pressure difference will not be the same as in the case of a
‘perfect semi-permeable’ membrane. If net water transport
occurs from the environment to the cell the solution outside
PRODUCT DESIGN
18.5.2 Iso-osmotic and Isotonic the cell is called hypotonic. And vice versa, when a net water
transport occurs from the cell to the environment the solu-
If two aqueous solutions with different concentrations of tion outside the cell is hypertonic. If no net water transport
dissolved substances are separated from each other by a takes place, both solutions are called isotonic.
semipermeable membrane, there is a net transport of water Iso-osmotic is a physico-chemical concept and only
from the solution with a lower concentration molecules or depends on the concentration of dissolved molecules and
ions to the solution with the higher concentration of ions. Isotonicity is the concept that takes into account, as
molecules or ions. The solution with the lower concentration well, the properties of the biological membrane in relation to
is called hypo-osmotic, while the solution with the higher the type of dissolved substances. Thus isotonicity should be
concentration is hyper-osmotic in relation to the other. When interpreted as a physiological concept. Therefore, in this
the concentrations of dissolved substances in the solutions context it is better to speak of selectively permeable instead
on either side of the semi-permeable membrane are equal to of semi-permeable. For most applications or routes of
each other, there will be no net transport of water across the administration (bio-membranes), the number of substances
membrane. In such a case we call the two solutions for which there is a difference between iso-osmotic and
iso-osmotic. isotonic is limited. For this reason, terms such as hypertonic
When cells are brought into contact with a solution and a and hypotonic are commonly used while actually hyper- or
cell membrane would behave as a semi-permeable mem- hypo-osmotic, respectively, are meant.
brane, the solution within the cell will try to become
iso-osmotic to that outside of the cell. This water transport
will cause damage to the cell. It must therefore be ensured 18.5.3 Non-ideal Solutions
that there is little or no net water transport from the solution
into the cell or vice versa. If an active substance is On the basis of paragraph Sect. 18.5.1, it would be expected
administered in a low concentration solution, the osmotic to calculate as follows: if the composition of the fluid is
value will be less than that of the blood. To achieve an given in millimoles, determine whether or not the dissolved
iso-osmotic concentration, NaCl or glucose can be added. substances dissociate and if so how many ions are formed.
When the active substance has to be administered in a high, For example, a solution of 1 mmole of glucose in 1 L of
hyper-osmotic concentration, consideration should be given water yields 1 mosmol, but a solution of 1 mmole of NaCl
to reducing the concentration by dilution. If this is not or 1 mmole CaCl2 in 1 L of water yields 2 or 3 mosmol,
possible, then, under certain conditions a solution with a respectively. After summing the contributions of all
hyperosmotic concentration can be administered, preferably components it can be verified whether or not the total
into a vein with a good flow so dilution will take place strength is approximately 300 mosmol.
swiftly (see Sect. 13.5.5). This way of calculating only applies to so-called ideal
The cytoplasmic membrane of an erythrocyte or a corneal solutions. In an ideal solution of substance A in a solvent B,
epithelial cell and other physiological membranes, however, the interactions between A and B, A and A, and B and B are
do not always behave as a semi-permeable membrane. Cell equal. In practice, however, non-ideal solutions are more
membranes are to some extent also permeable to some common. As a result, at an equal concentration of molecules
molecules other than water. Some molecules or ions, such or ions, the osmolarity of a non-ideal solution can be differ-
as urea, ethanol, and ammonium salts, are able to pass ent from that of an ideal solution. This difference in
osmolarity is expressed by a correction factor f. This correc- Table 18.21 Dissociation types and f-values of various substances
tion factor is specific to each substance and in dilute Molar freeze point
solutions independent of the concentration. At very high, Dissociation type depression (in C/mol) f-value Examples
clinically irrelevant, concentrations, the correction factor Non-dissociating 1.9 1.0 Glycerol
may change due to association of the dissolved components. Glucose
The osmolarity of a solution can be calculated as follows: Sorbitol
Urea
G Weak electrolytes 2.0 1.05 Alkaloids
f ð18:15Þ
M Bases
Boric acid
where G is the concentration of the solute in grams per litre Di-divalent 2.0 1.05 Magnesium
and M the molecular weight of the dissolved substance. The electrolytes sulfate
f-values are mentioned in Table 18.21 as group averages. Zinc sulfate
In a preparation, the active substance (if present in Mono- 3.4 1.8 Sodium
monovalent chloride
dissolved form) and the excipients (e.g. buffering agents, electrolytes Silver nitrate
preservatives, antioxidants, and disodium edetate) all con-
Phenobarbital
tribute to the osmotic value of a preparation. sodium
If 290 mosmol is taken as the iso-osmotic value, a solu- Mono-divalent 4.3 2.3 Sodium
tion of the substances A, B, . . . is iso-osmotic with blood electrolytes sulfate
under the following condition: Di-monovalent 4.8 2.5 Zinc chloride
electrolytes
GA GB GH
fA þ fB þ . . . þ f H ¼ 0:290 ð18:16Þ Mono-trivalente 5.2 2.7 Sodium citrate
MA MB MH electrolytes
Tri-monovalent 6.0 3.2 Aluminium
where GA, GB, .... are the concentrations of the solutes in electrolytes chloride
grams per litre, MA, MB, .... the molecular weights of the Tetraborate 7.6 4.0 Borax
dissolved substances, and fA, fB, ..... the correction factors
associated with dissociation of the solutes. To make a solu-
tion iso-osmotic, an excipient can be added. In (18.16) this
excipient is indicated with an H.
then be calculated using the molecular weight and the
type of dissociation. Betaxolol hydrochloride has a
18.5.4 Calculation of Osmotic Value molecular weight of 343.9. The degree of dissociation
and the pKa cannot be easily found in the literature.
If an active substance or excipient substantially contributes to Based on its chemical structure, however, it can be
the osmotic value, it may be necessary to calculate this contri- concluded that this is a salt of a secondary amine. The
bution. This can be done in practice by three different calcula- so-called f-value of this type of molecules is 1.8. The
tion methods. The choice of the method depends on which contribution of betaxolol hydrochloride is then (G/M)
physical characteristics of the substances are available. f ¼ (20/343.9) 1.8 ¼ 52 mosmol per litre.
Betaxolol hydrochloride therefore contributes for
Method 1: If the molecular weight and the dissociation type (52/290) 100 % ¼ 18 % of the iso-osmosis. As a
(f-value, Table 18.21) are known, the osmotic value can be consequence, excipients should contribute for the
calculated using a part of equation 18.16, namely: remaining 82 % to make an isotonic solution.
GA
fA
MA
Method 2: If the iso-osmotic concentration of a substance is
known, the osmotic value can be easily calculated. In
Method 1 is exemplified by the calculation of the Martindale, these values are often specified in the descrip-
osmotic value of betaxolol 1 % eye drops: tion of substances [11]. In the Merck Index and in the
Suppose that no iso-osmotic concentration of the sub- Handbook of injectable drugs, the iso-osmotic concen-
stance (betaxolol) is known. The osmotic value can trations for a large number of substances are listed in a
table [6, 37].
(continued)
obtained, gives for each substance in the amount used the

Method 2 is exemplified by the calculation of the amount of NaCl which corresponds to the osmotic value. The
osmotic value of Pilocarpine Eye Drops 2 % FNA sum of the products of all individual components represents the
(Table 18.22): strength in NaCl equivalents of the total solution. Because the
overall strength of the solution should be 0.9 NaCl equivalents,
Table 18.22 Pilocarpine Eye Drops Solution 2 % [38]
the relative contribution of the active substance to the osmotic
Pilocarpine hydrochloride 2g value is known. The amount of iso-osmotic stock solution to be
Benzalkonium chloride 0.01 g added can be calculated as described above.
Borax 0.375 g
Boric acid 0.7 g
Disodium edetate 0.1 g Method 3 is exemplified by the calculation of E value
Water, purified ad 100 mL and NaCl equivalents for a thiamine-injection 25 mg/
mL (Table 18.23):
A 4.1 % w/v solution of pilocarpine hydrochloride is Table 18.23 Calculation of E value an NaCl equivalents for a
iso-osmotic (293 mosmol as determined by measuring thiamine injection solution
PRODUCT DESIGN
its freezing point depression). A 2 % w/v pilocarpine Per 100 mL E NaCl-eq
hydrochloride thus contributes to about 50 % of the Thiamine-hydrochloride 2.5 g 0.21 0.525
iso-osmotic value (the osmolarity as determined at Disodium edetate 0.01 g 0.20 0.002
pH 6 is 147 mosmol). The other 50 % should be
provided by the excipients. Iso-osmotic stock solutions
This gives a total of at E ¼ 0.527 sodium chloride
(see also Sect. 10.7.1) for the preparation of eye drops
equivalents. 0.9 g of sodium chloride per 100 mL is
could be very useful for the purpose of easy calculation.
iso-osmotic. This means that almost 0.373 g per
The stock solution Boric acid-benzalkonium solution
100 mL should be added.
FNA (see Table 10.10) is nearly iso-osmotic (boric
acid is iso-osmotic at a concentration of 19 mg/mL).
The contribution to the osmotic value of the
benzalkonium chloride 100 mg/L is too small and can
be neglected in the calculations. Without adjusting the
18.5.5 Importance of Osmotic Value in Dosage
pH, 50 % v/v of Boric acid-benzalkonium solution
Forms
would be needed. But because the stability of pilocar-
pine is optimal at pH 6.5, the pH is adjusted with
With the aid of the three methods described in Sect. 18.5.4 it
3.75 mg/mL borax to 6.5. As 3.75 mg/mL borax
can be calculated whether or not a pharmaceutical prepara-
contributes 15 % to the osmotic value, 35 % is left for
tion is iso-osmotic. Hypo-osmolarity can usually be avoided
the Boric acid-benzalkonium solution.
as it can be compensated by the addition of excipients in
calculated quantities. Hyper-osmolarity may be inevitable
due to dosage reasons, for example when a high dose of an
Method 3: If no iso-osmotic concentration is known, it can active substance has to be administered in a small volume.
be calculated with the aid of the sodium chloride equivalent, The extent to which hyper-osmolarity is tolerated will
also known as tonicic equivalent or E-value. The sodium depend on the route of administration and administration
chloride equivalent is defined as: site. The tolerance for parenteral administration, for exam-
ple, increases in the order: subcutaneous < intramuscular <
freeze point depression per gram of compound A intravenously. This has to do with the fact that of these three
E¼
freeze point depression per gram NaCl routes, the intravenously administered dose spreads most
ð18:17Þ rapidly, and thus dilutes most rapidly in the body and the
subcutaneously administered dose most slowly. For the same
For each substance, the E value can be calculated if the dissoci- reason, the tolerance is greater when the solution is injected
ation type of that substance is known [39]. In practice, tables are into a large blood vessel than in a small blood vessel. The
used in which the E-values for a large number of substances are tolerance is also determined by the volume infused. In Sects.
listed. These tables can be found in references [6, 37]. The 13.5.5 and 13.6.3, more information is given about the
calculation using E-values proceeds as follows. The concentra- relative importance of iso-osmosis for different types of
tion of each of the solutes, expressed as a percentage, is parenterals. The osmolarity of an eye wash should be much
multiplied with the corresponding E value. The product thus more accurate than that of an eye drop. This is because the
eye drops, which are administered in small volumes, are 18. Zure oordruppels met hydrocortison 1% FNA. Jaar 2009.
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Microbiology
19
Hans van Doorne, David Roesti, and Alexandra Staerk
Contents 19.6.1 Sterility Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

19.6.2 Requirements for Non-sterile Products and Raw
19.1 Characteristics of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
19.1.1 Organisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 19.6.3 TAMC and TYMC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
19.1.2 Interaction with the Environment . . . . . . . . . . . . . . . . . . . . . . . . 384 19.6.4 Specified Micro-organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
19.1.3 Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 19.6.5 Alternative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
19.1.4 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
19.1.5 Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
19.1.6 Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
19.1.7 Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
19.2 Biological Contaminants of Pharmaceutical Abstract
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Microbial contamination of pharmaceutical preparations
19.2.1 Growth and Survival: Extrinsic Factors . . . . . . . . . . . . . . . . . 385 may cause health hazard to the patient (e.g. infection,
19.2.2 Growth and Survival: Intrinsic Factors . . . . . . . . . . . . . . . . . . 385
pyrogenic or allergic reaction), altered therapeutic activity
19.3 Potential Biological Contaminants . . . . . . . . . . . . . . . . . . . . . 386 of the product, or other decrease in quality (turbidity, loss
19.3.1 Prions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
of consistency, altered pH). This chapter provides a gen-
19.3.2 Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
19.3.3 Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 eral introduction on pharmaceutical microbiology by
19.3.4 Endotoxins/Pyrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 focusing on the essential properties of micro-organisms.
19.3.5 Biofilms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 First of all the basic characteristics of life and the types of
19.3.6 Fungi (Moulds and Yeasts) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
biological contaminants and potentially infectious agents
19.4 Fate of Micro-organisms in Pharmaceutical of pharmaceutical products will be discussed: viz. prions,
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392 viruses, mollicutes, bacteria, fungi, and endotoxins. In the
19.5 Biological Contamination of Pharmaceutical next section factors affecting survival and growth of
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 micro-organisms are discussed. In addition to well-
19.5.1 Impact of Microbial Contamination . . . . . . . . . . . . . . . . . . . . . 393
19.5.2 Origin of Microbial Contamination . . . . . . . . . . . . . . . . . . . . . . 393
known factors such as time, temperature, and chemical
19.5.3 Prevention of Microbial Contamination . . . . . . . . . . . . . . . . . 394 and physical characteristics of the environment, attention
19.5.4 Elimination and Destruction of Micro-organisms . . . . . . . 396 will be paid to biofilm formation. Primary microbiological
19.6 Examination of Pharmaceutical Products . . . . . . . . . . . . 397 contamination is prevented by implementing an adequate
microbiological quality control and quality assurance
program and by following cGMPs during production.
Some of the information in this chapter has been adapted and updated
Microbiological quality control of pharmaceutical
from: H. van Doorne, A Basic Primer on Pharmaceutical Microbiology, preparations and monitoring of production areas depend
edited by Richard Prince, co-published by PDA DHI Publishing Il, on the detection and quantification of micro-organisms.
USA. The classical, growth based, methods and some of the
H. van Doorne (*) commercially available alternative methods are
Department of Pharmaceutical technology, University of Groningen, discussed.
Groningen, Netherlands
Understanding essential microbiological concepts is
necessary in designing both microbiologically stable
D. Roesti A. Staerk
pharmaceutical products and ensuring an effective qual-
Biological & Microbiological Services, Novartis Pharma, Stein, AG,
Switzerland ity control and monitoring program within the
e-mail: [email protected]; [email protected] manufacturing or preparation facility.

384 H. van Doorne et al.
Keywords 19.1.5 Growth

Micro-organisms Contamination Hygiene
Microbiological examination Sterility test Growth is the increase in biomass. A growing individual
increases up to a point in size in all of its parts. Reproduction
is the result of a series of biochemical events that result in
the production of a new individual (asexually, from a single
19.1 Characteristics of Life parent organism, or sexually, from at least two differing
parent organisms). In microbiology growth is often used as
Although there is no universal definition of life, scientists a synonym for reproduction.
generally agree that living systems share all or at least the Dormancy is a state of decreased metabolic activity in
characteristics: organisation, interaction with the environ- which there is no growth, i.e. no increase in biomass. It may
ment, adaptation, metabolism, growth, motility and be a dynamic state in which the number of newly formed
communication. cells balances the number of dying cells. The duration of this
period is relatively short (hours, days). Dormancy of bacte-
rial spores may continue for considerably longer periods
19.1.1 Organisation of time.
Organisms are composed of one or more cells, which are the

basic units of life. Each cell must be highly organised 19.1.6 Motility
because growth and multiplication can only occur when
the individual biochemical processes are synchronised. In Many cells and organisms can move under their own power.
higher organisms, organisation within the organs, and com- Movement to a new location may offer the cell new
munication with other organs are essential for the normal resources. Motility however is not a characteristic of all
functioning of the body. living organisms. Animals are typically motile, whereas
plants are non-motile. In micro-organisms motility is depen-
dent on the type of organism and sometimes even on the
19.1.2 Interaction with the Environment stage of the life cycle the cells have reached.
Cells respond to chemical and physical input from the envi-

ronment. A response is often expressed by motion. Chemo- 19.1.7 Communication
taxis, the movement of a cell in response to a concentration
gradient of a substance, is an example of such an interaction. Throughout evolution humans and animals have developed a
multitude of ways for communication. Micro-organisms
(bacteria, yeasts and moulds) can communicate through a
process called quorum sensing. Quorum sensing is the regu-
19.1.3 Adaptation lation of gene expression in response to fluctuations in cell-
population density.
Adaptation is the accommodation of a living organism to its Quorum sensing exemplifies interactive social behaviour
environment. It is fundamental to the process of evolution, innate to the microbial world that controls features such as
by which cells change their characteristics and transmit these virulence, biofilm formation, antibiotic resistance, swarming
new properties to their offspring. motility, and sporulation [1, 2]. In gram-negative bacteria,
small molecules (e.g. acyl homoserine lactone (ALH) [3])
serve as signals to recognise microbial cell population size.
19.1.4 Metabolism When a signal exceeds some threshold concentration the
expression of specific genes is changed [4].
Metabolism involves the uptake of nutrients from the envi- If a microbial cell is introduced into a pharmaceutical
ronment, their conversion to energy (adenosine triphos- preparation or onto a surface it will sense whether suitable
phate: ATP) and cellular components, and the deposition conditions (nutrients, moisture, etc.) for growth are available
of waste products (e.g. carbon dioxide: CO2) or metabolites (interaction with the environment). If possible the cell will
(e.g. toxins or antibiotics) into the environment. Living adapt to its new habitat, and start to metabolise the available
things require energy to maintain internal organisation nutrients. Eventually growth will take place. Motility of
(homeostasis) and to produce the other phenomena individual cells will facilitate colonisation of other sites.
associated with life. Production of toxins (in case of a pathogen) is a demanding
19 Microbiology 385
biochemical process and will occur only when quorum sens- 19.2.2 Growth and Survival: Intrinsic Factors
ing indicates that a sufficiently large population has
developed. 19.2.2.1 Water
Thus the interplay between all these characteristics deter- The presence of water is essential to every form of life
mine whether a cell will be able to grow in a specific including micro-organisms. In the late 1930s, it was
product, or on a surface. recognised that water activity (or aw), as opposed to water
content, was the more significant factor in studying the
relationship of water to microbial growth. The aw value is
defined as the proportion between the water vapour pressure
19.2 Biological Contaminants
of the product and the vapour pressure of pure water at a
of Pharmaceutical Preparations
common temperature.
Lowering the water content has historically been a con-
Survival and growth of micro-organisms in pharmaceutical
venient method to protect foods from microbial spoilage.
preparations is governed by extrinsic factors (particularly
Examples where the available moisture is reduced are dried
temperature) and intrinsic factors (product composition and
fruits, syrups, and pickled meats and vegetables. Low water
physico-chemical characteristics). The combination of
PRODUCT DESIGN
activity will also prevent microbial growth within pharma-
intrinsic and extrinsic factors will determine the types and
ceutical preparations, see also Sect. 22.3.3. Water activity
number of micro-organisms that will develop in a product or
values supporting microbial growth of a number of repre-
on a surface.
sentative micro-organisms are provided in the USP [5]. That
chapter also suggests a strategy for microbial limit testing
based on water activity.
19.2.1 Growth and Survival: Extrinsic Factors Pharmaceutical cleaning operations usually involve a
final rinse with water of suitable pharmaceutical quality.
19.2.1.1 Temperature To prevent microbial growth, it is essential to dry the object
Temperature has a strong influence on whether an organism as soon as possible after rinsing.
can survive or thrive. Temperature exerts its influence indi- Although water is essential for microbial growth, a low
rectly through water (which has to be in the liquid state), and aw value does not necessarily lead to cell death. For instance,
directly through its influence on the organic molecules com- some dry raw materials, especially those of natural origin,
posing the living cells. may be heavily contaminated with both endospores and
Mesophilic organisms are widespread in nature. They vegetative cells. Freeze drying in a suitable medium, for
have the potential to grow in a temperature range of roughly instance, is an excellent way to preserve pure cultures of
8–45 C. At temperatures above 30 C some contaminants of viable micro-organisms. A water activity below 0.6 does not
water and air including different types of bacteria and enable micro-organisms to grow. Solid oral dosage forms
moulds will fail to grow or grow more slowly. The optimum such as tablets have in general an aw value lower than 0.5
growth temperature for pathogenic bacteria is around 37 C which means that these products remain stable from a
with an upper range from 44 C to 48 C. Legionella microbiological point of view over long periods of time if
pneumophila (L. pneumophila) is an exception; it will the product is stored in a waterproof blister that remains
grow at temperatures up to 55 C. integral.
Geobacillus stearothermophilus is a thermophile and
grows at temperatures between 50 C and 65 C. It is used
as a test organism (biological indicator) to verify the efficacy 19.2.2.2 Nutrients
of moist heat sterilisation processes. Micro-organisms require for their growth suitable nutrient
For reasons of chemical stability some preparations must sources of elements (e.g. C, H, O, P, S, N), minerals
be stored frozen. Under these conditions (no liquid water) (e.g. Na+, Ca2+, Mg2+) and trace elements (e.g. Cu2+,
microbial growth is not possible. However, the majority of Mn2+, Co2+). Even in a relatively nutritionally poor medium
the preparations are either stored refrigerated (4–8 C) or at such as distilled water, the number of micro-organisms may
room temperature (20–25 C), which will allow growth of be as high as 105–106 colony forming units (CFU)/mL,
most mesophilic micro-organisms. According to European indicating that nutrients are present in sufficient quantity to
Good Manufacturing Practice (EU-GMP) regulations water allow proliferation of water-borne bacteria such as the
for injection (WFI) should be produced, stored and pseudomonads. The presence of readily assimilated
distributed in a manner which prevents microbial growth, substances such as sugars or polyalcohols in dosage forms
for example by constant circulation at a temperature above such as creams or syrups can lead to an increased probability
80 C (see also Sect. 27.5.2). of microbial adulteration of those products.
19.2.2.3 pH addition, some active substances may show substantial

A pH range of 6–7 does not exert any discernible selective antimicrobial activity.
influence on growth of pharmaceutically relevant types of
organisms. Below pH 6, growth of many bacteria will start to
be inhibited. Pathogenic and toxinogenic bacteria generally
19.3 Potential Biological Contaminants
will not grow at pH values below 4.5, but they may survive
long times of immersion in weakly acidic solutions. Yeasts
19.3.1 Prions
and moulds unlike bacteria, generally tolerate acidic media
quite well. Optimum pH of most fungi is about pH 5. At
19.3.1.1 Brief Description of Prions
more alkaline conditions, pseudomonads will predominate.
A prion – short for proteinaceous infectious particle – is a
For example, Ps. aeruginosa is known to grow at a pH range
unique type of infectious agent. Prions are composed of
of 6–9.
abnormal isoforms of a normal host-encoded membrane
protein, termed prion protein (PrPc). Abnormally folded
19.2.2.4 Redox Potential
prion protein catalyses the refolding of normal prions into
Microbes are classified as aerobes or anaerobes. This is now
abnormal forms. Prions are not considered life. However,
defined in terms of oxidation-reduction potential (Eh). Gen-
their biological origin and their potential effect on animals
erally, the range at which different micro-organisms can
and human beings warrant a brief discussion.
grow are as follows: aerobes +500 to +300 mV; facultative
The term ‘prion diseases’ refers to a group of neurode-
anaerobes +300 to 100 mV; and anaerobes +100 to less
generative disorders. These include scrapie (in sheep and
than 250 mV. The redox potential of a normal aerobic
goat), Kuru (prion disease endemic amongst cannibalistic
nutrient medium is about + 300 mV. Thioglycolate medium,
tribes in Papua New Guinea), bovine spongiform encepha-
which is used for growth of anaerobic bacteria has an Eh of
lopathy (in cattle) and Creutzfeldt-Jakob disease (CJD)
about 200 mV. For reasons of chemical stability, the redox
(in humans) [6]. Prion diseases are characterised by long
potential of some pharmaceutical preparations is kept at a
incubation periods ranging from months to years and are
low level by means of reducing agents such as sulfite,
invariably fatal once clinical symptoms have appeared. In all
tocopherol or ascorbic acid. The effect of a reduced redox
prion diseases the infectious prions are generated in the brain
potential on the microbial flora of such preparations has
of the afflicted animal. In the rare cases of interspecies
never been studied.
transmission, such as from cattle to humans a ‘template
assisted replication’ takes place. This means that the prions
19.2.2.5 Substances with Antimicrobial Properties
that replicate in the human brain have the amino acid
The number and types of micro-organisms that may develop
sequence encoded by the DNA of the host (human being)
in various pharmaceutical dosage forms is greatly influenced
and not the sequence of the donor animal [7].
by the presence of substances with antimicrobial properties.
Antimicrobial active substances can be divided into three
groups, as follows: 19.3.1.2 Prions as Contaminants
• The first group consists of substances used for therapeutic of Pharmaceutical Preparations
or preventive antimicrobial purposes, for example: BSE was first diagnosed in the United Kingdom in 1986 and
antibiotics, chemotherapeutics, and disinfectants. a large number of cattle and individual herds have been
• The second group consists of preservatives (see Sect. 23.8), affected. Interspecies TSE transmission is restricted by a
used to guarantee the microbiological quality of the product number of natural barriers, transmissibility being affected
throughout its shelf life. For example: esters of hydroxy- by the species of origin, the prion strain, dose, and route of
benzoic acid, quaternary ammonium substances and sorbic exposure.
acid are widely used in pharmaceutical and cosmetic Transmission of scrapie to sheep and goats occurred
preparations. Other preservatives that are used include phe- following use of a formol-inactivated vaccine against conta-
nol, chlorhexidine, benzoic acid and benzyl alcohol. gious agalactia, prepared with brain and mammary gland
• The third group consists of excipients with ‘collateral’ homogenates of sheep infected with Mycoplasma agalactiae
antimicrobial activity that are principally added to dosage [8]. Iatrogenic transmission of human prion disease can
forms for reasons unrelated to their (sometimes weak) occur through medical or surgical procedures. An example
antimicrobial activity. For example, sodium lauryl sulfate is the injection of hormones such as gonadotropins extracted
is known to inactivate some gram-positive bacteria. Sim- from cadaver pituitaries. Current evidence indicates that,
ilarly, edetate has weak antimicrobial activity, and it with respect to the risk of TSE infection, urinary-derived
confers synergistic antimicrobial properties when com- gonadotrophins appear to be safe [9]. The risks of urine-
bined with quaternary ammonium substances. In derived fertility products could now outweigh their benefits,
19 Microbiology 387
particularly considering the availability of recombinant The virions are metabolically inactive because they are
products [10]. devoid of a self-generating energy system, transfer RNA,
Cases of CJD have also been attributed to the use of ribosomes, and so forth. Many viruses do contain enzymes
contaminated instruments in brain surgery and with the that become essential in rendering these agents infectious to
transplantation of human dura mater and cornea [11]. susceptible hosts. Viruses are obligate intracellular parasites.
Suppliers of materials may minimise the risks of contam- Replication occurs only inside the cell of a suitable host.
ination of TSE by ensuring [12]: Replication usually leads to destruction of the host cell.
• The source animals and their geographical origin Sometimes the viral DNA is incorporated into the genetic
• Nature of animal material used in manufacture and any material of the host. This principle is successfully used in
procedures in place to avoid cross-contamination with genetic engineering, where viruses are used as vectors to
higher risk materials incorporate a new gene in a cell.
• Production process(es) including the quality control and Viruses are causative agents of many human, animal, and
quality assurance system in place to ensure product con- plant diseases. AIDS, SARS, and avian flu are viral diseases,
sistency and traceability which are nearly daily covered by the headlines in papers
Manufacturers of pharmaceutical preparations select their and by the news items on radio and television. In 1917–1919
a ‘Spanish flu’ pandemic killed over 50 million people. The
PRODUCT DESIGN
raw materials so they are TSE free (see also Sect. 23.1.7).
This can be ensured either by purchasing materials from virus involved was most probably a mutation of some avian
non-animal origin or from non-TSE relevant animal species virus. The Avian flu pandemic (caused by the H5N1 variant)
(e.g. porcine instead of bovine). If material from was, by comparison very small, as it has caused ‘only’ about
TSE-relevant animal species is purchased, it should be deliv- 150 fatalities. The great concern for virologists and
ered with a certificate that confirms it free of TSE. Regular epidemiologists is the extremely high mortality rate (over
audits verifying this assumption should be performed by the 50 %) of infections with this virus. In the form of vaccines,
manufacturer at the material’s supplier manufacturing site. viruses are inactivated or attenuated so as to prevent diseases
Prions, unlike the normal PrPc proteins, are very resistant to in susceptible populations.
inactivation. The only methods that appear to be completely The Baltimore classification is the preferred way of
effective under worst-case conditions are strong sodium classifying viruses. Viruses are grouped into families
hypochlorite solutions or hot solutions of sodium hydroxide depending on their type of genome (DNA, RNA, single-
[13, 14]. Some cross contamination can be avoided by the stranded (ss), double-stranded (ds) etc.) and their method
use of disposable instruments, e.g. in tonsillectomy [15]. of replication.
A series of important medicines is derived from animal or
human sources and may potentially be contaminated with
undesired virus particles. Such medicines include:
19.3.2 Viruses • Coagulation factors, immunoglobulins and albumin from
human blood plasma
19.3.2.1 Brief Description of Viruses • Vaccines and monoclonal antibodies from cell cultures
A virus is a non-cellular genetic element, which is dependent • Proteins from cells altered by genetic engineering
on a suitable host cell for its multiplication. Their size • Homoeopathic preparations of animal origin
generally ranges from 20 to 300 nm. It has been argued
extensively whether viruses are living organisms. The
majority of virologists consider them as non-living as they 19.3.2.2 Viruses as Contaminants
lack many of the characteristics of life, such as independent of Pharmaceutical Preparations
metabolism. Viruses exist in various states throughout their Vaccination is one of the most important public health
life cycle. In the extracellular state a virus particle is called a accomplishments. However, since vaccine preparation
virion. involves the use of materials of biological origin, such as
Virions are composed of a core of genetic material, which Chinese Hamster Ovary cells, vaccines are susceptible to
can either be in the form of DNA or ribonucleic acid (RNA), contamination by micro-organisms, including viruses
and a protein coat or capsid. In some viruses (enveloped [16–18]. Several cases of viral vaccine contamination have
viruses) the capsid is surrounded by a lipid bilayer mem- been reported. For example, human vaccines against polio-
brane. Attached to these membranes are specific proteins, myelitis were found to be contaminated with SV40 virus
which may play a role in the attachment of the virion to the from the use of monkey primary renal cells. Several veteri-
host cell, or release from the host. Thus, haemagglutinin and nary vaccines have been contaminated by pestiviruses from
neuraminidase are two important enzymes present in the foetal calf serum [19]. In 2010 the detection of fragments of
envelope of the influenza virus. a porcine circovirus was the reason for a temporary
withdrawal of some commercial vaccines from the Spanish bacteria adapt to their new environment by repairing dam-
market [20]. aged structures and synthesising enzymes to catabolise
Several methods are being used or in development to nutrients in the medium. The second phase, the most spec-
reduce infectivity of blood products, including solvent- tacular, is the exponential phase during which nutrients in
detergent processing of plasma and nucleic acid cross- the medium are metabolised rapidly leading to a rapid dou-
linking via photochemical reactions with methylene blue, bling of the population of bacterial cells. The population of
riboflavin, psoralen and alkylating agents. Several Escherichia coli cells under optimal growth conditions can
opportunities exist to further improve blood safety through multiply each 20 min. This would mean that after 8 h the
advances in infectious disease screening and pathogen inac- population would reach one million cells and after 43 h, the
tivation methods [21, 22]. One potential way to increase the volume of cells produced would be equivalent to the volume
safety of therapeutic biological products is the use of a virus- of planet earth! Once nutrients start to deplete, the exponen-
retentive filter [23]. Plasma pools may be submitted to sero- tial growth is slowed down and the amounts of cells in the
logical tests and/or genome amplification assays before they overall population remains stable; this is the third phase
are released for further fractionation [24]. called the stationary phase. In this phase, secondary
Multidose containers and the environment were found to metabolites such as antibiotics are produced in higher
be the source of a number of nosocomial viral infections quantities. The last phase is when no more nutrients are
[25–33]. available and the amount of bacterial cells starts to drop.
Presence of viruses in pharmaceutical preparations may In the human microflora, there are at least 10 times more
be verified by performing either in vivo tests by inoculating bacterial cells than human cells and most of them are harm-
the product directly in animals (e.g. rabbits, mice) or in-vitro less. Human bacterial infections are mainly caused by strict
tests such as polymerase chain reaction (PCR) or cell culture pathogenic species (less than 2 % of bacterial species) or by
safety tests. opportunistic pathogens when the immune system of the
person is depleted. Bacteria may cause a large variety of
infections, the most common being food poisoning, pneu-
19.3.3 Bacteria monia, skin infection, urinary tract infection, throat and
mouth infection, meningitis, eye infection. Depending on
19.3.3.1 Brief Description the infectious agent, the minimum amount of micro-
Along with the Archea, bacteria belong to the prokaryotic organisms provoking an infectious dose varies greatly. For
organisms, i.e. cells that do not possess a real nucleus and instance in some cases, only 10 cells of Shigella dysentriae
that reproduce asexually. They are unicellular micro- need to be ingested to provoke dysentry but at least a 1,000
organisms with a size in general ranging from 0.2 to 10 μm. cells of Vibrio cholera to provoke cholera [34].
Their extraordinary diversity in terms of biochemical
processes and metabolic characteristics enable bacteria to
adapt themselves to a large variety of environments. Indeed, 19.3.3.2 Mollicutes
some species have the capacity to grow in anaerobic Mollicutes, also known under the trivial name mycoplasmas,
(absence of free oxygen in the air) environments by using are the smallest free-living prokaryotic organisms and for
other electron acceptors than oxygen, such as sulphates or years were thought to be viruses because they passed through
nitrates or by fermentation. Other species may use energy the usual bacterial filters. They resemble protoplasts, because
and carbon sources for growth from not only organic they lack a cell wall, but they are relatively resistant to
substances but also from carbon dioxide and light energy. osmotic lysis due to the presence of sterols in the cell mem-
For this reason, bacteria have colonised most habitats on brane. In this respect the mycoplasmas form an exceptional
earth (soil, water, animals, plants) and even the most group, because sterols are absent in other prokaryotic cells.
extreme environments such as deep-sea fumaroles or Mycoplasmas are widespread in nature and many are animal,
geysers. plant or human pathogens. Most mycoplasmas that infect
Another fascinating (but critical in terms of product humans are extracellular parasites. Examples of human path-
safety) characteristic of bacteria is their capacity to grow ogenic mycoplasmas are Mycoplasma pneumonia (infections
extremely fast if the environmental conditions in terms of of upper respiratory tract), and Mycoplasma genitalium (non-
nutrient availability, moisture and temperature become gonococcal urethritis) [35].
favourable. Mycoplasma contamination is a major concern for vac-
During growth, an individual cells first increases in size cine and biotechnological industries since the organisms
and then the cell is divided in two parts (binary fission). In may cause disease and may interfere with cell culture
nutrient media, bacteria follow four growth phases (see [36]. Peptones, and animal sera used as components of cell
Fig. 19.3). The first is the lag phase, during which the culture media may be sources of this contamination [37, 38].
19 Microbiology 389
Mycoplasmas can be cultured in liquid or on solid media. Pili and Fimbriae

However, in contrast with other bacteria, their growth is The surface of cells of some bacterial species is covered with
slow, and a microbiological assay as described in the many (10 to several thousands), thin (3–25 nm), and long
Ph. Eur. is time-consuming (at least 28 days). Alternative, (up to 12 μm) threads called pili, or fimbriae. They play a
rapid methods, based on nucleic acid technologies such as role in the initial adhesion of bacteria to host tissues and
PCR, have been developed [36, 39]. Under certain inanimate surfaces [43, 44]. Attachment to a surface is the
conditions these methods may be used as an alternative first step in biofilm formation. Upon attachment on tissue
method instead of the official, growth based method [40]. cells they may trigger a number of biochemical signals from
the host, which ultimately leads to the bacterial disease [45].
19.3.3.3 Structure
Bacteria may be composed of the following structural Capsule or Slime Layer
elements (see Fig. 19.1): Capsules and slime layers – collectively called glycocalix –
• Flagella consist of source polysaccharide material secreted by the
• Pili and fimbriae cell. A capsule is a rigid structure, whereas a slime layer,
• Capsule or slime layer or loose extracellular slime, is more flexible, with diffuse
PRODUCT DESIGN
• Cell wall boundaries. The glycocalix has several functions. It is
• Cytoplasmic membrane involved in cell attachment and it may protect cells from
• Cytoplasm being digested, a phenomenon known as phagocytosis.
• Spores Whilst encapsulated strains of Streptococcus pneumoniae
Cytoplasm, cytoplasmic membrane and cell wall are always are highly pathogenic, non-encapsulated mutants are
present. The presence of the other components depends on completely avirulent [46, 47]. Dextran, a slime layer product
the type of micro-organism, the culture conditions and the of Leuconostoc mesenteroides of relatively low molecular
growth phase. weight can be used as a therapeutic agent in restoring blood
volume [48].
Flagella
Bacteria become motile by means of flagella [41]. Bacterial Cell Wall Constituents
flagella are protein threads which originate in a defined The outer surface of the bacterial cell plays an important role
region of the cytoplasmic membrane and protrude through in the adhesion of the cell to various surfaces. In addition to
the peptidoglycan layer and the outer membrane. The num- the factors that have been discussed, adhesion may also be
ber of flagella per cell and their position depends on the mediated by so-called surface-associated adherence factors,
species. Pseudomonas aeruginosa (Ps. aeruginosa) has usually designated as adhesins. Adhesion, which is the first
only one (polar) flagellum at the tip of the cell, whereas step in a series of events leading to colonisation, biofilm
Escherichia coli (E. coli) has numerous flagella spread formation and ultimately infection, is a specific process in
over the entire cell surface (peritrichous). Flagella may which the adhesin “recognises” a receptor on the host sur-
play an important role in pathogenicity [41, 42]. face. This specificity explains why micro-organisms such as
cytoplasmic membrane
mesosome cytoplasm
pili
genetic
material
ribosomes
flagellum
Fig. 19.1 Structural elements of plasmid cell wall
the bacterial cell capsule
Influenza or Mycobacterium tuberculosis can cause targeted Some genetic information such as antibiotic resistance
infection of the respiratory tract but otherwise are relatively may be encoded in plasmids – DNA molecules that are
harmless when contacting other host tissues. independent of the genome and that can replicate them-
The cell wall gives the cell its shape and strength. The cell selves. Some plasmids contain a set of genes (in the
wall must resist the internal osmotic pressure of the cell that tra region) that enable the transfer of the plasmid by cell to
is estimated to be about 2 bar. The composition of cell walls cell contact (conjugation). The plasmid is replicated during
of gram-positive bacteria is very different from those that this process and its genetic information (e.g. antibiotic
stain gram-negative. resistance) is thus transferred to the recipient cell. There
are both intra-species and inter-species plasmid transfer
Gram-Positive Cell Wall phenomena. The cytoplasm may also contain reserve mate-
Peptidoglycan is the common cell wall component of bacterial such as polyhydroxybutyric acid, and other substances of
ria (excluding mollicutes) and gives the wall its shape and uncertain function (e.g. polyphosphate, volutin).
strength. It is a polymer consisting of a backbone of
alternating N-acetylglucosamine and N-acetylmuramic acid 19.3.3.4 Bacterial Endospores
residues, cross-linked with small peptide bridges. Peptido- Some gram-positive rods such as the genera Bacillus,
glycan accounts for about 80–90 % of the wall of gram- Geobacillus and Clostridium are capable of forming
positive bacteria and for about 10 % of the gram-negative endospores that enable these genera to survive harsher
cell wall. conditions, such as exposure to heat, radiation, or chemicals.
Bacterial spores are resistant forms of life. Some experts
have suggested that they may remain viable (capable of
Gram-Negative Cell Wall (Outer Envelope) life) for millions of years.
The gram-negative cell wall contains only a shallow pepti- The bacterial spore has a complex structure, consisting of
doglycan layer. On the outer side of this layer is the outer various layers, including coat and cortex, all of which play a
membrane, a complex structure consisting of four major role in long-term survival (see Fig. 19.2).
components: phospholipids, lipopolysaccharide, proteins Endospore formation is a non-reproductive process: one
(e.g., porins), and lipoprotein. Lipolysaccharide (endotoxin) cell produces only one spore which, after germination,
is responsible for the pyrogenicity of the gram-negative produces one vegetative cell.
bacteria. Bacterial sporulation occurs when growth decreases due
to exhaustion of an essential nutrient. It is a complicated
Cytoplasmic Membrane process requiring the participation of more than
The cytoplasmic membrane, or plasma membrane is a phos- 200 enzymes. Conversion to a vegetative cell involves
pholipid bilayer into which proteins/enzymes are embedded. three steps: activation, germination and outgrowth. Activa-
The function of the cytoplasmic membrane is to act as a tion can be accomplished by heating the spores to a
selective permeability barrier between the cytoplasm and the non-lethal temperature. Germination can be induced by a
exterior environment. A mesosome is an organelle of bacte- variety of events, including exposure to nutrients (amino
ria that appears as an invagination of the plasma membrane acids, sugars, or purine nucleosides), non-nutrient
and functions either in DNA replication and cell division, germinants (dodecylamine, lysozyme) and heating
energy production, or excretion of exoenzymes. Flagella [49]. The spore loses its characteristic constituents, and
(if present) originate in a special structure in the cytoplasmic heat resistance decreases dramatically. In the last stage
membrane (see the section on Flagella under Structure of the water is taken up, and metabolism (synthesis of ATP,
Bacterial Cell).
Cytoplasm
The cytoplasm is a viscous liquid, which contains all other
essential elements for the living cell. The genetic material is
mainly organised in the genome, a circular string of DNA.
There is no discrete bacterial nucleus. The genetic code is
translated into messenger RNA and then transported to the
ribosomes, where the protein synthesis occurs. The building Fig. 19.2 The bacterial spore. # 2003 Ricca and Cutting, Journal of
blocks of the proteins (amino acids) are transported to the Nanobiotechnology 2003, 1:6, doi:10.1186/1477-3155-1-6, published
ribosomes by means of transfer RNA. by BioMed Central
19 Microbiology 391
proteins and genetic material) resumes. Heat activation is an commercially most successful alternative method, which
important factor in the occurrence of a shoulder in the replaces the rabbit pyrogen test for bacterial impurities in
survival curve of bacterial spores upon heating. medicines with a test using human cells, could save the life
Destruction of bacterial spores is the ultimate goal of of 200,000 rabbits a year.
sterilisation processes. Bacterial spores are typically used
in biological indicators for validation and monitoring of
sterilisation processes.
19.3.5 Biofilms
Biofilms are multicellular, microbial communities held

19.3.4 Endotoxins/Pyrogens
together by a self-produced extracellular matrix that adhere
to biological or non-biological surfaces [51]. A biofilm has a
Pyrogens are substances that cause a febrile reaction. Two
defined architecture, and it provides an optimal environment
groups of pyrogens can be distinguished: exogenous and
for the exchange of genetic material between cells,
endogenous pyrogens. The exogenous pyrogens form a het-
e.g. spread of antibiotic resistance. Cells within a biofilm
erogeneous group of substances; the most important one is
may communicate via quorum sensing (see Sect. 19.1.7),
PRODUCT DESIGN
lipopolysaccharide (LPS) from the cell wall of gram-
which may in turn affect biofilm processes such as detach-
negative bacteria. LPS, also known as endotoxin, has anti-
ment of cells. The ability to form biofilms is a universal
genic properties (O antigen) and causes fever when injected
attribute of bacteria and many other micro-organisms.
intravenously. Lipoteichoic acid, muramyldipeptide, porins,
Elimination of bacteria in this mode of growth is chal-
glycans and nucleic acids, are examples of non-endotoxin
lenging due to the resistance of biofilm structures to both
pyrogens originating from bacteria (gram-positive and
antimicrobials and host defences.
gram-negative), yeast and moulds.
Biofilms have great importance for public health because
The pyrogenic activity of LPS is much higher than that of
of their role in certain infectious diseases and their role in a
most other pyrogenic substances. This is the reason why an
variety of device-related infections. Biofilm infections on
in-vitro limit test for LPS (the Limulus Amoebocyte Lysate,
indwelling devices or implants are difficult to eradicate
or LAL test) generally suffices for quality control purposes
because of their much better protection against macrophages
of parenteral medicines and raw materials, including water
and antibiotics, compared to free living cells, leading to
for injection.
severe clinical complications often with lethal outcome.
The European Pharmacopoeia requires the rabbit pyrogen
test for a number of vaccines, some antibiotics, and specific
excipients including glucose, if intended for the preparation
of large volume parenterals (see Sect. 32.8). These products 19.3.6 Fungi (Moulds and Yeasts)
may be contaminated with pyrogens other than LPS, or are
known to inhibit the LAL test. Fungi are widespread in nature and have considerable eco-
A third test, the monocyte activation test (MAT) is based nomic and medical importance, because:
on the in-vitro activation of human blood cells by pyrogens. • They may contaminate and cause spoilage and deteriora-
This leads to the release of pro-inflammatory cytokines tion of pharmaceutical preparations. Mould and yeasts
tumour necrosis factor alfa (TNF-alfa), interleukin-1 beta are the second cause of FDA recalls in non-sterile
(IL-1beta) and interleukin-6 (IL-6) that are determined by pharmaceuticals [52].
Enzyme-Linked Immuno Sorbent Assay (ELISA). Conse- • This group of organisms is used by producers of active
quently, the MAT will detect the presence of both exogenous substances, including antibiotics, such as penicillins by
and endogenous pyrogens in the test sample. The MAT is Penicillium species, or alkaloids, such as ergotamine by
suitable, after a product-specific validation, as a replacement Claviceps purpurea.
for the rabbit pyrogen test [50]. • Some fungi are pathogenic to humans. They may cause
The reagent for the LAL is isolated from the blood of the infections (e.g., Trychophyton sp. or Candida sp.), or
horseshoe crab (Limulus polyphemus). The blood is col- produce toxic substances (e.g., aflatoxin by Aspergillus
lected from wild animals. Many animals do not survive flavus).
(mortality rates of up to 30–50 % have been reported), and Two groups of fungi are relevant in the context of pharma-
this living fossil is threatened with extinction. It is to be ceutical products or processes: the moulds and the yeasts.
expected that in the near future the MAT test or other Their physical differentiation is not always clear, because
alternatives for the LAL test and the rabbit test will be some fungal species (e.g., Candida, Histoplasma and Cryp-
more generally introduced. The development of such new tococcus) show dimorphism, a phenomenon in which a
methods will significantly reduce animal testing. The filamentous and a yeast-like stage both exist.
Moulds are obligate aerobic micro-organisms; they grow The cell wall of fungi consists of 80–90 %
on the surface or in the uppermost layers of the substrate. polysaccharides. Chitin is a common constituent of fungal
Characteristic of moulds is the filamentous body, the myce- cell walls, but is replaced by other substances such as man-
lium. Vegetative growth of moulds occurs at the tip of the nan, galactosan or chitosan in some species. Peptidoglycan,
individual filaments (hyphae). the common constituent of bacterial cell walls is never
Depending on the species, hyphae may be divided into present. This phenomenon explains why fungi are insensi-
compartments by means of septa (Eumycetes). Each septum tive to antibiotics that inhibit murein synthesis, such as the
contains a pore, which allows flow of cytoplasmic penicillins and the cephalosporins. Sterols are essential
constituents from one compartment to another. The lower structural components of the fungal cytoplasmic membrane.
fungi (Phycomycetes) have aseptate (coenocytic) hyphae; This characteristic makes fungi sensitive to antibiotics that
the mycelium is a multinucleated cell. interact with sterols, such as nystatin and amphotericin.
Asexual reproduction of moulds normally occurs by
means of spore formation. From the mycelium special
branches reach up into the air. At the tip of these 19.4 Fate of Micro-organisms
conidiophores the spores (conidiospores) are formed on a in Pharmaceutical Preparations
genus specific structure. The colour of mould colonies on
solid substrates (e.g., different shades of green for Penicil- In the previous sections the characteristics of potential
lium species, or black for Aspergillus niger) is entirely due to contaminants of pharmaceutical preparations and their
the massive production of these conidiospores. requirements for survival and growth have been discussed.
Mould spores may cause significant issues in the produc- There appears to be a complicated interplay between the
tion of pharmaceutical preparations since they survive des- type and characteristics of the micro-organisms (e.g. spore
iccation and may be transported via air, personnel or formation), their ability to form biofilms, the composition of
material flow into products. the environment, and external factors, particularly the tem-
The spores are readily dispersed into the environment and perature. The fate of a micro-organism in a pharmaceutical
may form a new mycelium. Because of mechanical forces, preparation depends on this interplay. Four different curves
such as those exerted during vortexing, hyphae may break up may be observed when numbers of colony forming units
into smaller fragments, which may also form new mycelia. (CFU) are plotted against time (Fig. 19.3).
Clumps of conidiospores may also break up into smaller units. Microbial growth follows the well-known sigmoid growth
Such fragmentation caused by vigorous mixing in the course curve, with lag phase, log phase and maximum stationary
of microbiological examination of pharmaceutical samples phase. Microbial destruction under influences of heat, radia-
may lead to considerable uncertainty in fungal counts. tion or chemicals is frequently a first order kinetic process.
Yeasts are typically unicellular organisms. Yeast cells are When microbial destruction is plotted on a semi-logarithmic
spherical or oval. Growth (asexual reproduction) takes place scale, a straight line is observed. A ‘shoulder’ is sometimes
by a process called budding. A new cell is formed as an observed at the beginning of the curve. This lower death rate
outgrowth of the mother cell, the daughter cell enlarges and is attributed to the genetic repair mechanisms of the cells,
finally the two cells separate. Pathogenic dimorphic fungi e.g. when exposed to low doses of UV radiation. Bacterial
usually form yeast-like cells in the human body and a myce- spores must be ‘activated’ before they can germinate and
lium at room temperature (e.g. Histoplasma). Candida sp. is grow out to become prototypical vegetative cells. This phe-
an exception because it forms hyphae in the host tissue. nomenon may also cause a ‘shoulder’ in survival curves. At
Sexual reproduction is associated with many yeasts and the end of the survival curve, a ‘tail’ may be observed,
moulds. A stage in which spores are formed is always indicating the presence of resistant cells or clumps of cells.
involved in the sexual process. Depending on the type of True dormancy is found only in bacterial endospores. Never-
sexual spore formation four groups of moulds can be distin- theless, even vegetative organisms can produce an effective
guished: Ascomycetes, Basidiomycetes, Zygomycetes, and state of dormancy because of either a relatively slow death
Oomycetes. The spores are called ascospores, basidiospores, rate or growth and kill rates that offset each other.
zygospores, and oospores, respectively. In pharmaceutical preparations another type of curve is
Fungi for which no sexual reproduction has been sometimes observed. An initial decrease in the number of
demonstrated are classified as fungi imperfecti colony forming units may occur, followed by an increase.
(Deuteromycetes). The majority of fungi thus far classified This phenomenon can be observed when analysing data
fall into this category. Penicillium and some Aspergillus from preservative efficacy testing of inadequately preserved
species are well-known representatives of this group. dosage forms. It is the reason why in pharmacopoeial
19 Microbiology 393
Fig. 19.3 Fate of micro-

organisms in pharmaceutical
preparations
PRODUCT DESIGN
preservative efficacy tests the number of viable cells must be 19.5.2 Origin of Microbial Contamination
followed for a period of 28 days (see Sect. 32.8).
The contamination can be primary or secondary. Primary
contamination occurs at the premises or during preparation:
• Personnel. Personnel account for the majority of
19.5 Biological Contamination contaminations in the clean room environments. This
of Pharmaceutical Preparations can be explained by the high number of micro-organisms
located on or in the human body. The organisms may be
19.5.1 Impact of Microbial Contamination introduced into the environment due to inadequate
gowning or hygiene, infrequent or ineffective hand wash-
Microbial contamination of pharmaceutical products may ing and disinfection procedures, unqualified behaviour
result in deterioration of the product or direct hazard to the (non-clean room adequate) of personnel, etc. In the asep-
patient. tic production of sterile pharmaceutical preparations liv-
Whether a contaminated pharmaceutical product will ing micro-organisms should not enter the aseptic filling
trigger infection or disease in the patient depends on various area and the product should not contain any viable micro-
factors such as: organism. In those situations, low-level microbial
• Number of micro-organisms (CFU per g or mL) contaminations of products occur mostly at critical
• Ability of the contaminant to grow and metabolise interventions near to the product during processing.
components of the product Microbial contamination of non-sterile pharmaceutical
• Properties of the particular strain preparations may not originate primarily from the
• Immunocompetence of the patient, due to disease (AIDS) human body, but raw materials, equipment, air and pack-
or use of immunosuppressiva aging material may also play an important role
• Route of administration • Raw materials. Raw materials from natural origin may be
Deterioration or spoilage of the product because of microbial highly contaminated with micro-organisms especially
growth may result in several effects including: spore-forming bacteria and moulds and in some cases
• Loss of texture because of metabolism of oil/fat phase with more critical Enterobacteriaceae. Soon after a publi-
• Loss of organoleptic quality because of production of cation on salmonellosis in more than 200 persons caused by
olfactory products the contamination of thyroid tablets with two types of
• Loss of preservative efficacy because of metabolism of Salmonella originating from the raw material [53],
the preservative proposals for the examination of non-sterile pharmaceutical
• Loss of package integrity because of excessive gas preparations and acceptance criteria were published [54].
production • Water. Water may be used to clean equipment and clean
• Loss of therapeutic activity because of metabolism of the rooms as well as a product component. Water contains
active substance(s) water-borne micro-organisms that may grow under low
• Release of toxigenic substances, including toxins nutrient conditions. In a recent review of FDA product
(e.g. aflatoxin) and pyrogens recalls, almost half (48 %) of them were due to
contamination by water-borne micro-organisms such as 19.5.3.1 Procedures

Burkholderia cepacia, Pseudomonas species, or The following procedures and measures concerning
Ralstonia pickettii [52]. facilities should mitigate the risk of microbiological
• Air. Micro-organisms may be carried over from dust or contamination:
soil particles and may be transported into manufacturing • Qualified Personnel. Only trained and qualified personnel
areas by personnel, material or airflow. Mould spores for should enter areas where products are manufactured or
instance were carried over from a highly contaminated prepared. Personnel should wear dedicated gowning
source into the production room [55]. which provides a physical barrier between the body and
• Equipment. Equipment may be contaminated if inappro- the working environment. The more critical the activity
priate cleaning, disinfection or sterilisation procedures or product microbiological requirements, the stricter the
have been performed. gowning. Gowning may consist for instance of overalls,
• Primary packaging. The microbiological quality of pri- face masks, gloves (which are disinfected with ethanol)
mary packaging material is critical for sterile or even goggles in case of aseptic processing. Personnel
preparations. Vials, ampoules and stoppers shall be sterile that have apparent illnesses or infected wounds should be
and free of pyrogens before filling. For non-sterile excluded from areas where open product is handled.
preparations the microbiological quality of the packaging Chapter Aseptic handling (Sect. 31.3.3) also discusses
material is less critical. Because of the production pro- gowning.
cess, bottles, tubes etc. will have only low levels of • Basic hygiene. Whereas the manufacturing of the most
contamination, provided they have been packed, stored microbiological-critical products (e.g. parenteral, intrave-
and handled under appropriate conditions. nous products) is strictly regulated and inspected, their
Secondary contamination may occur during storage, trans- preparation and application in hospitals is less subject to
port, and administration of the product. The root cause for control. Nevertheless, measures to prevent microbial con-
contamination during storage and transport is mainly insuf- tamination or proliferation are equally, if not more impor-
ficient closure integrity (see Sect. 24.3). Contamination dur- tant in this case. Basic hygiene rules include e.g. regular
ing administration can be avoided by suitable design of the cleaning and if appropriate disinfecting the hands with
primary package (see Sect. 24.1) and appropriate instruction alcohols, wearing sterile gloves for the preparation of
of the medical staff or patient (see Sect. 37.4). Tubes are less parenterals, disinfecting the outer surface of critical
prone to contamination than jars. In hospitals eye drops products before opening. See Chap. 31 for detailed
should only be used for one specific patient and preferably instructions on microbiological monitoring, disinfection
for one specific eye. procedures, operator qualification and validation of asep-
tic handling.
19.5.3 Prevention of Microbial Contamination For basic hygiene at the preparation of non-sterile
medicines the main points are given here.
Microbiological quality assurance and microbiological qual- Contact between the product and the operator is to
ity control should be part of the pharmaceutical quality be prevented. Thus:
system of any production site. Its main aim is to prevent • Equipment and production processes shall be
microbial contamination in case of products required to be designed so that direct contact between operator
sterile (e.g. parenteral medicines), or to reduce the microbial and product is minimised.
counts and avoid objectionable micro-organisms in case of • Under no condition shall the product be touched
non-sterile products (e.g. tablets). The elements of a Phar- with bare hands. If manipulation is unavoidable use
maceutical Quality System (PQS) that are crucial for utensils, such as forceps, or wear gloves. Gloves
microbiological quality regard adequate design of premises, shall be changed when appropriate, particularly at
procedures and controls. They are discussed in this section. every preparation and after obvious contamination
The principles are included in current Good Manufacturing such as sneezing and wiping the nose.
Practices (cGMP) guidelines (see Sect. 35.5.7), which are • Refrain from talking above the product. Coughing
legally binding for pharmaceutical manufacturers. and particularly sneezing are difficult to suppress.
Microbiological quality assurance (QA) refers to the Wearing a facial mask and changing it at least every
procedures in the quality system that ensures that 2 h will considerably reduce the risk of contamina-
microbiological requirements of the product are fulfilled. tion by this route. The operator shall inform his or
Microbiological quality control (QC) refers to the tests her superior in case of a disease such as a cold.
performed to verify that the product meets the required
specifications. (continued)
19 Microbiology 395
and 27.3). Clean room design should ensure that air,

• Facial hair shall be appropriately covered; this may personnel and material flow is optimal to prevent micro-
require the wearing of a head cover and a facial bial contamination from a less clean area to a cleaner
mask to cover moustaches and beards. This is also area. Isolators have been introduced as an alternative to
necessary from a safety point of view when conventional clean rooms for aseptic production. These
operating with rotating equipment such as an may be large installations, in which complex operations
ointment mill. such as large-scale aseptic filling of syringes can be
From a pure microbiological viewpoint wearing an performed.
overall doesn’t make sense other than the promotion Controlled environments also regard to aseptic
of an attitude of working cleanly and neatly. Already handling in pharmacies, where they are achieved using
after 1–2 h the overall bears as much contamination as laminar flow cabinets, biological safety cabinets or
the personal clothing. Directions for clothing are how- isolators (see Sect. 28.4).
ever also necessary to promote occupational safety and • Cleaning and disinfection. The procedures for cleaning
health (see Sect. 26.4.3). The overall has to remain in and disinfection (destruction of micro-organisms – but
the preparation area (thus taken off at lunch and coffee not necessarily spores – by chemical agents, see Sect.
PRODUCT DESIGN
breaks) and has to be cleaned according fixed schemes, 31.4.3) of equipment parts that are in contact with the
such as daily and when visibly contaminated. The product have to be validated. In addition, for the more
overall shall have long sleeves and cover completely critical products that are required to be sterile, the equip-
personal clothing. ment parts that are in contact with the product need to be
Washing hands must always occur: sterilised. Sterilisation (destruction of micro-organisms
• At the start of preparation including spores by heat) process of the manufacturing
• If hands are visibly dirty lines has also to be validated. For products, which are
• After using the toilets required to be sterile, the aseptic status of the production
• After sneezing and wiping the nose line is regularly evaluated by performing media fill
• Between two different preparation processes, simulations that consist of replacing the product with a
because of cross contamination microbial culture medium and evaluating if filled-media
Nails have to be kept short and proper hand washing containers remain sterile.
procedures include removal of watches, voluminous • Reducing bioburden. The preparation processes may
rings and bracelets (remaining off during the prepara- reduce or even eliminate living micro-organisms. For
tion process). instance on the preparation of tablets, the tableting of a
Washing hands technique requires preferably luke- granulate into a tablet may kill non-spore forming micro-
warm water, soap from a dispenser, proper attention to organisms by the shearing forces of the interparticulate
thumbs, sufficient duration and proper drying with a movement. Products required to be sterile are either ster-
towel because that will carry off micro-organisms too. ile filtered (filter 0.2 μm pore diameter, see Sect. 30.6)
or terminally sterilised directly in their container or pack-
age (e.g. steam sterilisation (Sect. 30.5.1), radiation (Sect.
30.5.3), ethylene oxide gas (30.5.4)).
• Controlled environments. Clean rooms in which pharma- • Water distribution system. The distribution and storage
ceutical preparations are prepared processed, and packed systems for water that is used for cleaning, sterilisation
are controlled for room pressure, humidity and tempera- and preparation should be devoid of biofilms. A distribu-
ture. They are segregated from other operating areas and tion system may be controlled by continuously
may be entered via separate air locks for personnel and circulating heated water (>80 C) in loops, avoiding
material. The incoming air of the clean rooms is filtered one-way systems and dead ends, and application of disin-
using HEPA (high efficiency particulate air) filters that fection steps such as adding ozone to the re-circulating
may retain more than 99.995 % of 0.3 μm air particles water (see Sect. 27.5.2). The latter processes are often
(see Table 27.4). The higher the microbiological quality called sanitisation. In addition to the physico-chemical
of the product or the critical the process step, the higher characteristics, water is monitored for microbiological
the clean room quality criteria. For instance in aseptic counts. For preparation on a smaller scale, the storage
processing of sterile products for critical areas where the of water should follow strict requirements as well, see
product is exposed to the surrounding environment, the further Sect. 23.3.1.
air should not contain more than 3,520 particles of 0.5 μm • Standing time. Other risk mitigating actions may include
size per cubic metre and should be devoid of viable defining maximum standing times for intermediate or
micro-organisms (see air classifications in Tables 27.2 final aqueous solutions if microbial growth is to be
expected, performing internal audits to ensure that

procedures are followed, and testing the product’s con- Compounding Center (NECC) meningitis outbreak in
tainer closure integrity. the USA [56]. On October 4, 2012, the CDC
(US Centers for Disease Control) and the FDA
(US Food and Drug Administration) issued a recall
19.5.3.2 Tests alert for pharmaceutical preparations produced by the
Microbiological testing is performed to monitor the NECC, following a multistate outbreak of fungal men-
microbiological bioburden and to ensure that the final prod- ingitis and other infections among patients who
uct complies with the regulatory microbiological received contaminated preservative-free methylpred-
specifications. It comprises: nisolone acetate epidural injections. Most patients suf-
• An environmental monitoring program in order to moni- fered infection by the fungus Exserohilum rostratum
tor the microbiological levels of classified rooms. Air, and in August 2013, CDC reported 749 cases and
product-contacting surfaces, working surfaces, floors and 63 deaths. After performing microbiological testing
personnel are sampled. Frequency and sampling locations of the unopened incriminated product lots, CDC con-
are defined based on a risk assessment. Maximum firmed presence of Exserohilum rostratum, along with
microbiological count levels should be defined either other fungi (e.g. Cladosporium cladosporioide, Asper-
based on historical data or on regulatory guidelines. If gillus fumigatus) and spore-forming bacteria
they are exceeded, this may signal a deviation from (e.g. Bacillus subtilis) [57]. After inspecting the
normal conditions that would require an investigation NECC preparation area, the FDA mentions in its
and an evaluation on the impact on the respective product report [58] that moulds and bacteria were found in
produced. Trending of environmental results may also be large numbers in many air and surface samples
performed in order to evaluate shifts in the overall where the products were prepared.
hygienic conditions over an extended period of time
to define appropriate corrective actions. See also
Sect. 31.6.1.
• Testing of primary packaging materials, raw materials
(excipients, active substances, water) and products 19.5.4 Elimination and Destruction of Micro-
according to internal or official methods and organisms
specifications. Microbial limits of pharmaceutical
preparations are given in relevant monographs of the A number of physical and chemical techniques to eliminate
European Pharmacopoeia. Section 19.6 provides a deeper or to destroy micro-organisms may be employed in order to
insight on the European test methods of pharmaceutical assure that the microbiological quality of the product
preparations and acceptance criteria. complies with pharmacopoeial requirements, immediately
• Monitoring water distribution and storage system. after production and throughout its shelf life. Since these
• Root cause investigation (see Sect. 35.6.15). When a test techniques are discussed in detail in other chapters, they are
does not fulfil a microbiological acceptance criterion, this mentioned only briefly.
is considered as a deviation or out of specification result.
This requires an investigation to determine the root cause
19.5.4.1 Physical Removal of Micro-organisms
of contamination, e.g. whether it occurred during labora-
Physical removal of micro-organisms (filtration, see Sect.
tory testing, sampling or manufacturing. If a source of
30.6) is applied for gases and liquids. High Efficiency Particu-
contamination has been found, corrective and preventive
late Air (HEPA) filters are used to remove viable and
actions are put in place to eliminate and prevent
non-viable particles from the air introduced in classified work-
re-occurrence of the contamination.
ing areas (see Sect. 27.5.1). Hydrophobic membrane filters are
used as vent filters on tanks and to filter production gases.
Failure to meet measures to prevent microbiological Membrane filtration of liquids is applied to reduce the
contamination of pharmaceutical preparations may bioburden of raw materials and of final products (see Sect.
have dramatic consequences. A major health issue 30.6). In an aseptic process, membrane filtration is the final
related to microbiologically contaminated pharmaceu- step before filling. During the production of a terminally
tical preparations was the 2012 New England sterilised product membrane filtration is applied to reduce
the bioburden.
(continued)
19 Microbiology 397
19.5.4.2 Physical Destruction of Micro-organisms release test for industrially manufactured sterile products.
Micro-organisms may be physically destroyed by means of Only under specific conditions, including an excellent track
dry heat (see Sect. 30.5.2), moist heat (see Sect. 30.5.1) and record and a high level GMP, national authorities may grant
ionising radiation (see Sect. 30.5.3). a product and site-specific approval for parametric release
Dry heat sterilisation is primarily applied for glassware and (release without performing a sterility test) (see Sect. 32.8).
some heat stable raw materials. The standard temperature is For many products prepared in hospital pharmacies or in
between 160 C and 180 C. Ointments and some powders institutions such as blood banks, the batch size is too small
may be treated at lower temperatures because they are not (one or only a few units) or the shelf life is too short
stable enough. Higher temperatures (250 C and above) are (<14 days) to perform a complete sterility test as described
used for the depyrogenation and sterilisation of glass vials. in pharmacopoeias. In such instances, such as with radio-
Moist heat sterilisation at 121 C for 15 min is the method pharmaceuticals (see Sect. 15.6.7), the pharmacist has to rely
of choice for terminal sterilisation of finished products. on the aseptic precautions during preparation (see Sect. 31.6).
Sterilisation by means of ionising radiation of pharma- The use of rapid microbiological methods (RMMs) may also
ceutical preparations is not allowed in a number of countries. be an alternative to test products with such short shelf lives.
Many active substances and raw materials are decomposed The objective of the sterility test is obviously to demon-
PRODUCT DESIGN
by the doses required for sterilisation. Some polymers strate that a batch is sterile, i.e. does not contain any viable
become brittle and glass may become discoloured. For micro-organism. There is an on-going debate on the rationale
these reasons there is only limited application for this of the sterility test. The test is a destructive one and relatively
sterilisation method for pharmaceutical preparations. Radia- small samples are taken from the batch. The results cannot be
tion sterilisation is however widely used in the medical extrapolated to items that have not been examined. For ter-
device industry. minally sterilised products a limit (Sterility Assurance Level,
SAL of 106) has been imposed for which there is no appro-
priate test methodology of sufficient sensitivity. The test will
19.5.4.3 Chemical Destruction of Micro-organisms
only detect those micro-organisms capable of growing to
Disinfection, sanitisation, decontamination, chemical
detectable levels under the defined incubation conditions
sterilisation, are only a few terms for these processes. Disin-
(media, temperatures and time). The sterility test is however
fection, defined as removal, destruction or de-activation of
the last possibility to detect any gross error in the production
micro-organisms on objects or surfaces, is the term of pref-
process. This means that applying an appropriate quality
erence in this book.
system with stable and well-controlled preparation and
Disinfection of surfaces (gloves, equipment, floors and
sterilisation processes (and not just performing a sterility
walls) is done with a range of products, including isopropyl
test on the final product) is the key to ensure that a product
alcohol, ethanol, quaternary ammonium compounds,
that purports to be sterile remains free of microbial contami-
biguanides and amphoteric agents. If a sporicidal activity is
nation. Regulatory initiatives strengthen the view that quality
required (as alcohols are not sporicidal), oxidising agents
cannot be assured by final product testing, but should rather
such as chlorine/hypochlorite, peracetic acid, or hydrogen
be assured by appropriate design of the manufacturing pro-
peroxide may be used.
cess (see Sect. 35.3). Consequently, these initiatives empha-
For medical devices a number of processes are available
sise process understanding and monitoring over final product
such as ethylene oxide and low-temperature hydrogen per-
testing. For the way in which the process is monitored to
oxide gas plasma sterilisation.
ensure sterility during aseptic handling, see Sect. 31.6.1.
The objective of preservation is to assure the
After several years of negotiation the sterility tests of the
microbiological quality throughout storage and the period
European Pharmacopoeia, The United States Pharmacopeia
of use. A number of substances, including parabens, chlor-
and the Japanese Pharmacopoeia are harmonised [59]. In the
hexidine, and sorbic acid are used (see Sect. 23.8).
next sections the five steps of this harmonised test, as
described in Ph. Eur. 2.6.1 will be discussed: sampling,
sample preparation, inoculation, incubation, and interpreta-
19.6 Examination of Pharmaceutical tion. Prior to the routine application of the test, a suitability
Products test with a range of specified test organisms shall demon-
strate that growth of these organisms is not inhibited due to
19.6.1 Sterility Test residual antimicrobial activity of the product.
Sterility tests appeared in the British Pharmacopoeia for the 19.6.1.1 Sampling
first time in 1932 and in the United States Pharmacopeia in The monograph specifies the minimum number of items
1936 [59]. Currently sterility testing is a legally binding that shall be examined in relationship to the batch size,
and the minimum volume/amount that shall be taken organisms. Limits depend on the route of administration,
from each container. The samples used should be repre- the nature of raw materials, the type of micro-organism,
sentative for the whole batch. Furthermore immediately and on the fact whether an antimicrobial treatment can be
after an intervention in an aseptic filling operation given to the product (cf. Table 19.1 for a few examples).
(e.g. re-adjustment of a filling needle) the probability of The more stringent criteria for the aqueous preparations
contamination may be increased, and specific sampling for than for non-aqueous oral preparations reflect the greater
sterility testing may be justified. This has to be specified in potential for microbial growth of the former. E. coli must
relevant procedures. be absent from most of the preparations because this is an
indicator organism for poor hygiene during production, or
19.6.1.2 Sample Preparation poor microbiological quality of the raw materials.
Sample preparation includes all operations necessary before Products intended for inhalation must be free of Staphy-
the actual examination can be performed, including opening lococcus aureus, because it may cause pulmonary infections.
of the primary packaging, withdrawal of the required This organism also indicates poor hygiene during produc-
amount and, if necessary, dilution or dissolution of the tion. Pseudomonas aeruginosa should be absent as well,
sample in a suitable liquid. because this organism may cause serious lung infections.
Because of the aqueous nature of these products the presence
19.6.1.3 Inoculation of this organism and other bile tolerant gram-negative bac-
The technique of membrane filtration is used whenever the teria is a serious potential risk. Bile tolerant gram-negative
nature of the product permits. The membrane is transferred bacteria form a complex group of micro-organisms compris-
to the growth medium, or the medium is transferred onto ing of the Enterobacteriaceae and many other strains (for-
the membrane. Alternatively, the prepared sample is merly Pseudomonads), including Burkholderia cepacia [63]
inoculated directly into the appropriate media. This method and Ralstonia pickettii [64]. Burkholderia cepacia is a
is only used when the product (e.g. some vaccines) cannot waterborne organism and causes great problems to the phar-
be dissolved or diluted in a nontoxic diluent. The media maceutical industry and hospitals. It may be resistant to
used are fluid thioglycolate medium (FTM) for aerobic, many commonly used disinfectants and preservatives, such
micro-aerophilic and anaerobic bacteria, and Soybean as chlorhexidine, and it may cause serious lung infections,
casein digest broth (SCDB) for aerobic bacteria and particularly in compromised hosts, such as cystic fibrosis
fungi. FTM and SCDB are incubated at 30–35 C and patients. Salmonella must be absent from 25 g of herbal
20–25 C respectively, both for a period of not less than preparations. This reflects the low infectious dose of this
14 days. This relatively long incubation period seems to be organism and the severity of infections.
justified, because an unacceptable proportion of Test methods for the microbiological examination are
contaminants would be missed by limiting incubation to described in Ph. Eur. Sections 2.6.12 [65] and 2.6.13 [66]
7 days [60]. respectively. Section 2.6.12 describes qualitative methods
for the determination of the total aerobic microbial count
19.6.1.4 Interpretation and the total yeast and mould count. Section 2.6.13 describes
The media are examined at intervals and at the end of the tests for specified organisms.
incubation period. If no growth is visually observed the
sample passes the test. Normally the sample shall be rejected
if growth is observed in at least one of the media. However 19.6.3 TAMC and TYMC
under certain conditions the test may be invalidated and in
that case be repeated. The total aerobic microbial count (TAMC) is defined as the
number of colonies observed on casein soya bean digest
agar. The total combined yeast and mould count (TYMC)
19.6.2 Requirements for Non-sterile Products is defined as the number of colonies observed on Sabouraud-
and Raw Materials dextrose agar. The assessment consists of four steps: sam-
pling, sample preparation/testing, incubation, and
Sections 5.1.4 and 5.1.8 of the European Pharmacopoeia [61, interpretation.
62] specifies microbiological quality criteria for non-sterile
pharmaceutical preparations and raw materials. They are 19.6.3.1 Sampling
stated as Total Aerobic Microbial Count (TAMC) and In general the sample size shall be 10 g or 10 mL. An
Total combined Yeast and Mould Count (TYMC) (see exception is made for those active substances for which the
Sect. 19.6.3) and requirements regarding specific micro- amount per dosage unit or per 1 g or 1 mL (for preparations
19 Microbiology 399
Table 19.1 Microbiological quality criteria of some pharmaceutical preparations

TAMC TYMC
(CFUa/g or (CFU/g or
Route of administration CFU/mL) CFU/mL) Specified micro-organisms
Non-aqueous preparations for oral use 103 102 Absence of Escherichia coli
(1 g or 1 mL)
Aqueous preparations for oral use 102 101 Absence of Escherichia coli
(1 g or 1 mL)
Rectal use 103 102 –
Oromucosal use 102 101 Absence of Staphylococcus aureus
Gingival use (1 g or 1 mL)
Cutaneous use Absence of Pseudomonas aeruginosa
Nasal use (1 g or 1 mL)
Auriculair use
Vaginal use 102 101 Absence of Pseudomonas aeruginosa
(1 g or 1 mL)
Absence of Staphylococcus aureus
PRODUCT DESIGN
(1 g or 1 mL)
Absence of Candida albicans
(1 g or 1 mL)
Transdermal patches (limits for one patch including 102 101 Absence of Staphylococcus aureus
adhesive layer and backing) (1 patch)
Absence of Pseudomonas aeruginosa
(1 patch)
Inhalation use (special requirements apply to liquid 102 101 Absence of Staphylococcus aureus
preparations for nebulisation) (1 g or 1 mL)
Absence of Pseudomonas aeruginosa
(1 g or 1 mL)
Absence of bile-tolerant gram-
negative bacteria (1 g or 1 mL)
Special Ph. Eur. Provision for oral dosage forms containing raw 104 102 Not more than 102 CFU of bile-tolerant
materials of natural (animal, vegetal or mineral) origin for which gram-negative bacteria (1 g or 1 mL)
antimicrobial pretreatment is not feasible and for which the competent Absence of Salmonella (10 g or 10 mL)
authority accepts TAMC of the raw material exceeding 103 CFU/g or Absence of Escherichia coli
CFU/mL (1 g or 1 mL)
Absence of Staphylococcus aureus
(1 g or 1 mL)
a
Colony forming unit (CFU): One or more micro-organisms that produce a visible, discrete growth entity on a semisolid, agar-based
microbiological medium
not presented in dose units) is less than 1 mg or 1 mL. In 19.6.3.3 Testing/Incubation

these cases the amount to be tested shall be not less than the Three methods may be used for the enumeration: membrane
amount in 10 dosage units or in 10 g or 10 mL of the product. filtration, plate count, and most probable number (MPN)
Any sample shall be representative for the whole batch. method. The advantages of the membrane filter method are
However batch sizes may range from extremely small its low limit of detection (LOD) of < 1 CFU/g or mL and
(e.g. for some biotechnological products) to very large the efficient separation of the micro-organisms from
(e.g. a batch of tablets). The Ph. Eur. does not describe components of the product, particularly antimicrobial
how the samples shall be taken and this must be put down agents. For the pour-plate method, the sample is generally
in local procedures. 1: 10 dissolved in the diluent, and 1 mL of the dilution
is mixed with the agar. This corresponds to a LOD of
10 CFU/g or mL. The LOD is sometimes higher
19.6.3.2 Sample Preparation (e.g. 100 CFU/g or mL) if the product needs to be further
If necessary the sample is dissolved and diluted in a suitable diluted due to microbial inhibition, or lower in case of
non-toxic diluent. Buffered sodium chloride-peptone solu- products with low microbial acceptance criteria. If the
tion to which an emulsifier and/or a neutraliser for antimi- spread plate count technique is used the LOD is a factor of
crobial agents may be added is widely used. ten higher (>100 CFU/g or mL), because only 0.1 mL of the
dilution can be spread over the surface of the agar plate. The those by Candida albicans have emerged as important
precision and accuracy of the MPN method is less than that of causes of morbidity and mortality in immunocompromised
the membrane filtration and the plate count methods. Unreli- patients (e.g., patients with AIDS, cancer chemotherapy, and
able results are particularly obtained for moulds. For these transplantations). Candida albicans biofilms may form on
reasons the MPN method is reserved for the enumeration of the surface of implantable medical devices. In addition,
TAMC in situations where no other method is available. hospital-acquired infections by Candida albicans have
Casein soya bean digest agar is incubated for 3–5 days at become a cause of major health concerns.
30–35 C. Sabouraud dextrose agar is incubated for 5–7 days In addition to these well-known organisms it has however
at 20–25 C. Duplicate plates are prepared for each dilution been demonstrated that other organisms (e.g. Burkholderia
and each medium. If the MPN method is used the tubes are cepacia, or Ralstonia pickettii) can cause infection when
incubated for 3–5 days at 30–35 C. present in pharmaceutical preparations. For this reason the
concept of ‘objectionable organisms’ was originally
19.6.3.4 Interpretation introduced in the USA. Objectionable micro-organisms are
At the end of the incubation period the colonies on the plates defined as contaminants that, depending on the
are enumerated. The number of CFU per gram or per mL of microbiological species, would adversely affect product
product is calculated for each medium from the arithmetic safety and product quality. So the assessment of microbial
means of the plates. Because of the relatively poor accuracy safety of a medicine has to include the examination of
and precision of microbiological enumerations, according to absence of objectionable micro-organisms as well. One
the Ph. Eur. an acceptance criterion may be interpreted as approach to determine whether an organism is objectionable
follows: is to perform a risk analysis [55], see also Chap. 21. Such an
101 CFU: maximum acceptable count is 20 analysis should address at least four issues:
102 CFU: maximum acceptable count is 200; etc. • Potential level of microbial contamination (total aerobic
microbial count, total yeast and mould count)
• Identity and characteristics of possible micro-organisms
19.6.4 Specified Micro-organisms present (pathogenicity, ability to metabolise product
components, ability to survive or even grow in the
The group of specified micro-organisms is a limited group of conditions of the product)
organisms which may be either pathogenic, or are indicator • Product characteristics (presence of antimicrobials, water
organisms for lack of hygiene during production. This group activity, route of administration, container and closure
includes a number of organisms that have been discussed in design)
a previous section, viz. Escherichia coli, Staphylococcus • Potential impact on patients (for instance: is the prepara-
aureus, Pseudomonas aeruginosa, and bile tolerant gram- tion meant for immunocompromised patients or for
negative bacteria. The group also includes: Salmonella, neonates)
Clostridium, and Candida albicans. Tests for the detection The examination of pharmaceutical preparations for
of these organisms are described in the pharmacopoeias specified micro-organisms involves generally the following
(e.g. Ph. Eur. 2.6.13 [65]). steps: sampling, sample preparation, resuscitation and
Salmonella belongs to the family of the Enterobac- enrichment, incubation on diagnostic or selective media,
teriaceae. Over 2,000 species are known. Salmonellae are and evaluation. Sampling and sample preparation is basi-
differentiated by means of biochemical reactions and by cally the same as for TAMC and TYMC determination and
serotyping. Salmonellae are pathogenic bacteria causing will not be further discussed.
food poisoning. The bacterium is present in many free-living
and domesticated animals. Pharmaceutical raw materials 19.6.4.1 Resuscitation and Pre-enrichment
that have been contaminated include carmine, pancreatic As a result of mild heat treatment, drying, or chemical
powder and thyroid powder. antimicrobial treatment, cells may be sublethally injured. A
Bacteria from the genus Clostridium are anaerobic, cell is, by definition, sublethally injured if it is unable to
sporeforming gram-positive rods. The spores are heat- grow on a selective medium that is typically suitable for
resistant and can survive in foods that are incorrectly or normal healthy cells of that type. Sublethally injured cells
minimally processed. The genus contains a number of dan- may recover when transferred to a suitable non-selective
gerous pathogens, including Clostridium botulinum, Clos- medium and thus regain all their normal characteristics,
tridium difficile, and Clostridium tetani. including resistance to selective antimicrobial agents and
Candida albicans is a fungus that grows both as yeast and pathogenicity. This recovery process is called resuscitation.
filamentous cells and is a causal agent of oral and genital The examination of non-sterile pharmaceutical products
infections in humans. Systemic fungal infections including for the presence of specified micro-organisms involves one or
19 Microbiology 401
Table 19.2 Media for the detection of specified micro-organisms

Specified micro-organism Resuscitation + non-selective enrichment Selective enrichment Diagnostic media
Bile-tolerant gram-negative bacteria TSB EE broth VRBG
Escherichia coli TSB McConkey broth McConkey Agar 42–44 C
Salmonella TSB Rappaport Vasiliades medium XLD
Pseudomonas aeruginosa TSB – Cetrimide agar
Staphylococcus aureus TSB – MSA
Clostridia Reinforced medium for Clostridia – Columbia agar
Candida albicans SDB – SDA
more steps with selective media. To increase the likelihood of alternative method is suitable for its intended purpose. This
detecting sublethally injured micro-organisms, the product is validation is based on demonstrating at least equivalent
initially incubated in a non-selective (enrichment) medium. performance of the RMM compared to the traditional
This non-selective culture thus may serve a twofold purpose: method and is performed according to Ph. Eur. 5.1.6., USP
to first resuscitate sub-lethally injured cells and, secondarily, <1,223 > or PDA TR-33 [68–70].
PRODUCT DESIGN
to facilitate their growth for purposes of further isolation and It is beyond the scope of this chapter to discuss all
identification. For some organisms a second enrichment step available technologies, just one example of each of three
in a selective medium is include in the method. Table 19.2 detection principles will be mentioned here, viz., a growth
gives an overview of the purposes of the media used for each based method, a non-growth based method and a nucleic
(group of) specified micro-organisms. acid determination method. For an encyclopaedic overview
If there is no growth in the selective medium, the the reader is referred to the literature [71].
corresponding specified micro-organism is absent and the
product complies with the requirement. If there is typical 19.6.5.1 Growth Based Method: ATP
growth in the diagnostic medium a confirmation of the Bioluminescence
presence of the specified micro-organism should be ATP is a metabolite present in all organisms (excluding
performed using either biochemical tests or other identifica- viruses). The amount of ATP per cell is species-dependent
tion methods (e.g. 16S rDNA sequencing). and also is dependent on the metabolic state of the cell. ATP
can be measured semi-quantitatively with the luciferin/lucifer-
ase system. This system (naturally occurring in the firefly) emits
19.6.5 Alternative Methods light in the presence of ATP. The sample is mixed with a special
reagent, which causes lysis of the cells, liberating the ATP,
In the previous sections only the conventional microbiological followed by addition of the luciferin and luciferase reagents.
methods, developed in the late ninetieth and first half of the The amount of emitted light is measured by means of a
twentieth century, have been discussed. All these methods are photomultiplier system and used as an indicator of the number
growth-based methods that have their own limitations (long of cells present. This principle can be applied for numerous
incubation periods, only viable micro-organisms that also purposes, such as the detection of micro-organisms in products
grow on the media can be recovered, variability in nutrient or monitoring of cleaning and disinfection procedures. Its use
media quality, etc.). In the past decades many new has been suggested for microbiological examination of sterile
technologies have been developed with the first aim to reduce and non-sterile pharmaceutical preparations [72, 73].
the time to obtain results of microbiological testing.
The use of such rapid microbiological methods (RMM) is 19.6.5.2 Non-growth Based Method: Solid State
beneficial in terms of reduction of throughput time for Laser Scanning Cytometry
release (especially of parenterals), early identification of A sample is filtered over a membrane filter and treated with a
product contaminations, allows for causal investigations to fluorogenic reagent. Living cells actively take up the reagent
be carried out earlier, making it easier to find and eliminate and convert it to a fluorescent substance. The filter is
contamination causes [67]. For short shelf life products scanned with a laser beam and the fluorescence is measured.
(<14 days), rapid microbiological methods are essential The system records the position of the fluorescent item, so
for assessing microbiological safety. In addition, automation that it can be verified microscopically that the signal was not
by alternative methods enables to reduce hands-on time, due to an artefact. The method is able to detect a single cell
human error and paperless data recording. within about 2 h post sample processing and testing. It is
Before microbiological testing can be performed with an used to monitor large water systems in pharmaceutical
alternative method, the user must demonstrate that the plants [74].
19.6.5.3 Nucleic Acid Based Identification: identity of cell substrates and viruses used in vaccine production. J
Virol Methods 179:201–211
Ribotyping 17. Chen D, Nims R, Dusing S, Miller P, Luo W, Quertinmont M,
Ribotyping measures the pattern that is generated when Parekh B, Poorbaugh J, Boose JA, Atkinson EM (2008) Root cause
DNA from an organism is treated with a restriction enzyme. investigation of a viral contamination incident occurred during
DNA is isolated from a pure culture. The genes encoding for master cell bank (MCB) testing and characterization–a case study.
Biologicals 36:393–402
16S rRNA are amplified with PCR, treated with one or more
18. Kekarainen T, Martinez-Guino L, Segales J (2009) Swine torque
restriction enzymes, separated by means of electrophoresis teno virus detection in pig commercial vaccines, enzymes for
and finally probed. The obtained genetic fingerprint is a laboratory use and human drugs containing components of porcine
stable marker that provides definitive species discrimination origin. J Gen Virol 90:648–653
19. Pastoret PP (2010) Human and animal vaccine contaminations.
or even characterisation below species level.
Biologicals 38:332–334
20. Bouzon AM, Diez DJ, Martinon-Torres F (2011) Circovirus and
impact of temporary withdrawal of rotavirus vaccines in Spain.
Hum Vaccin 7:798–799
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26 Sept 2013
Statistics
20
Herman Wijnne and Hans van Rooij
Contents Abstract
Preparation, manufacturing, quality control and dispens-
20.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
ing of medicinal products have always been associated
20.2 Basic Statistical Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 with the pharmacist. Traditionally the pharmacist has
20.2.1 Population and Sample . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
20.2.2 Central Value and Measures therefore been trained in pharmaceutical analysis, focus-
of Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 ing on analytical measurement of quality characteristics
20.2.3 Random and Systematic Errors . . . . . . . . . . . . . . . . . . . . . . . . . . 408 (identity, strength and purity) but the pharmacist was
20.3 Confidence Intervals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 marginally trained in statistical quality control that is
20.3.1 Probability and Confidence Intervals . . . . . . . . . . . . . . . . . . . . 408 related to manufacturing processes.
20.3.2 Confidence Interval of μ if the Standard Deviation The routine measurement of a characteristic or quan-
of the Population is Known . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
20.3.3 Confidence Interval of μ if the Standard Deviation
tity in a dosage form by an accurate and highly precise
of the Population is not Known . . . . . . . . . . . . . . . . . . . . . . . . . . . .411 analytical method will reduce the risk of rejecting batches
20.3.4 Confidence Interval of the Variance σ2, and the Standard when these truly comply or alternatively reduce the risk
Deviation σ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 of falsely accepting batches, when batches do not comply.
20.3.5 Outliers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
The collection of analytical data or data with format go
20.4 Acceptance Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 no-go is meaningless without a conclusion on rejection or
20.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
acceptance of a batch. In addition, a decision is worthless
20.4.2 Operating Characteristic (OC) Curves . . . . . . . . . . . . . . . . . . . 413
20.4.3 Acceptance Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 when not properly based on sound scientific statistical
20.4.4 Acceptance by Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 principles: a carefully conceived sampling plan that
20.4.5 Acceptance by Attributes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416 considers issues such as sample size and variability.
20.4.6 Content Uniformity of Dosage Forms . . . . . . . . . . . . . . . . . . . 418 The up scaling of production (batch size, numerous
20.5 Statistical Calculations and Numerical Operations . . 419 products in a single facility) and by consequence the up
20.5.1 Effect of More than One Deviation in a Process . . . . . . . . 419 scaling of complexity within industry as well as within
20.5.2 The Outcome is the Sum or Difference of Measurements 419
20.5.3 The Outcome is Obtained by Multiplying or Dividing
larger production facilities e.g. hospital pharmacies have
Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 led to the application of statistical quality control. Such
20.5.4 Rounding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 an approach has been in use since the middle of the past
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 century and is nowadays easy accessible by statistical
software programs.
This chapter discusses several statistical principles
that are used in pharmaceutical quality decisions, such
as: normal distribution, rounding, confidence interval,
standard deviation, outliers, operating characteristic
curves, acceptance sampling. Examples have been
H.J. Wijnne (*) embedded in a pharmaceutical context.
WynneConsult, Oostersebos 17, 7761 PS Schoonebeek,
The Netherlands
e-mail: [email protected] Keywords
Population Sample Confidence interval Standard
H.H. van Rooij
Independent Consultant and Qualified Person, OZ Voorburgwal 109N, deviation Outliers Acceptance sampling Content
1012 EM Amsterdam, The Netherlands uniformity

406 H.J. Wijnne and H.H. van Rooij
example the weight of the capsules. The set of all weights is

20.1 Introduction also called a population. In both cases, the population is
finite since the number of capsules in a batch is finite.
This chapter aims to refresh knowledge of basic statistical Populations may be finite or infinite. The set of true weights
principles [1] to which other chapters may refer as well. It of the capsules in a batch is an instance of a finite population,
may also be of use in providing relevant practical pharma- the set of distinct measurements of the weight of one specific
ceutical solutions to statistical problems. The chapter may be capsule (in principle) forms an infinite population.
of interest to all involved in the preparation of medicines
whether involved in large scale or small scale operations.
Including but not limited to: suppliers, buyers, QC state 20.2.1.2 Sample
laboratories, regulatory agencies, hospital pharmacists, qual- To study the properties of a (large or infinite) population a
ified persons and governmental auditors. limited number of elements of the population are chosen at
Population and sample are discussed in Sect. 20.2. The random. This subset of the population is called a sample.
properties of a population are studied in a representative The methods of drawing a sample from a population
random sample taken from that population. In pharmacy should be such that the sample is representative for the
preparation practice populations are for instance batches of population. In a random sample every element of the popu-
dosage units. Their properties are measured by analytical or lation has a defined (often an equal) chance of ending up in
biological assays and summarised as means, standard the sample.
deviations and many other sample statistics. Some basic A stratified sample is a sample where sets of elements
notions of probability distributions are briefly discussed. with certain characteristics are over- or under represented in
Confidence intervals are presented by simple mathemati- a planned way. For example the first 500 suppositories in a
cal formulas in Sect. 20.3 with examples from a pharmaceu- large production batch may be twice over represented with
tical control laboratory. Both Sects. (20.2 and 20.3) will lead the purpose of detecting starting up instability earlier in the
the reader to the conclusion that representative sampling, process. Sample statistics should of course be corrected for
sample size, variability, batch size and percentage defects this over- or under representation.
are highly interconnected. Functions on the sampled observations such as the
Section 20.4 explains and discusses the concept accep- sample mean, the sample standard deviation and many
tance sampling, its practices and interpretations. Performing others (see Sect. 20.2.2) are called (sample) statistics. They
assays on pharmaceutical preparations in a sample is not are random variables, which have a probability distribution.
sufficient warranty of quality, as valid conclusions with Observations from subsequent samples vary due to at least
respect to the population cannot be drawn without knowl- three sources of variation: deviations reflecting the variation
edge of the sampling method. Such conclusion would be in the population (e.g. variation of the true weights of the
acceptance or rejection of the batch. capsules in the batch), sampling error (deviations due to
For example, quality may consist of the correct content of differences between subsequent samples) and measurement
active principle in dosage units. Or quality may be errors.
questioned when glass-like particles are observed in a num- A sample statistic ideally is an unbiased estimator of the
ber of glass containers out of a large batch. The first example corresponding population parameter. An estimator is a ran-
is referred to as acceptance sampling by variables; the latter dom variable and is said to be unbiased, if upon an infinitely
is an example of sampling by attributes. large number of independent determinations its mean can be
The expressions producer’s risk, consumer’s risk, limit- proved to equal the true value of the parameter being
ing quality level (LQL) and acceptable quality level (AQL) estimated.
are explained in order to understand how important these
criteria are to warrant a high level of quality of medicines.
Finally, Sect. 20.5 completes this chapter by giving 20.2.2 Central Value and Measures
examples of statistical calculations and trivial numerical of Variation
operations encountered in daily practice. It includes how to
treat an apparent outlier. The arithmetic mean is a measure of the central value of a
population. It is defined as:
20.2 Basic Statistical Concepts 1X n
μ¼ xi ð20:1Þ
n i¼1
20.2.1 Population and Sample
i.e. the sum of the values of the variable (xi) considered,
20.2.1.1 Population divided by the number (n) of elements in the population. If
A population is a set of elements that match a certain the population is very large or infinite, its mean can only
description, such as a batch of capsules. Usually, a specific either be estimated from a random sample taken from the
characteristic of the elements is taken into consideration, for population, or its value can be derived from probability
20 Statistics 407
Histogram capsules weight Histogram capsules weight

n=20 n=2947
12 300
Mean 211.6
Mean 209.5
StDev 8.870 250 St Dev 8.503
10 N 20 N 2947
200
Frequency
8
Frequency
150
6
100
4 50
2 0
189 196 203 210 217 224 231 238
Weight (mg)
0
PRODUCT DESIGN
190 200 210 220 230 Fig. 20.2 Histogram of a large sample or population
Weight (mg)
Fig. 20.1 Histogram of capsule weights (n ¼ 20)

sample or population), the histogram appears to become
smoother. At an infinitely large number of observations
theory e.g. the mean of the standard normal distribution is by and an infinitesimally small class interval size a probability
definition zero. The calculated sample mean (m), density curve appears. Well known is the so called Gaussian
1X n or normal distribution, that applies to numerous situations in
m¼ xi ð20:1aÞ science e.g. the distribution of measurement errors, of
n i¼1
genetic variation or, generally, of the sum of a large number
is an unbiased estimate of the true mean (μ) of the of random variates, see Fig. 20.2. Other distributions are the
population. binomial distribution and the Poisson distribution.
Observed values of a population or sample show as a rule A quantitative measure of variation is the range, i.e. the
a certain degree of variation around the mean. There are a difference between the highest and the lowest value
number of options to quantify this variation. (if existing) in the population or in the sample. The signifi-
Observations or measurements are said to be accurate if cance of this parameter is limited because only two elements
they are unbiased estimates (Sect. 20.2.1) of the in the sample determine the degree of variation making it
corresponding true value, and are said to be precise unreliable.
(or reproducible) if their replicated measurements have low A more reliable measure of the variation of a population
variation. See Fig. 29.1 in chapter Basic Operations for a distribution is the standard deviation (σ):
schematic representation of accuracy and precision. X n
The term accuracy often is incorrectly used as precision is σ¼√ i¼1
ðμ xi Þ2 =n ð20:2Þ
meant and sometimes accuracy means accuracy and preci-
sion together. To avoid misunderstandings, it is i.e. the square root of the mean of the squared deviations of
recommended to use the terms accuracy and precision in the population values (xi) to the population mean (μ).
their proper meaning (see Sect. 32.16.6). Equation 20.2 is appropriate when the n elements form a
One option to quantify variability is to draw a graphical population, e.g. a batch consisting of 30 divided powders. If
representation of the frequency of certain values of the the n elements form a sample taken from a larger population
property concerned, called a histogram. The values are then Eq. 20.3 applies.
divided into classes. The standard deviation of the sample (s) when the popu-
Figure 20.1 Histogram of capsule weights (n ¼ 20) lation mean (μ) and standard deviation of the population (σ)
shows the weight distribution of a number of capsules in a are unknown is computed as:
histogram. It is a sample of 20 capsules with average X n
209.5 mg. The class interval size is 10 mg. The height of a s ¼√ i¼1
ðm xi Þ2 =ðn 1Þ ð20:3Þ
bar is a measure of the frequency.
When the number of observations is increased and the where m is defined in Eq. 20.1a and division is by n 1, the
class interval size is reduced (Fig. 20.2 Histogram of a large number of degrees of freedom.
The sample variance (s2) is an unbiased estimate (see 20.2.3 Random and Systematic Errors
Sect. 20.2.1) of the population variance (σ2), because it can
be proved that for k ! 1: Both random and systematic deviations may refer to the
2 actual properties of the elements in a population, but fre-
s1 þ s22 þ s23 þ . . . þ s2k =k ¼ σ2 ð20:3aÞ quently also to errors occurring during the manufacturing
process or errors occurring in the QC laboratory. The
Note that division in Eq. 20.3 by n instead of by n 1 weights of individual suppositories in a lot will exhibit
produces a biased, too small, estimate of the population random variation around the average, and when the wrong
variance. mold is used, the weights are systematically too high or
The population standard deviation of an analysis method too low.
will often be estimated from two or more duplicates, Another source of random or systematic deviations may
i.e. samples with n ¼ 2, taken from different populations: be the measurement process itself. When running a series of
X k six assays of the active substance in an oral solution, the
s ¼√ i¼1
d 2i =2k ð20:4Þ observed variability solely is caused by the analysis,
provided the active substance is completely dissolved in
where di ¼ the difference of two duplicate values, i ¼ 1, the solution and the solution is homogeneous.
2, . . ., k; k ¼ the number of duplicates; s has k degrees of Uncorrected background absorption in a spectrophoto-
freedom, since each independent duplicate attributes one metric UV–determination is an example of a systematic
(2 1) degree of freedom. error, caused by the measuring process. However, back-
The standard deviation has the same dimension as the ground absorption may also be caused by components from
mean to which it relates, e.g. 20 capsules, weighing the matrix in an unpredictable way and may then be random.
215.2 mg on the average may have a standard deviation The effect of random deviations on the determination of
amounting to 8.4 mg. the population mean can be eliminated by increasing the
To compare standard deviations the relative standard number of samples or the sample size. As a result the
deviation (rsd) or coefficient of variation, may be useful: observed mean approaches more and more the true mean
of the population. The effect of systematic deviations is
rsd ¼ s=m ð20:5Þ independent of the number of samples or the sample size,
and can only be eliminated by taking away the cause (the
The relative standard deviation is dimensionless and is correct suppository mold) or in case of the UV-determination
expressed in proportions or percentages. by correction for background absorption.
The standard deviation of a sample (Eq. 20.3) is an
estimate of the standard deviation of the corresponding
population distribution.
Quite a different notion is the distribution of a sample 20.3 Confidence Intervals
statistic such as the sample mean or the sample standard
deviation. For instance samples taken from a population 20.3.1 Probability and Confidence Intervals
with parameters μ and σ2 have themselves a distribution
with mean μ and variance σ 2m ¼ σ2 =n; where n is the sample When the population distribution is known, for example X is
size. The square root of σ 2m is often called the standard error normally distributed with mean μ and variance σ2, we may
of the mean or SEM: calculate the probability of X being equal to or larger than x
(X x). We use that principle for e.g. process control by
σm ¼ SEM ¼ σ=√n ð20:6Þ control charts. The production process has known targets for
μ and σ2 and when an uncommon value of variable X x is
If σ is unknown, it can be replaced by s, the sample standard observed, the production process should be adjusted.
deviation (Eq. 20.3). The equation expresses the well-known Very often the population is only known or assumed to
fact, that the sample mean becomes more precise with the have a normal (or other type of) distribution and we want to
reciprocal of the sample size. This ‘law of the large numbers’ estimate the unknown values of μ and σ2. To do that, we take
implies that for obvious reasons the standard error of the a sample from the population and determine the sample mean,
mean becomes zero if the sample size approaches infinity. m, and the variance of the sample, s2 (with n 1 degrees of
More generally the standard deviation of any statistic is freedom). Both are unbiased estimates (see Sect. 20.2.1) of
called a standard error of that statistic being a measure of the the corresponding population parameters μ and σ2, meaning
imprecision with which the statistic is determined. that, if we repeat the determination numerous times, the mean
20 Statistics 409
of all sample means approaches μ and, equally, the mean of The result should be interpreted carefully. We have only
all sample variances approaches the true value σ2. an estimate of the value of the population mean and we know
In practice, only one or a few determinations are that each time the limits of the confidence intervals change.
performed leaving us with uncertainty in the estimates of However, we can be confident that upon repeating the
the population parameters. assay sufficiently often, we approach the true value of μ
A confidence interval is then the interval of values of m more and more and that μ is within the calculated confidence
(or s2), that comprises the true value of μ (or σ2) in, say, 95 of intervals in say 95 % of the cases.
100 cases. The latter is called the confidence level and can be Confidence intervals provide a method of stating both
varied at will. In other words when we repeat the determina- how close the value of a statistic (e.g. the sample mean) is
tion a large number of times, we are sure that, in about 95 % likely to be to the value of a parameter (μ) and the probabil-
of the repetitions the true value of μ (or σ2) is captured by the ity of its being that close. Mark that the confidence level
confidence interval. 95 % is not the probability that the statistic is equal to the
An example is the assay of dexamethasone capsules using population parameter. It is a statement about our confidence
a sample of six capsules with observed mean m ¼ 97.4 % in the method we use to estimate the true value and to how
and standard deviation s ¼ 4.0 %. close we can come to it. Also the population parameter, μ, is
PRODUCT DESIGN
The 95 % confidence interval is (for details see a fixed value and has no probability distribution.
Sect. 20.3.2): The normal distribution is known as a bell shaped curve of
x against its probability density, f(x), and is characterised by
97:4 t5, 0:975 4:0=√6 < μ < 97:4 þ t5, 0:025 4:0√6 two parameters: the average, μ, and the variance, σ2, see
ð20:7Þ Fig. 20.3. The area under the probability density curve, f(x),
between two values, say x1 and x2, is equal to the chance of
where t5,0.025 (¼ 2.57) is the value of the t-distribution with finding a value between x1 and x2, P(x1 < X < x2), in the
6 1 ¼ 5 degrees of freedom and an upper tail probability population. If x1 ¼ 1 and x2 ¼ + 1 the area is equal to 1.
of 2.5 % and t5,0.975 (¼ 2.57) the lower tail probability of If μ ¼ 0 and σ2 ¼ 1 the normal distribution is called the
97.5 %. standard normal distribution. Any normally distributed
The lower limit of the 95 % confidence interval is 93.2 % variable, X, can be transformed to the variable Z that has
and the upper limit equals 101.5 %. the standard normal distribution through equation:
Mark that, when the determination is repeated again and
again, the confidence interval will change each time, Z ¼ ðX μ Þ = σ ð20:8Þ
because calculation of the upper and lower limits requires
the values of the sample mean and standard deviation whose Z can easily be seen to have the standard normal distribution
values will vary from sample to sample. with μ ¼ 0 and σ2 ¼ 1.
Fig. 20.3 Probability density Distribution Plot

function of the standard normal Normal, Mean=0, StDev=1
distribution with μ ¼ 0, σ 2 ¼ 1:
−1 6
5
65
96
.9
.6
Note:
−1
−1
1.
1.
1
68 % of the elements are between

0.4
μ + σ and μ – σ
Probability density function, f(z)
90 % of the elements are between

μ + 1.65σ and μ – 1.65σ
95 % of the elements are between 0.3
μ + 1.96σ and μ – 1.96σ
0.2
0.1
0.0
−3 −2 −1 0 1 2 3
Table 20.1 Upper tailed probabilities of the standard normal distribu- c

tion. More extensive tables for the standard normal distribution can be
found in books and on the internet b
z P (z < Z < 1) a
0.50 .3085
1.00 .1587 90 95 100
1.50 .0668 content (%)
1.645 .050
1.96 .025 Fig. 20.4 Confidence intervals (95 % confidence level).
2.00 .023 (a): μ ¼ 96.8, σ ¼ 0.8, n ¼ 1; 95 % confidence interval ¼ 96.8 1.6.
2.576 .005 (b): μ ¼ 96.8, σ ¼ 0.8, n ¼ 4; 95 % confidence interval ¼ 96.8 0.8.
(c): μ ¼ 96.8, s ¼ 0.6, n ¼ 4; 95 % confidence interval ¼ 96.8 0.95
3.00 .0013
Values of P (z < Z < 1) of the standard normal distri-

bution are called upper tail (or one-sided) probabilities. μ will be located in 95 out of 100 cases in the confidence
Since the normal distribution is symmetric, the lower tail interval. This is the double-sided 95 % confidence interval
probabilities P (1 < Z < z) have the same values as their of μ, the right-tailed form of the 95 % confidence interval is:
upper tail equivalents. They are usually tabulated as a func-
1 < μ < x þ 1:645 σ ð20:11Þ
tion of z in books and on internet sites, see Table 20.1 for a
small sample.
which says that the real value of μ will in 95 out of 100 cases
Thus from Table 20.1 it can be read that for the standard
be smaller than x + 1.645 σ. The value z0.95 ¼ 1.645
normal distribution a proportion of 1 2 0.1587 ¼ 0.683
corresponds to the upper tail probability of 0.05 in
or 68.3 % of the population is found between plus and minus
Table 20.1. The left tail confidence interval is analogous to
one standard deviation, σ, from the mean μ. The abscissa of
the upper tail interval.
the standard normal distribution is calibrated in standard
The sampling distribution of the mean of n independent
deviation units, see Fig. 20.3.
observations has mean μ and standard error equal to
Also for the standard normal distribution 2.5 % of the
elements is larger than 1.96, 2.5 % of the elements is smaller σm ¼ σ=√n, see Eq. 20.6.
than 1.96 and the remaining 95 % is between 1.96 and Assuming normal distribution of the sample mean, m, we
+1.96. Back transforming using Eq. 20.9 to the obtain for the 100(1α) % confidence interval:
corresponding normal distribution with parameters μ and
m zα=2 σ=√n < μ < m þ zα=2 σ=√n ð20:12Þ
σ2, 2.5 % of the elements is larger than μ + 1.96 σ, 2.5 %
of the elements is smaller than μ 1.96 σ and 95 % of the
where α/2 is the upper tail probability and zα/2 can be found
elements is between μ 1.96 σ and μ + 1.96 σ, i.e.
in Table 20.1. For instance zα/2 ¼ 1.96 if α/2 ¼ 0.025, giv-
μ 1:96 σ < x < μ þ 1:96 σ ð20:9Þ ing the 100(1 – 0.05) % ¼ 95 % confidence interval.
The width of the confidence interval is inversely propor-
comprises 95 % of the values of X, when X is normally tional to √n, which implies that if the sample size increases,
distributed with parameters μ and σ2, see also Fig. 20.3. the sample mean is a more precise, but not necessarily a more
So, if μ ¼ 100 and σ ¼ 5, X is between 100 1.96 5 accurate estimate of the population mean, see Fig. 20.4 Con-
¼ 90.2 and 100 + 1.96 5 ¼ 109.8. fidence intervals (95 % confidence level).
Worked Example: See Fig. 20.4 sub a. A control laboratory
for pharmacy preparations knows by experience that the
20.3.2 Confidence Interval of m if the Standard standard deviation of the determination of noscapine hydro-
Deviation of the Population is Known chloride in an oral solution by means of U.V.-measurement
equals 0.8 %.
Equation 20.9 can be converted to: When the outcome is 96.8 %, the true content of the oral
solution is with 95 % confidence 96.8 1.96 0.8,
x 1:96 σ < μ < x þ 1:96 σ ð20:10Þ i.e. between 98.4 % and 95.2 %. Or, the true content is
with 95 % confidence above 96.8 + 1.645 0.8 ¼ 98.1 %
Equation 20.10 is one version of the confidence interval (down to 0 %, which is in this example of course
defined in the introduction of this section. The real value of unrealistic).
20 Statistics 411
Note: when calculating the confidence interval please Values of t for different numbers of degrees of freedom and
check that the standard deviation, and not the relative stan- upper tail probabilities can be looked up in a t-distribution
dard deviation is used. table such as Table 20.2. More extensive tables can be
The choice of the confidence level is arbitrary. We could consulted in books and on the internet.
have chosen 99 % instead of 95 % confidence by replacing
1.96 with 2.58. A wider interval will have a higher probabil- Worked Example: See Fig. 20.4 sub c. The assay of
ity of including μ, but the statement loses precision. noscapine hydrochloride in the oral solution, see previous
example, has been run in fourfold but now the standard
Worked Example: See Fig. 20.4 sub b. The determination
deviation of the population is unknown and estimated by the
of noscapine hydrochloride in the oral solution, see previous sample standard deviation s ¼ 0.6 with ν ¼ 4 1 ¼ 3
example, will be quadruplicated. The mean of the four
degrees of freedom. The sample mean is 96.8 %. The upper
observations is 96.8 %.
tailed α/2 ¼ 0.025 t-value with ν ¼ 3 is t3, 0.025 ¼ 3.182.
The true content of the oral solution with 95 % confi- According to Eq. 20.13 the two-sided 95 % confidence
dence is between 96.8 1.96 0.8/√4 i.e. between 96.0 %
interval of the true content, μ, is 96.8 – t3, 0.025 s/√4 < μ
and 97.6 %.
< 96.8 + t3, 0.025 s/√4 ¼ 96.8 3.18 0.6/2 < 96.8 +
3.182 0.6/2 ¼ 95.8 < μ < 97.8.
PRODUCT DESIGN
20.3.3 Confidence Interval of m if the Standard
Deviation of the Population
is not Known 20.3.4 Confidence Interval of the Variance s2,
and the Standard Deviation s
If the standard deviation of the population (σ) is unknown,
confidence statements have to be based on the sample stan- The sample variance, s2, is an unbiased estimate (see
dard deviation, s. In the equation for the confidence interval Sect. 20.2.1) of the population variance, σ2, with ν degrees
(Eq. 20.12) the value zα/2 is replaced by the corresponding of freedom. The statistic νs2 has the chi-square distribution
value tν,α/2 of Student’s t-distribution. The result is: with ν degrees of freedom. The 100(1–α) % two-sided con-
fidence interval is:
m tν, α=2 s=√n < μ < m þ tν, α=2 s=√n ð20:13Þ
νs2 =χ 2ν, α=2 < σ2 < νs2 =χ 2ν, ð1αÞ=2 ð20:15Þ
The value of tν,α/2 depends on the number of degrees of
freedom (ν) and the desired confidence level, (1 α). The square roots of the upper and lower limits give the
Student’s t-distribution and t-test have been invented by confidence interval of the standard deviation, σ. Values of
Gosset (his pen name was Student) as early as 1908. χ 2ν;α=2 and χ 2ν, ð1αÞ=2 can be obtained from tables of the
The number of degrees of freedom is n 1, if the chi-square distribution. See Table 20.3 for a small selection
sample standard deviation, s, is obtained from one sample. of frequently occurring upper and lower tail probabilities and
It may eventually be obtained from a series of K samples by degrees of freedom. More extensive tables for the chi-quadrate
pooling si, i ¼ 1, 2, . . ., K with degrees of freedom νi, i ¼ 1, distribution can be found in books and on the internet.
2, . . ., K:
XK XK Worked Example. The Control Laboratory determines the
s2p ¼ s2 =
i¼1 i
ν
i¼1 i
ð20:14Þ content distribution of a batch of capsules on six capsules.
The estimated standard deviation is computed as is 3.7 or
Table 20.2 Values of tn,a/2 for selected upper tailed probabilities, a/2, and degrees of freedom, n, of the t-distribution
Degrees of freedom
α/2 2 3 5 10 20 1
.50 0.000 0.000 0.000 0.000 0.000 0.000
.30 0.617 0.584 0.559 0.542 0.533 0.525
.20 1.061 0.978 0.920 0.879 0.860 0.839
.10 1.886 1.638 1.476 1.372 1.325 1.279
.05 2.920 2.353 2.015 1.812 1.725 1.645
.025 4.303 3.182 2.571 2.228 2.086 1.960
.010 6.965 4.541 3.365 2.764 2.528 2.327
.005 9.925 5.841 4.032 3.169 2.845 2.576
Table 20.3 Values of w2n, a=2 for selected upper tailed probabilities, a/2, and degrees of freedom, n, of the chi-quadrate distribution
Degrees of freedom, ν
α/2 2 3 5 10 20 100
.975 0.050 0.220 0.830 3.25 9.59 74.22
.95 0.103 0.352 1.145 3.94 10.85 77.93
.90 0.211 0.584 1.610 4.87 12.44 82.36
.10 4.61 6.25 9.24 15.99 28.41 118.50
.05 5.99 7.82 11.07 18.31 31.41 124.34
.025 7.38 9.35 12.83 20.48 34.17 129.56
3.72 ¼ 13.69 for s2 with 6–1 ¼ 5 degrees of freedom. From Table 20.4 Dixon’s Q-test limit values (Gardner-version)
Table 20.3 χ 25; 0:025 ¼ 12.83 and χ 25; 0:975 ¼ 0.83 giving for Test criterion n Limit values
the 95 % confidence interval of σ2: 5 13.69/12.83 < σ2 α ¼ 0.05 α ¼ 0.01
< 5 13.69/0.83 or 5.34 < σ2 < 82.5. The 95 % confi- Eq. 20.16 or 3 0.970 0.994
dence interval of the standard deviation σ, is Eq. 20.17 4 0.829 0.926
2.30 < σ2 < 9.08. 5 0.710 0.821
If the sample size had been 11 capsules, then σ (the 6 0.628 0.740
standard deviation of the population) with 95 % confidence 7 0.569 0.680
x2 x1 xn xn1
is between 2.6 and 6.3 (α ¼ 0.05 and ν ¼ 10). or 8 0.608 0.717
xn1 x1 xn x2 9 0.564 0.672
The example illustrates that the confidence interval of s is
10 0.530 0.635
relatively large, especially if the number of degrees of free-
11 0.502 0.605
dom (ν ¼ n 1) is small.
12 0.479 0.579
xn xn2 13 0.611 0.697
xn x3 14 0.586 0.670
20.3.5 Outliers 15 0.565 0.647
16 0.546 0.627
An outlier is an element in an observation series with a value 17 0.529 0.610
that deviates from the other values in the series in such a way 18 0.514 0.594
that the value cannot be from the same population as the 19 0.501 0.580
20 0.489 0.567
other observations in the series.
21 0.478 0.555
Outliers occur due to numerous causes, for instance an
22 0.468 0.544
outlier might occur due to unnoticed irregularities during the
23 0.459 0.535
execution of a measurement (wrong filling up to the mark,
24 0.451 0.526
bubble in pipette, reading errors, spelling mistakes, etc.). In 25 0.443 0.517
principle, the outlier presumed must not be removed unless it 26 0.436 0.510
can be identified as caused by an error in the process that 27 0.429 0.502
produced the observation. 28 0.423 0.495
To prove that the outlier is outside the expected range of 29 0.417 0.489
observations a statistical test may be of help. A common 30 0.412 0.483
statistical approach may be to apply the Q-test of Dixon. Q is
defined as the ratio of the deviation of the discordant value from (d) when the value of Q is greater than the value from the
its nearest neighbours with respect to the range of the values. Q-table (see Table 20.4) belonging to the correct
The procedure for testing suspected outcomes is as value of n and the desired alpha level, then the
follows: suspected value will be deleted.
1. If the suspected outcome does not affect the final conclu-
sion, then the observation is not deleted.
x2 x1
2. If it does, then an outlier test is performed, for example Q ¼ ð20:16Þ
Dixon’s Q-test: xn x1
(a) sort all values to size (x1, x2, . . . xn1, xn) or
(b) check whether the suspected value is now x1 or xn xn xn1
(c) calculate Q with Eq. 20.16 if x1 is the suspect value, Q ¼ ð20:17Þ
xn x1
or with Eq. 20.17 if xn is the suspected value
20 Statistics 413
The Eqs. 20.16 and 20.17 apply from n ¼ 3 to n ¼ 7. For Product or Population-Orientation. The requirement for
larger values different equations are used, see Table 20.4. content is mandatory for any batch of the active substance
or the finished medicinal product, in statistical terms the
Worked Example. Four replicates during an assay were
population. Quality control (QC) department has to check
found: 100.5, 98.3, 92.3 and 101.6 %.
whether the batch complies with specifications by taking a
Is the third value an outlier?
sample from the population. The requirements are formulated
Q-TEST:
product or population-oriented. This is an impossible mission,
The values are ordered by size:
strictly speaking, as the results by QC are by definition subject
x1 ¼ 92.3, x2 ¼ 98.3, x3 ¼ 100.5 and x4 ¼ 101.6
to random fluctuations. QC will guarantee the patient-
Applying Eq. 20.16 gives Q ¼ 0.65. This value is smaller
consumer that the batch does comply although a small chance
than the value (0.829) in the Q-table at n ¼ 4 and α ¼ 0.05.
of non-compliance exists; meaning the content of the product
The hypothesis that x1 is an outlier can be rejected.
is less than (say) 95 %. On the other hand, QC will guarantee
the producer that there is a small chance of rejecting batches
as being not complying, although the actual content is (say)
20.4 Acceptance Sampling 98 %. However, QC selects the sample size and other statisti-
PRODUCT DESIGN
cal parameters and will determine the chances. These
20.4.1 Introduction parameters are in principle not laid down precisely in
pharmacopoeias.
Producers of medicines (pharmaceutical industry, hospital
pharmacies and others) warrant their customers a definite Analysis or Sample-Orientation. The formulation of
content of active substance as agreed upon or required by requirements for Content Uniformity (CU) however is cho-
established specifications. This section discusses compli- sen the other way around. The pharmacopoeia has
ance with release specifications. End control by inspection formulated in every detail, how the sampling plan has to be
or by taking samples for chemical and biological assays performed and what outcome will lead to rejection or
provides some quality guarantee that is however limited by approval of the batch investigated. These requirements are
the random errors, inherent in the sampling procedure and in formulated analysis or sample-oriented. The requirements
the analytical method. Each release method, if executed and the influence on consumer’s risks (the chance that the
according to a predefined sampling plan offers a statistical consumer gets a safe product) as well as on producer’s risk
guarantee computed as an Operating Characteristic (OC) (the chance that a batch is incorrectly rejected) can be
function and displayed as the OC curve as will be shown in derived from the procedure and laid down in the Operations
Sect. 20.4.2 in detail. Characteristic (OC). The chances of acceptance are of
The confidence in the efficacy and safety of a medicine by course dependent on quality characteristics of the
a consumer (patient), the latter represented by inspection or investigated batch such as mean content, standard deviation
regulatory agencies, is based partly on the warranty by the of the assay and percentage outliers. The OC does not
producer and further on requirements laid down in formulate quality specifications, but is only a listing of
pharmacopoeias and other documents such as the marketing chances, either to reject or to accept, as a function of a
authorisation. The correct interpretation of the results of this quality characteristic.
system, called statistical quality control [2] or SQC is crucial The product or population-orientated formulation of a claim
to understand the character of the guarantee, when provided compels QC to find out how the analysis will be set up to
or asked for. In Sect. 20.4.3 the significance of this system guarantee that the requirements of the pharmacopoeia are
will be discussed more in depth. met as good as possible for the population/batch involved.
Sections 20.4.4 and 20.4.5 present two types of analyses and What “as good as possible” exactly means is not stated, but it
their OC Curves, respectively called Acceptance by variables is clear that the chance a patient will get a product 100 %
and Acceptance by attributes, illustrated with pharmaceutical compliant with specification, is not 100 %.
examples. Section 20.4.6 on Content uniformity of dosage The second pharmacopoeial strategy (analysis or sample-
forms shows how the determination of uniformity of content oriented) in principle does not provide the QC department
or mass of individual units can be performed, when needed. freedom to determine or to adjust the precision of the analy-
sis apart from the error of the assay. The pharmacopoeia has
laid down requirements for analysis and sample size. Preci-
20.4.2 Operating Characteristic (OC) Curves sion is fixed by the analytical protocol and is mainly deter-
mined by the sample size prescribed. The test procedure
Requirements as to the content of medicines are formulated provides information on the chance that a batch will be
traditionally by pharmacopoeias: Product A contains not less accepted, given a certain combination of quality
than 95 % of active substance a. characteristics of the units in the batch: mean content,
standard deviation of the individual contents, percentage A consistent statistical quality control system is of critical
outliers. The set of acceptance probabilities of a batch as a significance for the protection of the patient, who has regu-
function of all possible combinations of quality latory bodies and the health care inspection on his side, and
characteristics of the batch is called the operating character- for a transparent control of the products of the pharmaceuti-
istic of the procedure. The operating characteristic as a rule cal industry and other medicines producing parties.
takes the form of a graph or series of graphs (OC curves), in The following definitions of quality parameters have been
which the probability of acceptance of the batches is taken partly from the site Six Sigma Glossary [3]:
displayed on the y-axis against e.g. the population central • The Acceptable Quality Level (AQL) is the maximum
value μ or proportion of defectives π. percentage of defectives or the maximum deviation from
The OC provides a complete but complex summary of the label claim that is acceptable as a long-term average. It is
requirements for the population to comply with. The protec- the poorest quality level for the supplier’s process that a
tion of patient or consumer against the risk of receiving a consumer would consider to be acceptable as a process
low quality product is the primary objective of regulatory average. AQL is a property of the supplier’s manufac-
bodies and inspectorates and efforts should be aimed at turing process, not a property of the sampling plan.
maintaining low acceptance probability values of batches • Producer’s Risk is the probability that a batch with a
with a relatively inferior quality. quality equal to, or better than, the AQL will be rejected.
The chance that a batch of inferior quality will be released It is equivalent to the Type I Error in statistical hypothesis
is called consumer’s risk. A consumer’s risk of 10 % is in testing and is often denoted with α.
general widely accepted. Inferior or unacceptable quality is • The Limiting Quality Level (LQL) is the proportion of
defined as the Limiting Quality Level (LQL). nonconforming items or the percentage content
High acceptance chances of good quality batches are on associated with the consumer’s risk. It can be regarded
the contrary predominantly in the interest of the producer. as the minimum quality that the customer would not want
The chance that a complying batch (good quality) will be to accept, even for a single batch. The Lot Tolerance
rejected and not released is called the producer’s risk. Good Percent Synonyms for LQL often encountered are lot
quality is called Acceptable Quality Level (AQL). The pro- tolerance percent defective (LTPD) and rejectable quality
ducer may set himself an acceptable quality level, giving level (RQL), the latter two used as a level of protection
regard to costs of manufacturing, stock position and cus- against individual lots of poor quality. LQL is a level of
tomer service level (i.e. complaint rate). lot quality specified by the consumer, not a characteristic
Specifications, AQL, LQL and an example of an OC of the sampling plan.
curve will be presented in the next subsection. • Consumer’s Risk is the risk that a consumer will accept a
batch of worse quality than the LQL. It is equivalent to a
Type II Error in statistical hypothesis testing and is often
20.4.3 Acceptance Plans denoted with β.
• The Operating Characteristic function and curve repre-
The system of statistical end control, as mentioned in the sent the probability of accepting a product over a range of
previous section is called Acceptance Sampling. Elements nonconforming items or proportions.
are diverse parameters such as AQL, Producer’s Risk, LQL, Two different types of acceptance plans are frequently used:
Consumer’s Risk, the method of inspection or analytical Sampling by variables and Sampling by attributes.
procedure and the OC curve derived from them. Typically Sampling by variables refers to inspection based on
a plan contains not only the maximum and minimum limits measurements on a continuous scale. The key parameter is
of the content of product or batches but also the relative the mean content (μ) of the population. The concept of
frequencies by which the outcome on content may be passed Sampling by variables is presented in Sect. 20.4.4.
(or not) and what should be done: accept or reject. Sampling by attributes refers to ‘go-no go’, ‘good or bad’
Unfortunately this type of acceptance sampling is not inspection. The outcome variable is discrete, usually binary,
always applied. One reason is without doubt that just stating and the key parameter is the proportion (π) of units with a
the content alone as requirement is not sufficient. A detailed specified property in the population. The concept of Sam-
procedure for the assay method is required from which the pling by attributes is presented in Sect. 20.4.5.
margins follow or a tolerance interval is given from which
the details of the assay method can be derived. Mixing up of
these two approaches leads to an unclear situation. In the 20.4.4 Acceptance by Variables
following subsections the second approach will be followed
as it is mostly used in the Statistical Quality Control (SQC) If the outcome variable is continuous, sampling by variables
and Statistical process control (SPC) community. is the method of choice to construct an acceptance plan.
20 Statistics 415
Fig. 20.5 OC-curves for two Operation Characteristic

sample sizes (n ¼ 3 resp. n ¼ 7)
1.00
of the spectrophotometric n= 3
determination of noscapine 0.90 n= 7
hydrochloride with σ ¼ 0.8 % AQL/Producer's risk
and fixed limiting quality levels 0.80 LQL/Consumer's risk
of LQL ¼ 86 % and β ¼ 5 %,
and AQL ¼ 95 % with
acceptance probability
0.70
α ¼ 10 %. The OC-curve for
sample size n ¼ 7 complies with 0.60
the predefined conditions
0.50
0.40
0.30
0.20
PRODUCT DESIGN
0.10
0.00
80.0 85.0 90.0 95.0 100.0
content (percentage)
Compared to discrete variables, continuous variables have a where x is the value of the content and μ is the value of x for
large information content so that small or moderate sample which the acceptance probability equals 0.5, as in this exam-
sizes are sufficient for a powerful test. The probability dis- ple μ ¼ 51 %. We assume a normal distribution of Z with
tribution of the sample mean should be known and prefera- σ/√n as the standard error (see Eq. 20.6) of the assay.
bly normal, either because the population distribution is Deviations above label claim, 100 %, will be neglected in
normal, or the sample is large enough to let the distribution this example, but can be calculated in an analogous way by
of the sample mean approach normality (central limit mirroring.
theorem). The OC curves in Fig. 20.5 are for two sample sizes,
n ¼ 3 and n ¼ 7. The first generates too large a consumer’s
Worked Example. A regional supplier of pharmacy
risk (0.14) and a producer’s risk of 0.09. The second (n ¼ 7)
preparations routinely prepares an oral solution of noscapine
provides the values asked for: consumer’s risk 0.05 and
hydrochloride. The label claim is 100 % and the standard
producer’s risk 0.09. Since the number of replicates is dis-
deviation of the spectrophotometric determination for the
crete, the producer’s risk 0.09 is somewhat smaller than the
release decision, σ ¼ 0.8 %, is known from historic data.
required value of 0.10. For the same reason LQL equals only
The limiting quality levels for this product have been fixed at
approximately the left-tailed limit of the one-sided 95 %
LQL ¼ 86 % with a consumer’s risk, α, of about 5 %, and the
confidence interval of μ.
AQL is set to 95 % with a producer’s risk, β, of about 10 %.
The significance of acceptance sampling is not princi-
Figure 20.5 shows OC-curves for two sample sizes
pally to take a decision about the release of individual
(n ¼ 3 resp. n ¼ 7) of the spectrophotometric determination
cases. If the LQL is passed the respective product has to be
of noscapine hydrochloride.
rejected. An OC curve is not necessary for that decision, as
The supplier’s laboratory has to design the assay and the
the LQL is fixed externally by agreement or by regulations.
respective OC curve in such a way that the OC curve fits
The OC curve supports the policy of the producer and
between the points (0.05, 86) and (0.90, 95) as presented in
controlling laboratories and their mutual discussions. The
Fig. 20.5. This can only be done by manipulating the number
LQL defines an inferior product, not fit for its intended use
of replicates of the assay, because this is the only degree of
that should not be handed out to the patient. The consumer’s
freedom. The OC curve inclusive the number of replicates
risk indicates the chance that a borderline product still
are derived from the limiting values LQL and α, AQL and β
reaches the patient. The AQL is meant as a kind of long
and not the other way around.
term average in the manufacturing of the product, a kind of
The OC function is the cumulative distribution function of state of the art quality stamp. It is not meant as a criterion to
the standard normal distributed variable Z: allow individual batches to pass QC. The associated
producer’s risk is not the chance that a product will be
Z ¼ ðx μÞ= σ=√n ð20:18Þ rejected, as is often thought. It is the relative frequency
that the state of the art quality (the AQL) will be met. As 20.4.5 Acceptance by Attributes
such AQL and producer’s risk are a quality seal for the
producer’s production process, not for any incidental prod- If the outcomes of the inspection of the units of a sample are
uct. From this perspective acceptance sampling is not only a binary, e.g. approve or reject, Acceptance by attributes is the
tool to block unwanted products, not fit for use, but it can be method of choice to design acceptance plans. Such data or in
used to support and manage the quality policy of the com- general discrete variables contain much less information
pany and governmental institutions. Producer’s risk could than continuous variables resulting in larger sample sizes
better be named producer’s ambition. and sometimes complex sampling plans in order to get
Industry has accepted a default release specification for sufficient statistical power. Military Standard (MIL-STD-
the active substance of the label claim 5 %. This would 105A) [4] and ISO 2859–1 [5] are often used standards for
imply that in the long run, given a label claim of 100 %, a acceptance by attributes plans. Binary data occur in the
real content between 95 % and 105 % is warranted in a investigation of content uniformity of individual dosage
pre-specified proportion of the products at release. This forms, where the aim is to test for large deviations of con-
proportion is called producer’s risk and should be between tent, see also Sect. 32.7.2.
5 % and 10 % (in the example 10 %) as is usually accepted Since the sample sizes are large, up to n ¼ 1,000, the
within the Statistical Quality Control (SQC) community. inspection of the individual units should be cost-effective
The corresponding content limits are thus identical to the and not be time-consuming. Examples are the visual inspec-
acceptable quality level or AQL as defined above. The tion of defective packaging materials, including labels
producer may propose to loosen these limits, when the active or closure of containers. It is not so easy to establish
substance is e.g. hygroscopic, electrostatic or otherwise dif- errors in preparation that can have serious consequences,
ficult to handle, or when the active substance is degrading e.g. microbiological contaminations.
considerably within the shelf life permitted. Figure 20.6 shows a number of OC-curves for a popula-
Batches below the Limiting Quality level (LQL) tion with an unknown percentage of defectives sampled with
conversely are not acceptable for the consumer/patient or three different sample sizes (n ¼ 30, 50, 100).
buyer and should not be released. The LQL represents the Defective units are counted as ‘no-go’. Acceptance crite-
consumer’s risk. The AQL is closer to the label claim (con- rion, c, is c ¼ x ¼ 0 in this case, meaning that the batch is
tent stated on the inner and outer label) and could be identi- accepted if no defectives are found. For binary data (go,
cal to label claim 10 % with a consumer’s risk of no-go) the probabilities of x ¼ 0, 1, 2, . . ., n defectives are
5–10 %, in the above example 5 %. calculated using the binomial distribution:
Content specifications of medicinal products in industrial
practice are twofold: specifications at release and n n
PðxÞ ¼ π ðn πÞnx ð20:19Þ
specifications at end of shelf life (EOS). Specifications at x
release apply to the finished product at the time of leaving
the production plant. Specifications at end of shelf life apply where:

to the product until the date of expiration. Both types of n n!
is the binomial coefficient, ,
specifications can be included in (separate) OC curves. The x x!ðn xÞ!
establishing of specifications is not a statistical problem, but π is the proportion defectives in the population (the batch),
the task of parties, such as buyers/suppliers, controlling n is sample size.
institutions and so on. Obviously, they have to take statisti- If the population is limited in size, sampling without
cal possibilities and limitations into account. For example, replacement leads to exhaustion of the population. Then
by bringing LQL closer to AQL one may expect that non the hypergeometric distribution is applied to calculate the
compliance with AQL will lead to more rejects. A steeper chances P(x). However differences are mostly small or neg-
OC curve can be realised by increasing the number of ligible and will not be further be discussed here.
replicates of the analysis or by decreasing the standard The values of AQL ¼ 1 % respectively LQL ¼ 5 % are
deviation of the assay method or both. established or agreed upon by producer and buyer of the
Preparation in (hospital) pharmacies of products with a product and can be read from the graph, while 10 % is
short period between production and administration or use assumed to be the target for producer’s risk and consumer’s
may require other approaches, especially when the batch risk. As explained in the previous Sect. 20.4.4 the OC has to
size varies between 20 and 1,000 and where sample size is be designed in such a way that the curve passes through
a limiting condition. points (1, 0.90) and (5, 10) as best as possible.
20 Statistics 417
Fig. 20.6 Operation Operation characteristic

characteristics of samples of three 1.00
different sizes from the same
population n = 30
0.90
n = 50
0.80 n = 100
AQL/Producer's risk
0.70
LQL/Consumer's risk
0.60
0.50
0.40
0.30
0.20
0.10
PRODUCT DESIGN
0.00
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
percentage failures in population
The OC curves of the three different sampling plans with Finally, a fourth and fifth sampling plan are possible in
sizes n ¼ 30, 50 and 100 are presented in Fig. 20.6. Using a which two steps lead to a decision (two steps, 1 and 2 in
sample size of n ¼ 50 the producer can guarantee an LQL of Fig. 20.7).
maximal 5 % defects in the population with a chance of 8 % 4. x ¼ 0: acceptance of batch; x > 1: no acceptance of the
(consumer’s risk) of exceeding that percentage. A sample batch; x ¼ 1: sample again, size identical or different and
size of n ¼ 100 provides a much lower risk and a stricter count number of defective units x’. If x’ ¼ 0: acceptance
LQL could have been agreed upon. of the batch, else no acceptance.
An AQL of 1 % defects in the population has been 5. x ¼ 0 or x ¼ 1: acceptance of batch; x > 2: no accep-
chosen in this example. The producer’s risk is then tance of the batch; x ¼ 2: sample again, size identical or
extremely high, namely about 25 % for a sample size different and count number of defective units x’. If
n ¼ 30 and will increase even more for larger sample x’ ¼ 0: acceptance of the batch, else no acceptance.
sizes. Apparently it is not possible to obtain the desired Relaxing the acceptance criterion (n ¼ 50) appears to be
acceptance plan by manipulating the sample size. The disadvantageous for the consumer’s risk and of advantage for
following example shows how to improve the characteristic the producer’s risk. Acceptance at 0 or 1 defective units in the
and get a better result by changing the acceptance criterion sample instead of only 0 defects increases the consumer’s risk
as well. to 28 % from 8 % in the first example. At the same time the
We would like to find an OC curve in which the producer’s risk decreases from 40 % to 9 %. This approach is
consumer’s risk remains small, while the producer’s risk obviously not acceptable. The stepwise approach is much
decreases. Possibly, around the AQL of 1 % defectives in better, but unfortunately not good enough. A second sample
the population the acceptance chance can be increased by of 50 units, drawn when the first sample contains one and not
accepting 0 or 1 defects in the sample while staying at an more than one defective unit (plan 4 above) does not change
AQL level of about 1 %. the consumer’s risk much compared to that in plan 1 (only
Figure 20.7 shows the OC curves of five different sam- acceptance at zero defective units in the sample): 8 % changes
pling plans of which the acceptance criteria are: to 9 % and reduces the producer’s risk from 40 % to 21 %.
1. x ¼ 0, no defects in the sample: acceptance of the batch; This (21 %) is still above the acceptance probability of
whereas x > 0, one or more defectives in the sample: 10 % agreed upon, but more options are not available in this
batch not accepted. particular case. If an AQL of 0.5 % instead of 1 % would
2. x ¼ 0 or x ¼ 1, zero or 1 defect in the sample: accep- have been agreed upon, the producer’s risk would have been
tance; whereas x > 1, two or more defective units in the 7 % instead of 21 %, which complies with the original
sample: no acceptance. agreement. But then the producer would in the long run
3. x ¼ 0, 1 or 2, 2 defectives at the most in the sample: have been obliged to supply a product with maximal 0.5 %
acceptance; whereas x > 2, three or more defective units defective units. Probably he did not consider this a wise
in the sample: no acceptance. option. These kinds of considerations will not be addressed
Fig. 20.7 OC curves of five Operation characteristic

different sampling plans for the 1.00
same population, n ¼ 50 defects = 0
0.90 defects = 1
defects = 2
0.80 two-step 1
two-step 2
0.70 AQL/Producer's risk
LQL/Consumer's risk
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
percentage failures in population
here. The consequences of exceeding consumer’s or the determination of the content of each single unit. The
producer’s risk are difficult to oversee as well. If the mean and the relative standard deviation are then calculated.
consumer’s risk of 10 % is exceeded, this will not immedi- The variation observed is caused by:
ately lead to the destruction of the batch, when e.g. the defects • Variation of weights across the individual unit
are in the packaging materials. The defective units can simply • Variation in mixing (non-homogeneity)
be removed or replaced. On the contrary if the defective units • Random error due to the analytical method
are posing a safety hazard for human health, e.g. a If the last component of variation is indeed negligible
microbiological contamination on a part of a batch of relative to the other two sources of variation, in a next
ampoules, then statistics settles the matter and the whole step the variations due to weight and due to mixing can be
batch has to be destroyed, because it is not possible to find split up. This is important if corrective or preventive
all contaminated ampoules without destroying them all. If actions have to be taken, when commonly accepted
however the producer’s risk is exceeded, there is no direct requirements for content uniformity are not met (see also
consequence for the release of the batch: just release the Sect. 4.6.5).
batch. The producer and an inspecting authority should con- To this end, both content of each unit and its weight are
sider that as a signal to review the production process more determined. If the observed distributions of weight and con-
closely and when needed or possible to improve that process. tent are in the same order of magnitude, then this is an
The design of an acceptance plan is therefore not only a indication that the content distribution will be caused mainly
statistical exercise, but requires a review of all potential by differences in weight of the capsules. If alternatively the
options and interests. The options have a technical character: weight distribution is considerably smaller than the spread in
what is feasible from a technical and economical point of content, then mixing probably contributes significantly to
view and will give a reliable outcome; interests are in variation. Mixing is never perfect in suspensions of a solid
guaranteeing a safe and efficacious medicine and are in the in a liquid or in mixtures of two solids. In addition, physical
interests of the producer. segregation may occur.
The net amount of the active substance in a separate unit
corrected for random deviation of the weight of the unit, g,
20.4.6 Content Uniformity of Dosage Forms may be calculated from:
This section provides basic knowledge to understand the g ¼md ð20:20Þ

current requirements of the Ph.Eur. as described in Sect.
32.7.2. where m is the sample mean of the weights of all units
The examination of the distribution of active substance divided by the weight of a single unit, and d is the measured
across individual dosage forms (content uniformity) implies content of the same unit.
20 Statistics 419
Table 20.5 Content uniformity analysis of a sample of six dexamethasone capsules

Capsule Weight (mg) Assay % Corrected assay % (content)
1 161.6 103.5 100.9a
2 155.9 93.5 94.5
3 154.5 95.7 97.6
4 156.9 91.5 91.9
5 154.3 100.5 102.6
6 162.7 99.7 96.6
Mean 157.6 97.4 97.4
Standard deviation 3.6 4.6 4.0
s/m (percent) 2.3 4.7 4.1
s2/m2 (percent2) 5.3b 22.1c 16.8d
a
Calculation of content of this capsule: (157.6/161.6) 103.5 ¼ 100.9
b
Variance due to differences in weight
c
Total variance
d
Variance due to imperfect mixing
PRODUCT DESIGN
The variation in g is then calculated from two measured
components i.e. the total variance of the content of the units, 20.5 Statistical Calculations and Numerical
d, and the variation in the weights of the units, m, with the Operations
aid of the modified Eq. 20.22 from Sect. 20.5.3:
20.5.1 Effect of More than One Deviation
σ 2g =g2 ¼ σ 2m =m2 þ σ 2d =d2 ð20:22aÞ in a Process
σ 2g represents the variance due to (de-)mixing which is the If an outcome is a function of two or more measurements
total variance of the dosing unit, σ 2d ,
corrected for the vari- (or steps in a measurement or a manufacturing process)
ance due to differences in weights, σ 2m . every step contributes to the variation of the final outcome.
The variances σ 2m and σ 2d will be estimated by the The variation may be calculated using the squares of the
standard deviations, i.e. the variances of the individual
corresponding sample variances s2m and s2d . The denominator
measurements.
of m, i.e. the sample mean of the weights, is assumed to be a
To calculate the total variance there are two possibilities:
constant and precise estimate of the population mean leaving
1. The outcome is the sum or difference of measurements
the numerator, the individual weight of each unit, as the
2. The outcome is the product or quotient of measurements
chance variable. It is assumed that the analysis and other
Application of the Eqs. 20.21 and 20.22 assumes inde-
errors are either negligible, or are included in one of the
pendence of the errors in the measurements, i.e. x and y
other components of variation, though it makes sense to
should be uncorrelated in the underlying population.
include these explicitly in the equation, if estimates are
available.
For example, six capsules of a batch of dexamethasone 20.5.2 The Outcome is the Sum or Difference
capsules are weighed and the content of dexamethasone in of Measurements
each capsule is determined. Weights and contents are listed
in Table 20.5 and further calculations are presented there. If the final outcome, z, equals the sum or difference of two or
In accordance with Eq. 20.22 the last row of the table more measurements (x, y, . . .) then the variance of the
states 5.3 (for weight) and 16.8 (for corrected assay) sum up outcome is equal to the sum of the variances of the individ-
to 22.1 (for corrected assay). The conclusion is that 5.3/22.1, ual measurements. So, if z ¼ x þ y or z ¼ x y; then:
or 24 % of the total variation in the content of the capsules is
due to variation in the weights of the capsules and 16.8/22.1, σ 2z ¼ σ 2x þ σ 2y ð20:21Þ
or 76 % of the total variation is due to mixing. In conclusion
a first step would be improvement of mixing in order to Worked Example. An example is the weighing of a tube
improve content uniformity. with sterile eye ointment base during the aseptic process of
preparation of a suspension-eye ointment. The first weighing

of the tube is 100 g with a standard deviation σx ¼ 0.5 g and
after sampling the desired amount from the preparation, the
second weighing of the tube results in 95 g with a standard
deviation of also σy ¼ 0.5 g. The standard deviation of the
sample (5 g eye ointment base) σz can be calculated from
Eq. 20.21:
σ 2z ¼ 0:52 þ 0:52 ¼ 0:50
The standard deviation σz ¼ √0.50 ¼ 0.71 g. This example

shows immediately that outcomes based on measure- Fig. 20.8 Density, f (x), of the uniform probability distribution of the
ments of a difference are more unfavourable than single values, x, in the rounding interval Δ
measurements. The relative standard deviation amounts to
0.71/5 ¼ 0.14 g or 14 %, while the standard deviation
20.5.4 Rounding
of separately weighing 5 g of eye ointment base is about
0.5/5 or 10 %.
When finalising an outcome on a limited number of decimal
In this example, the smaller standard deviation in direct places we add a random error to that outcome. By rounding
weighing would however not compensate for the disadvan- off an outcome to one decimal place, e.g. 5.136 into 5.1, all
tage of less secure aseptic processing conditions. values in the interval 5.150 into 5.050 are represented in the
Standard deviations of two or more variables are always rounded value 5.1.
added up as their variances, even if the result is calculated as We designate the rounding interval with the Greek letter
the difference between two observations. Δ. In this example Δ ¼ 0.1. Because all values in the inter-
val are equally likely, the uniform distribution is the proba-
bility distribution of these values, see Fig. 20.8. The uniform
20.5.3 The Outcome is Obtained by Multiplying distribution has as variance σ 2a ¼ Δ2 =12. When rounding
or Dividing Measurements to one decimal place, the standard deviation will be
σa ¼ 0.1/√12 ¼ 0.03.
If the final outcome, z, equals the product or quotient of The original, not rounded outcome contains a random
two or more measurements (x, y, . . .), so if z ¼ x y or error by itself. For example, if σo ¼ 0.05, the total standard
z ¼ x=y; then: deviation in the rounded outcome using Eq. 20.21 is:
σ 2z =z2 ¼ σ 2x =x2 þ σ 2y =y2 ð20:22Þ σ2 ¼ σ 20 þ σ 2a
In our example, the standard deviation of the total rounded

Equation 20.22 is an approximation, since it is derived using
outcome σ ¼ √(0,052 + 0.032) equals 0.06, not much larger
Taylor’s series expansion.
than the standard deviation in the original, not rounded
Worked Example. An example is the preparation of one litre outcome.
of saline. The content is the quotient of the weighed amount If we would have rounded one decimal place more, 5.136
of NaCl and the measured quantity of water. will become 5, we would have generated an additional
0.9 g of NaCl has been weighed with a standard deviation σa ¼ 1/√12 equals 0.288 and the standard deviation in the
of 5 %, so σx ¼ 0.045 g. The container is filled with water final result would be σ ¼ √(0.052 + 0.2882) equals 0.294.
up to 1,000 mL with a relative standard deviation of By rounding so roughly, the standard deviation is nearly
5 %, then σy ¼ 50 mL. The standard deviation of the con- completely determined by the rounding procedure.
tent of the physiological salt solution, calculated with If we want however no more than a 1 % increase in σ, we
Eq. 20.22 is: must ensure that:

σ 2z = z2 ¼ 0:0452 =0:92 þ 502 = 1,0002 ¼ 0:005 σa =σ0 ¼ Δ=√12 σ0 < 0:01 ð20:23Þ
Hence the relative standard deviation is: σz/z ¼ In conclusion, the rounding interval Δ should be < 0.035 σ0.
√0.005 ¼ 0.07 or 7 %. The concentration (z) is 0.9 g NaCl So rounding to one decimal place is only allowed if σ0 > 3.
per 1,000 mL water, so that the absolute standard deviation σz Rounding off to two decimal places is allowed when
equals 0.9 0.07 ¼ 0.063 g NaCl per 1,000 mL of water. σo > 0.3, and so on.
20 Statistics 421
In some cases, we apply an observation method that in a 3. But increase it by 1 if the next digit is 5 or more (this is
similar way leads to the introduction of a random error in the called rounding up)
final outcome. For example, we always read 0.1 mL if we So:
use a 10 mL measuring pipette, calibrated in tenths of a 36.4584 rounded in 2 decimals becomes 36.46
millilitre. Actually we round off the observation to one 56.8734 rounded in 2 decimals becomes 56.87
decimal place without mentioning or realising that. 89.6651 rounded in 2 decimals becomes 89.67
The same thing happens when weighing 10 g. The 89.665 rounded in 2 decimals becomes 89.68
weighing program and the printer report as weighing result 29.335 rounded in 2 decimals becomes 29.34
10 g, if the reading is between limits 1 % (see also Sect.
29.1.6), or between 9.9 and 10.1 g.
All values in the interval of 0.1 g are then equally likely
References
and their distribution is uniform. We introduce a standard
deviation of σa ¼ 0.1/√12 ¼ 0.03 g, solely as a result of 1. Bolton S (1990) Pharmaceutical statistics: practical and clinical
reading the pipette or due to the reporting routine of the applications. Marcel Dekker, New York
balance. All such errors should, according to Eqs. 20.21 2. Grant EL, Leavenworth RS (1996) Statistical quality control, 7th
edn. The McGraw-Hill Companies Inc, New York
PRODUCT DESIGN
and 20.22 in Sects. 20.4.2 and 20.4.3, be added to other
3. MiC Quality, Six Sigma Glossary. http://micquality.com/six_sigma_
variances, when calculating or assessing the random error in glossary/index.htm
the final result. 4. Military Standard Sampling procedures and tables for inspection by
Rounding off is in practice applied according to the attributes. Military Standards (MIL-STD-105A) known also as
ABC-STD-105
following rules:
5. Sampling procedures for inspection by attributes – part 1: Sampling
1. Decide which is the last digit to keep schemes indexed by acceptance quality limit (AQL) for lot-by-lot
2. Leave it the same if the next digit is less than 5 (this is inspection. ISO 2859–11999; Cor 1–2001, Amd 1–2011
called rounding down)
Quality Risk Management
21
Contents Abstract
Firstly the chapter approaches risk management in a gen-
21.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
eral sense, including the phases of risk assessment (risk
21.2 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 identification, risk analysis and risk evaluation), risk
21.3 Risk Management Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 control (risk reduction or mitigation, and risk acceptance),
21.3.1 Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 risk documentation and communication, and risk review.
21.3.2 Risk Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
21.3.3 Risk Communication and Documentation . . . . . . . . . . . . . . . 426
Then some methods for risk assessment are explored
21.3.4 Risk Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 further, such as matrix type and Failure Mode Effect
Analysis (FMEA) using risk priority numbers (RPN).
21.4 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
21.4.1 Risk Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Quality risk management (QRM) is illustrated by prac-
21.4.2 Risk Analysis and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 tical examples about logistics, equipment, pharmaceuti-
21.4.3 Risk Acceptance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 cal care on the wards and clinical pharmacy.
21.4.4 Risk Documentation and Communication . . . . . . . . . . . . . . . 428
QRM finds its way into medicines regulations as it is
21.5 Practical Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 seen as a systematic process for the assessment, control,
21.5.1 Evaluation of Distributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 communication and review of risks to the quality of the
21.5.2 Equipment – Washing Machine . . . . . . . . . . . . . . . . . . . . . . . . . . 429
21.5.3 Aseptic Handling on Wards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
medicinal product. A structured and documented man-
21.5.4 Risk Management in Clinical Pharmacy . . . . . . . . . . . . . . . . 431 agement of risks is a requirement in EU GMP as well as in
the European Pharmacopoeia (Ph. Eur.). A guideline with
21.6 Regulations and Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
21.6.1 QRM Evolving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 a description of QRM elements together with appropriate
21.6.2 GMP and ICH Q9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 tools is to be found in ICH Q9, mainly directed at
21.6.3 Regulations for Pharmacy Preparation (Ph. Eur. and CoE manufacturing. Finally implementation of QRM in the
Resolution) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Pharmaceutical Quality System is briefly elaborated.
21.7 QRM and Pharmaceutical Quality Systems . . . . . . . . . . 434
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Keywords
Quality Risk management Risk assessment ICH
Q9 Risk analysis
21.1 Orientation
Pharmacists will, in their work, reflect on all processes for

which they are responsible, with the purpose of improving
Y. Bouwman-Boer quality and availability of medicines and hence to minimise
Royal Dutch Pharmacists Association KNMP, Laboratory of Dutch
any risk of harm to patients. Quality risk management
Pharmacists, The Hague, The Netherlands
e-mail: [email protected] (QRM) offers a structure and tools for a systematic approach
to these efforts. The process usually consists of the phases
L. Møller Andersen (*)
Region Hovedstadens Apotek, Herlev, Denmark risk assessment (Sect. 21.3.1) (with sub processes risk iden-
e-mail: [email protected] tification, risk analysis and risk evaluation) and risk control

424 Y. Bouwman-Boer and L. Møller Andersen
Fig. 21.1 Elements of the risk

Risk identification Delimiting the process
management process and
Failure modes
companion activities or topics
Hazards
Risk analysis Severity

Probability
Detectability
Risk assessment
Risk evaluation Comparing estimated

risks
Risk reduction Reduce occurrence

Increase detectability
Risk control
Risk management
Risk acceptance Delimit efforts
Define accepted risks
Risk documentation and communication Documenting

Giving account
Risk review Monitoring effects
(Sect. 21.3.2) (with the sub processes risk reduction and risk acceptance), risk communication and risk review. Figure 21.1
acceptance), see Fig. 21.1. shows consecutive elements of the risk management process
This structured approach helps to substantiate and keywords indicating companion activities or topics.
considerations and decisions. It eases documentation, and This section explains these elements and illustrates them
thus may help to communicate about them. with a simple example case of small-scale filling capsules
This chapter explains the basics of Risk Management with a powder mixture.
applying it to the field of preparation and product care in
pharmacies, that is from logistics to prescription assessment,
from production to pharmaceutical care on the wards 21.3.1 Risk Assessment
(Sect. 21.5). Essentials of frequently used methods will be
described (Sect. 21.4). QRM aimed at quality of medicines Risk assessment consists of the identification of hazards
has found its way to regulations (Sect. 21.6), for large-scale (Risk identification), followed by the analysis (Risk analy-
manufacturing as well as for preparation in pharmacies. sis) and evaluation (Risk evaluation) of risks associated with
Some guidance is given for implementation of QRM in the occurrence of those hazards. As a simple illustration the
pharmaceutical quality systems (Sect. 21.7). extemporaneous preparation process of capsules according
to a standard formulation is taken as to illustrate the
principles involved.
21.2 Definitions
21.3.1.1 Risk Identification
ICH Guideline Q9 is the reference document on quality risk At first the process for which the risks have to be assessed is
management for pharmaceutical preparations [1]. Therefore defined and delimited as well as its hazards that have to be
in this chapter mostly ICH Q9 definitions are used. Many of focused upon.
them are identical to those of the International Standards
Organisation (ISO, see also Sect. 35.7.2).
The definitions are tabulated in Table 21.1. As said the process to be assessed is limited to
the extemporaneous preparation process of capsules
according to a standard formulation. Let the focus be
on a quality defect that will lead to not meeting the
21.3 Risk Management Process requirements for content uniformity.
Risk management basically implies risk assessment (with
subsequently risk identification, risk analysis and risk evalua- Secondly the separate process steps are identified and
tion), risk control (with subsequently risk reduction and risk coupled to possible deviations or ‘failure modes’ (What
21 Quality Risk Management 425
Table 21.1 Risk management definitions

Harm Damage to health, including the damage that can occur from loss of product quality or availability
Hazard The potential source of harm
Quality risk Risk management directed at the quality of the (medical) product
management
Risk The combination of the probability of occurrence of harm and the severity of that harm
Risk management The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling,
communicating and reviewing risk.
Risk acceptance The decision to accept risk
Risk analysis The estimation of the risk associated with the identified hazards
Risk assessment A systematic process of organising information to support a risk decision to be made within a risk management process. It
consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.
Risk communication The sharing of information about risk and risk management between the decision maker and other stakeholders.
Risk control Actions implementing risk management decisions.
Risk evaluation The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the
significance of the risk.
Risk identification The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem
PRODUCT DESIGN
description.
Risk mitigation Risk reduction
Risk reduction Actions taken to lessen the probability of occurrence of harm and the severity of that harm
Risk review Review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and
experience about the risk
Severity A measure of the possible consequences of a hazard
might go wrong?) as well as to the consequences (harms or

effects) of these. or easily measured by in-process control of the capsule
weights. Both deviations will lead to insufficient con-
tent uniformity. Both severities are assumed to be
The process of the preparation of capsules is com-
equally large.
posed of several steps or unit operations. One step
concerns mixing the active substances and excipients,
giving the powder mixture. Another step is filling
empty capsule bodies with the powder mixture. Possi-
21.3.1.3 Risk Evaluation
ble deviations are: insufficient mixing and uneven
Risk evaluation is the comparison of the estimated risks.
filling respectively. The effect in both cases is insuffi-
cient content uniformity.
It can be concluded that insufficient mixing poses a
larger risk than uneven filling.
21.3.1.2 Risk Analysis

Risk evaluation will make risk prioritising possible. The
Risk analysis estimates the risk of every deviation that
use of a (semi-) quantitative scale can make risk evaluation
has been identified. The estimation consists of three
more sophisticated. The determination of a risk criterion for
aspects:
risk acceptance is another addition. See Sect. 21.4.2.
• The severity of the consequences of the deviation
• The probability of its occurrence
• Its detectability (before it can lead to any consequences)
21.3.2 Risk Control
Insufficient mixing may be estimated (in a specific The purpose of risk control is the reduction of the risk to an
situation: operator, equipment, pharmacy setting) as a acceptable level, followed by a check to consider if any new
risk that probably will occur and not be detected by an risks, introduced by the introduction of the control of
in-process control. Whereas uneven filling seems a identified risks, are acceptable. Risk control consecutively
little less probable and may be noticed by the operator exists of the elements: risk reduction (some sources use the
term: risk mitigation) and risk acceptance.
(continued)
21.3.2.1 Risk Reduction risks. These elements are, for instance, availability and the
Risk reduction investigates all critical process steps to draw pharmacologic qualities of the active substance.
up measures that reduce the occurrence of the risks or
improve the detectability. But any measure should not lead
The standard operating procedure for extemporane-
to the introduction of new risks.
ous preparation of capsules should reflect the decisions
on quality risk management of that process. The level
For the reduction of the risk of an inhomogeneous of quality risk management should be accounted for in
powder mixture, the mixing process needs more atten- the quality manual of the pharmacy.
tion. The operator can be taught to perform mixing
correctly (see Sect. 29.4 about mixing quality),
monitor their way of operating from time to time
by observation or by assaying content uniformity
of pilot batches, or introduce personal qualification
21.3.3 Risk Communication and Documentation
and requalification for the preparation of capsules.
Communication with stakeholders about the risk
In large-scale preparation an in-process control by
assessment’s results is important to give account of one’s
Near Infra Red (NIR) is used to detect inhomogeneity
professional decisions. By ensuring that key stakeholders are
(see Sect. 17.7), however for small-scale preparation
engaged in both the data collection process for the risk
NIR is not commonly used.
assessment and the decision-making for risk control, the
For the improvement in the capsule filling tech-
decision-maker will get commitment and support for his
nique, teaching, observation and monitoring may
QRM. Documentation will make communication easier.
be used as well. An in-process control on capsule
There should be a report for every risk assessment, of
weights after filling will increase detectability sub-
which the level is proportional to the level of risk.
stantially. Ultimately each batch may be analysed
before release.
Would these measures introduce new risks? Proba- Section 2.2.3. depicts models for a structured risk
bly any interruption of an operation for an in-process assessment of a prescription for extemporaneous
control can lead to mix-ups. And weighing may cause preparations. The physician and the patient will be
a risk of cross contamination. the most important stakeholders in that situation, the
latter also represented by the competent authority. But
the insurance company may be stakeholder as well
because of the resources.
21.3.2.2 Risk Acceptance
Risk acceptance requires decisions about how much effort to
reduce risks is feasible in terms of cost and benefit.
21.3.4 Risk Review

Analysis of each batch will take too much time and
money (excess active substance needed) to be an The experience and results of measures taken to diminish
option for extemporaneous preparations. The qualifi- risks should be monitored and reviewed to decide if the
cation of operators for the preparation of capsules, by chosen approach works. As with other elements of QRM,
validation and monitoring may be feasible. This may the level and formality of the review should be proportional
lead though to specialisation of operators and thereby to the level of risks.
to a decrease of flexibility.
Knowledge about mixing and filling being critical

The amount of effort used for risk control should be steps in capsule preparation are well known from
proportional (“commensurate” is the Q9 terminology) to professional education or literature and the effects
the significance of the risk. In pharmacy preparation it will of the efforts can be anticipated. Monitoring the
generally lead to more quality investments in stock prepara- actual effects however may confirm knowledge or
tion compared with extemporaneous preparations due to the sometimes may reveal unforeseen aspects. Moreover
higher number of patients that will be exposed. it will usually contribute to the motivation of the
In pharmacy preparation other elements will contribute to operators.
the balance that has to lead to acceptance (or not) of specific
A ‘brainstorm’ is a useful technique to start risk identifi-

21.4 Methods cation. This may start with a presentation of a problem using
preliminary information or already processed data. A pre-
More can be said about methods for risk identification, risk liminary evaluation of the possible harms to the patients may
analysis and risk evaluation. In Sect. 21.3 these phases were be presented to increase motivation. The brainstorm may be
defined, and, as the capsule preparation example, executed rather informal or more structured depending on the issue,
in an informal, rather simple way. That section was meant as the participants and traditions in the organisation. The goal is
an introduction to the phases of risk management and the achieving, within short time, as many ideas as possible and
terminology. It also meant to convey the idea that defining engaging and focussing the participants.
and delimiting the process steps and thinking about risks Any risk identification may include a compilation of
with all staff concerned will already lead, halfway, to a observations, trends and other available information. For
proper result. more complex issues, a suitable presentation of background
If risk management applies to a more complex or a less information and relevant data together with a targeted
well-known process, some experience and methods may be review of literature is advisable. Collecting and depicting
helpful for a more formal risk assessment. They will be this knowledge in a way that also can be used by other
discussed following the sequence of: risk identification,
PRODUCT DESIGN
professionals may be very helpful in an expected rather
risk analysis, risk evaluation. They also facilitate proper long QRM process. Furthermore, depictions as these may
documentation, which is essential for being transparent facilitate handling of new knowledge or understanding. For
about decisions. listing and depicting the results flowcharts and process
mappings are commonly used, if possible with marking of
already known critical steps. As easy to use tools the
21.4.1 Risk Identification Fishbone/Ishikawa diagram, flowcharts and mind maps are
mentioned. Reference is made to [2] for further information
For any risk assessment method it is crucial that the problem about these tools.
or risk issue is well defined, described and understood.
A common mistake is to start the risk analysis before the
process to be analysed is well defined and well delimited. 21.4.2 Risk Analysis and Evaluation
Such an approach is easy to imagine because a problem often
creates a sense of urgency that tempts one into action though When the problem or risk issue is well understood an
the framework is not yet understood. This mistake will most appropriate tool for risk analysis has to be chosen. For the
likely result in waste of time and personnel frustration. hazards identified during the brainstorm the associated risks
A risk assessment can be performed retrospectively or has to be estimated. This may be a qualitative description
prospectively. If an adverse event – whether a complaint, a eventually using semi-quantitative descriptors, as “high”,
deviation or adverse effect – happens it will be analysed “medium” or “low” or it may be a quantitative analysis
retrospectively. Staff will be convinced about the necessity with scores according to a pre-defined scale. The estimation
for any action. When staff do not report incidents however or of risks in Sect. 21.3 occurred following a qualitative
do not qualify them as important the improvement process method. It enabled the prioritisation of two risks within a
may be missed. For risk assessment a blame-free culture in rather simple process and no comparison to a fixed value was
the organisation is very important. felt to be necessary.
Prospective methods look at which risks may occur and The numerical scores to be used in a (semi-) quantitative
assess the severity of these risks, in order to subsequently risk analysis have to apply to the factors severity, probability
choose which actions should be taken to prevent errors and and detectability. The scale may be linear or non-linear,
deviations. In the preparation of medicines prospective for instance logarithmic. Addition or multiplication of
methods can be used for the initiation of new activities or these scores will lead to risk scores. These can be put in a
purchasing a new equipment (see Sect. 21.5.2), as part priority sequence: the harm with the highest scores should
of change control (see Sect. 35.6.10) and in planning of be dealt with the highest priority (efforts and formalities).
qualification and validation activities (see Sect. 34.14). And the score can also be compared with a fixed limit,
In practice a mixed approach of a retrospective and pro- for instance in case of a decision if any action has to be
spective method is often encountered. The capsule-filling taken at all.
example in Sect. 21.3 may appear to be a pure prospective In this way a quantitative method may improve the prac-
method but by using process knowledge it also has, in fact, ticability of the outcomes (by putting priorities) and it may
retrospective elements. help documentation and communication. This may apply to
situations when the process to be analysed consists of a large that can play a role in accepting a residual risk are: no
number of steps or if many different measures have to be alternative clinical treatment, the exposure limit to
considered. genotoxic substances (see Sect. 26.3.3), financial invest-
Qualitative methods are suitable in relation to relatively ments in quality control measures, or harm to a patient
simple issues where as quantitative methods may be neces- through loss of availability.
sary for more complex or comprehensive issues.
Many tools for risk analysis are in use. ICH Q9 Briefing
Packs [2] describes many of them. The best-known method 21.4.4 Risk Documentation and Communication
might be the Failure Mode Effect Analysis (FMEA). FMEA
is basically done in the following way: Documentation of a qualitative method may be a simple
• Draw a schematic representation of the process and name description of the issue dealt with, including assessment of
in a ‘brainstorm session’ the ways in which the process associated risks and a conclusion regarding necessary action,
could possibly fail (failure mode). if any. Though simple, such a QRM process should also be
• Name the effect of every failure mode and classify the documented: which risks were defined and balanced and
severity of that effect on a scale. who accepted the residual risk.
• Classify the probability of each failure mode and rate it Again it should be emphasised that the use of informal
on a scale. risk management processes could be acceptable if the risk
• Classify the chance of each failure mode to be detected assessment and the conclusion are well documented.
after occurrence and before leading to consequences and As an example: documented decision about whether or
rate this chance on a scale. not fulfilling a physician’s requirement for a pharmacy prep-
• Calculate for each failure mode a risk priority number aration is a first step in giving account of or even in involving
(RPN) by multiplying the ratings for severity, probability stakeholders in responsibilities (see Sect. 2.2.3).
and chance of detection.
• The failure modes with the highest RPN should be
addressed first, preferably by eliminating them or reduc- 21.5 Practical Examples
ing the frequency of occurrence. A final possibility for
improvement is increasing the detection chance. The This section discusses some applications of risk assessment
alternative is accepting the risk. in preparation and pharmacy practice. In this book more
An example of this method is given in Sect. 21.5.2. A very examples can be found: see Sect. 34.14.2 on parametric
complete and dedicated description of the FMEA method, release at autoclaving; Sect. 2.2. on prescription assessment;
executed as a RPN mode, is to be found in the ICH Q9 Sect. 26.7.3 on occupational safety and health risk matrix.
Briefing Packs [2]. It also contains, for instance, a list
of severity scores coupled to resources.
Instead of RPNs a matrix may be used to visualise risks, 21.5.1 Evaluation of Distributors
especially if risks are diverse and difficult to compare, using
a single tool. The use of matrices is exemplified in A hospital pharmacist has to decide how often it is necessary
Sects. 21.5.1 and 21.5.3. to evaluate the suppliers of licensed medicines. The team
starts to enumerate elements and qualities of the supply
process: timeliness, clinical need of the medicine, unique-
21.4.3 Risk Acceptance ness of distributor, distributor’s quality assurance system,
business relation with the supplier etc.
Risk acceptance can be a formal decision to accept the It is decided to focus the risk assessment on two qualities:
residual risk or it can be a passive decision in which residual clinical need of the medicine and uniqueness of distributor.
risks are not specified. For some types of harms, even Each quality may be scored as: acceptable, relevant or
the best risk control might not entirely eliminate risk. critical.
In these circumstances it might be agreed that an appropriate For the quality ‘clinical need of the medicine’ the team
quality risk management strategy has been applied and decides to score as follows:
that quality risk is reduced to a specified (acceptable) level. • Clinical need is low: non-deliverability of medicine is
This (specified) acceptable level will depend on many not really important for the patient; patient care is not
parameters and should be decided on a case-by-case basis. at risk or the medicine is easily substituted (risk score:
For in every case specific measures are created for acceptable).
diminishing the risks, for instance in-process controls may • Clinical need is moderate; non-deliverability of medicine
contribute significantly to decrease the risks of extempora- does not directly affect the patient; patient care may
neous preparation, see Sect. 34.6. Examples of parameters suffer discomfort (risk score: relevant).
Table 21.2 Risk matrix for the assessment of audit frequency of distributors. Darker shades reflect higher priority
Uniqueness of distributor
Clinical need Acceptable Relevant Critical
Acceptable Assessment not necessary Once per 3 years Once per year
Relevant Once per 3 years Once per 3 years Once per year
Critical Once per year Once per year Once per year
• Clinical need is high: non-deliverability directly affects be sterilised subsequently – a risk analysis could be executed
the patient; patient care is at risk (risk score: critical). with a RPN mode of a FMEA (see Sect. 21.4.2). The risk
For the quality ‘uniqueness of distributor’ the team decides score is the result of the multiplication of the scores on
to score as follows: Severity, Probability and Detectability.
• Other distributors are available (risk score: acceptable). A Risk Assessment document may consist of a descrip-
• Access to other distributors is doubtful (risk score: tive part reflecting the logic and an attached table listing
relevant). hazards, possible causes and controls, scores and comments.
• No other distributor (risk score: critical). Table 21.3 reflects only a part of such a table for the risk
PRODUCT DESIGN
The pharmacist puts the combination of the qualities in a risk assessment of the washing machine.
matrix system and connects the scores to the frequency of From the risk analysis it is concluded that risks related to
assessing the distributors (Table 21.2). the washing machine are low when compared to other equip-
A risk assessment is always temporary. For instance the ment and will only indirectly affect patients. Critical aspects
elements Distributor’s own quality assurance system and and critical parameters are identified and will be part of the
business relation with the supplier will probably appear to URS. The most critical aspects are related to ineffective
be much more important and determine the way of washing process or contamination of utensils or materials
evaluating the suppliers. Furthermore the scores will have by the chamber.
to be changed for instance at a risk review after 2 years.
In a matrix only two effects can be combined. If more
effects have to be considered, subsequent matrices can be 21.5.3 Aseptic Handling on Wards
created.
The aim of this example of risk assessment is to assess the
risks in order to prioritise measures to improve safety of
21.5.2 Equipment – Washing Machine reconstitution on the ICU ward [3]. Two hazards of reconsti-
tution of parenteral medicines admixtures are focussed upon:
A risk assessment can be used quite naturally in the process microbial contamination (in fact: loss of sterility) and faulty
of drafting a User Requirements Specification (URS) for composition. The probability of microbial contamination
equipment utilities. By clarifying the intended use of the and faulty composition is related to the number of steps
equipment and investigating the hazards, their possible during the process that are critical for microbial contamina-
causes and ways to control them in the actual context, tion (see Sect. 31.3.2) or faulty composition respectively.
the URS will be a fine starting point for purchasing and for The number of critical steps are multiplied by 2 if the
the subsequent qualification. The risk assessment is to be medicine is mentioned in the Institute for Safe Medication
updated as soon as actual brands and types of a specific piece Practices’ (ISMP) list of high-alert medications [4]. In this
of equipment have been chosen. As a conclusion a ‘level of way the severity in case of faulty composition is taken into
risk’ can be determined for specific equipment, placed in account.
specific locations and used for well-defined purposes. If such For prioritising actions both hazards (microbial contami-
a ‘level of risk’ is determined for several pieces of equip- nation and faulty composition) were related to the frequency
ment in a department, it may serve other purposes as well, of administration. The top 10 of both frequency lists are
for instance prioritising validation and frequency of mainte- taken into the risk assessment. The risk matrix puts the
nance or determination of the replacement period for specific frequency of administration against the risk of contamina-
equipment. tion or the risk of faulty composition respectively (¼
The responsibility for the QRM is consequently and Tables 21.4 and 21.5). These matrixes visualise which
unambiguously placed at the user of the equipment. For a products have to be improved first. Risk reduction can be
rather complex piece of equipment – e.g. a washing machine achieved by decreasing the number of steps, for example by
to be used in the Aseptic department of a large hospital pharmacy preparation of premixed preparations or prefilled
pharmacy for washing utensils and other materials that will syringes.
430
Table 21.3 Risk analysis (part) of a washing machine
Severity
Risk
Occurrence
Detectability
Hazard Potential causes Controls SOD Comments
Contamination Contaminated air or Washing machine is placed in class C 1 1 5 5 Severity and occurrence is low as only well trained employees will
of chamber unintended use of the room have access to the room. Furthermore no other activities take place
washing machine near to the washing machine
Microbiological Stagnant water in chamber The chamber and drain will be controlled 1 1 5 5 Low severity: Washed utensils and materials will be autoclaved within
contamination or tubes for dryness and disinfection with alcohol defined timespan after wash (maximum for standing clean)
after use Low occurrence: Washing and final rinse takes with +80 C
Wash with empty chamber if more than WFI + controls
8 h empty standing High detection score because detection is not possible
Control of surfaces in chamber as part of URS requirements (among others):
routinely Environmental control • Effective drainage of tubes, pipes, surfaces
• No remaining water in drain
• Easy to clean, dry and inspect
• Tubes for water easy to disassemble, the same for pneumatic valves
for inlet of water.
Effectiveness of drain and management of valves have to be
documented in the Operational Qualification (OQ)
Surfaces in direct contact with materials of pharmaceutical grades
should be very smooth stainless steel (low Ra)
Preventive maintenance has to be defined
Contamination Chemicals or particles from Preventive maintenance 1 3 3 9 Occurrence level 3 as final wash and rinse are with +80 C WFI.
from the surfaces or installation of Utensils and materials in contact with WFI of pharmaceutical grade.
washing the washing machine Preventive maintenance is necessary due to the aggressiveness of
machine purified water.
The equipment is approved for the intended use e.g. in accordance with
ISO DS/EN ISO15883.
All parts in direct contact with utensils and materials are of
pharmaceutical grade steel (A316L). Other parts such as tubes, gaskets
and packaging materials have to be dedicated for pharmaceutical
purposes
Ineffective Wrong temperature or time Alarms for functioning, temperature and 5 1 3 15 Severity is scored high (5) especially due to risk for blocked nozzles.
washing Clogged nozzles time URS requirements (among others):
process Too low water pressure Visual control of nozzles before start of • Well defined alarms with informative text in display
Program changed or washing • After an alarm the washing process will be restarted from the
interrupted with or without Impossible for users to interrupt or change beginning
intention program • Accuracy for critical measuring equipment and certificates for
calibration as appropriate.
• Alarms for blocked nozzles or easy visual control
• At least three user-levels (user, supervisor, technical service)
• Supplier will train users as well as Technical Service
Y. Bouwman-Boer and L. Møller Andersen
Table 21.4 Microbiological contamination hazard as risk factor for related to microbiological contamination; p ¼ perfusor syringe; i ¼
prioritising the improvement of reconstitution of parenteral medicines injection/short infusion. Darker shades reflect higher priority
on wards (data from [3] with permission). MC: number of critical steps
Score MC 0 or 1 2 3 ≥4
Frequency
Seldom (1) phosphate (p) morphine (p) prednisolone (p)
amiodaron (p)
Frequent (2) amoxicillin + dopamine (p) bupivacaine +
clavulanic acid (i) midazolam (p) fentanyl (p)
meropenem (i) morphine (i)
ketanserin (i)
Often (3) pantoprazole (i) magnesium sulfate (i) enoximone (p)

metoclopramid (i)
Very often (4) insulin (i) erytromycine (i)
PRODUCT DESIGN
Table 21.5 Faulty composition hazard as risk factor for prioritising a faulty composition; S ¼ severity factor (1 or 2, see text); p ¼
the improvement of reconstitution of parenteral medicines on wards perfusor syringe; i ¼ injection/short infusion. Darker shades reflect
(data from [3] with permission). F ¼ number of critical steps related to higher priority
Score F x S 1 or 2 3 or 4 5 or 6 ≥7
Frequency
Seldom (1) prednisolone (p) amiodaron (p)
morphine (p)
phosphate (p)
Frequent (2) amoxicillin + ketanserine (i) dopamine (p) morphine (i)
clavulanic acid (i) midazolam (p)
meropenem (i) bupivacaine +
fentanyl (p)
Often (3) metoclopramide (i) magnesium sulfate (i)
pantoprazole (i) enoximon (p)
Very often (4) cefotaxim (i) erytromycin (i) insulin (p)
Generally the reconstitution of perfusion syringes (p) The ICH Q9 strategy and tools can be adapted for a
takes more process steps and is carried out, mostly, on framework for clinical pharmacy, such as described in [5].
high-risk medicines but they are used less frequently than The very start of a QRM process is again the description of
injection solutions and short infusions (i). Insulin and the work process. As an outcome of their study the team list
bupivacaine/fentanyl perfusor syringes have the highest a series of decisions that have to be made and specified, for
scores. instance by creating SOPs. In this way the priority in creat-
ing SOPs is led by the risk analysis. The team realise that
QRM may contribute to the protection of the clinical phar-
macist who is aware that the risk of patient hazard never can
21.5.4 Risk Management in Clinical Pharmacy be excluded but who is held to reduce that risk to an accept-
able level.
QRM may also be applied to clinical pharmacy, which is Another framework for QRM for clinical pharmacy can
easy to suggest when the example of 21.5.3 would be be taken from the ISO 9001 for healthcare: EN15224, espe-
extended to processes such as the prescription and adminis- cially from the practical implementation guide Sect. B.4.2.
tration of the medication. Apart from the pharmacy staff also Risk management [6]. In this way QRM of clinical phar-
other disciplines (physicians, nurses) will be involved in the macy can be integrated into the existing QRM of the phar-
risk assessment. macy and the hospital.
Executing a retrospective risk assessment is compulsory

21.6 Regulations and Standards for licensed medicines in relation to potential recalls,
complaints and non-conformities. The main issue is to
21.6.1 QRM Evolving ensure the immediate application of effective standard
work procedures so that any risks to patients are dealt with,
The field of QRM in pharmacy is very much evolving as with due diligence. The authorities expect documentation of
experiences and knowledge is obtained in individual QRM in relation to acknowledged product errors in cases
enterprises as well as by authorities and professional bodies. reported as complaints. Also reported adverse events are to
QRM has found already its way into several medicines be included in the group of events that require a comprehen-
regulations and standards: sive QRM. For deviations the consequential risks are in gen-
• Good Manufacturing Practice (GMP see Sect. 35.5.7) eral easy to manage, as the affected products are not yet
• Guide to Good Practices for the Preparation of Medicinal released. A fast and effective limitation of an acknowledged
Products in Healthcare Establishments (PIC/S GPP see production error is crucial anyhow in order to decide whether
Sect. 35.5.5) the error may also be present in released products that may be
• Pharmaceutical Preparations Monograph of the European used by patients. After the assessment of the acute needs for
Pharmacopoeia (Ph. Eur.) (see Sect. 35.5.3) corrective actions, retrospective methods examine which
• Resolution CM/ResA P(2011)1 on quality and safety causes have led to an actual error or deviation, in order
assurance requirements for medicinal products prepared to prevent the recurrence of it. As tools in connection with
in pharmacies for the special needs of patients (CoE complaints and non-conformities GMP requires that
Resolution see Sect. 35.5.4) “an appropriate” level of Root Cause Analysis (RCA, see
EU GMP Chap. 1 on Pharmaceutical Quality System Sect. 35.6.15) is applied. Usually followed by a corrective
highlights the inter-relation of the basic concepts of Quality and preventative action (CAPA, see Sect. 35.6.15).
Management, Good Manufacturing Practice and Quality
Risk Management and emphasises their fundamental impor-
tance to the production and control of medicinal products. The pharmacist not only has to manage risks of insuf-
QRM as described in EU GMP and related guidance ficient product quality or loss of availability, but also
provides a framework as well as common definitions and other risks, such as health risks of his personnel
terminology. So it is possible to express risk assessments and or financial risks. EU GMP focuses on the risks to
explain appropriate actions in this relation. This facilitates product quality. QRM is an element of the Quality
an effective and constructive dialogue with stakeholders, Management System in parallel to requirements of EU
competent authorities included, in relation to prospective GMP Chap. 1 (see Sect. 21.6.1). Even though e.g. health
as well as retrospective quality-related issues. and safety of the operators and environmental risks are
equally important in a societal perspective, these
considerations, from a GMP viewpoint, have to be
taken care of in other ways. For an illustration of this
21.6.2 GMP and ICH Q9 opinion, compare the warning for pharmaceutical
inspectors: “Inspectors should be cautious when
EU GMP defines QRM as “a systematic process for the reviewing assessments which include other business-
assessment, control, communication and review of risks to related risks (e.g. environmental, occupational health
the quality of the medicinal product. All efforts in QRM are &safety) in addition to quality risk assessments. As
aimed at minimising any risk for the patients due to inappro- whilst these factors are important in a holistic sense
priate quality of the products”. QRM is elaborated in EU there is a danger that they may compromise quality” [7].
GMP in Part III as ICH Q9 Quality Risk Management.
ICH Q9 provides principles and examples of tools for
quality risk management that can be applied to different
aspects of pharmaceutical quality, most of them directed
to complex manufacturing situations. Very useful Briefing 21.6.3 Regulations for Pharmacy Preparation
Packs [2] offer an explanation as to how to use the QRM (Ph. Eur. and CoE Resolution)
tools as well as training.
Application of QRM principles and its elements are to In pharmacy preparation, management of risk, whether
be found in chapters and annexes of GMP Part I (Basic structured or not, is used on many occasions within the
requirements for Medical Products). Within GMP it helps lifecycle of the medicine (see Sect. 35.4). QRM starts with
to find the cause of an adverse event, which enables the assessment of the physician’s request for pharmacy prep-
the efficient reduction of the chances of recurrence of the aration (see Sect. 2.2). The scientific and professional knowl-
event. edge of a pharmacist has to be used to decide whether the
required medicine can be produced. The Ph. Eur. monograph preparation of parenterals without terminally
Pharmaceutical preparations acknowledges this situation: sterilisation provide a higher level of risk than e.g.
In considering the preparation of an unlicensed pharmaceutical cutaneous preparations.
preparation, a suitable level of risk assessment is undertaken. • Preparation process
The risk assessment identifies: – Type of preparation process; generally risk is consid-
– the criticality of different parameters (e.g. quality of active ered to increase with the preparation types:
substances, excipients and containers; design of the prepara-
tion process; extent and significance of testing; stability of • Reconstitution
the preparation) to the quality of the preparation; and • Extemporaneous preparation of products for one or
– the risk that the preparation may present to a particular a few patients
patient group. • Stock production
The CoE resolution directs QRM to the quality manage- Each of these groups can be further subdivided in
ment system for preparation stating: different levels of risks. For example a simple recon-
“Before preparation, a risk assessment should always be stitution of a well-known sterile product in closed
carried out in order to define the level of the quality assur- systems has a lower risk profile than reconstitution in
ance system which should be applied to the preparation of excess of instructions in the SPCs.
PRODUCT DESIGN
the medicinal product.” And: “The Product dossier should – Feasibility of preparation. Considerations may include
therefore state the considerations about the risk of pharmacy questions such as:
preparation versus unavailability of the product and should • Are the pharmacy facilities and equipment suitable
contain more information for products with a higher risk.” for this kind of preparation?
The Risk Assessment should refer to: • Does the pharmacy have previous experiences with
• Dosage form and administration route similar types of preparation so systems and person-
• Amount prepared nel is ready for production?
• Pharmacological effect – Potential risks for cross contamination and mix-ups
• Pharmacotherapeutic window (will cause risks for other patients)
• Type of preparation process • Testing. Is it possible and feasible to introduce tests and
• (Way of) supply thereby reducing risks:
For a risk assessment in line with these recommendations, – In-process controls of critical steps
the following list of parameters may be useful for the risk – Assay of the active substance
definition phase (see also Sect. 2.2.3 especially for forms – Test of the finished product
framing the balancing of such risks against the benefits): • Stability of the medicine
• Active substances and excipients. Assessment may – Can labelled shelf life be justified, for example based
include questions such as: on analytical data or literature references?
– Are the substances well known (maybe described in a – The risk due to instability is especially relevant for
pharmacopoeia) or is it e.g. a chemical substance never stock batches; for extemporaneous products that are
used in pharmaceutical preparations before? immediately administrated to a single patient at least
– Is the manufacturer of the active substance and critical physical stability and a short term chemical stability
excipients audited and certified and well known or is has to be guaranteed.
little known about that company? • Patients: Ph. Eur. requires that considerations should be
– Will the active substance be stable during the shelf life given to particular groups of patients. Important elements
of the products or will degradation take place? are, among others:
• Containers. Assessment regards whether it is possible to – Identification of any identical or similar licensed
find suitable containers medicine; licensed medicines provide a lower risk
– Able to protect the product during its shelf life level due to the comprehensive requirements for
– Not providing a risk of leachables or in other ways authorisation
introduce a risk to the suitability for the intended • The expected benefit for the patient, including the
method of administration consequences of getting no medication;
• Design of the product and method of preparation. Impor- – How many patients will be medicated with the prepa-
tant elements are related to: ration; The level of efforts and documentation is
– Dosage form; suppositories and other dispersions expected to increase with the number of patients
are more difficult to prepare than solutions; exposed to the medicine.
systems should be in place to ensure that the output of the

21.7 QRM and Pharmaceutical Quality QRM process is periodically monitored and reviewed, as
Systems appropriate, to assess new information that may impact on
the original QRM decision. Examples of such changes include
It is neither always appropriate nor always necessary to use a changes to control systems, changes to equipment and pro-
formal risk assessment using the tools given by ICH Q9. The cesses, changes in suppliers or contractors and organisational
use of informal risk assessment (using empirical tools and/or restructuring.” For pharmacy preparation foreseeable changes
internal procedures) can be acceptable, as is illustrated by also apply to the therapeutic alternatives or new information
Sect. 21.3 and by the several forms discussed in Sect. 2.2.3 on adverse effects (see also Sect. 35.4.2).
applied to small-scale preparation. However QRM should
be part of the local pharmaceutical quality system (PQS)
(see Sect. 35.6.8).
For the inclusion of QRM in the PQS it has to be listed References
which areas of the pharmacy activities, organisation and
processes have to be assessed, always including the initial 1. European Commission. EudraLex—Volume 4. Good Manufacturing
Practice (GMP) Guidelines. Part III, GMP related documents.
prescription assessment and the ultimate goal to benefit the Quality Risk Management (Q9 ICH), January 2011. http://www.
patient. ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
As for other elements of the PQS also for QRM the 2009/09/WC500002873.pdf. Accessed August 2014
implementation should be traceable, for instance when in 2. International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
dialogue with the authorities. Responsibilities for initiating Use (ICH). Quality Risk Management ICH Q9 Briefing Pack. http://
QRM processes and for acceptance of any remaining www.ich.org/products/guidelines/quality/q9-briefing-pack.html.
risks have to be described clearly. The governance of docu- Accessed August 2014
mentation has to be established, as templates, including 3. Ris JM, Van Leeuwen RWF, Boom FA (2010) VTGM op de ICU
(“Parenteral admixtures on the ICU”): mind the steps! PW
guidelines for filling them out, have to be available before Wetenschappelijk Platform 4(1):11–17
performing the risk assessment. 4. Institute for Safe Medication Practices. ISMP list of high-alert
QRM procedures can establish useful functions within a medications in Acute Care Settings. http://www.ismp.org/Tools/
PQS such as providing the basis for training. highalertmedications.pdf. Accessed August 2014
5. Wunder C, Hein R, Idinger G (2013) Development of quality risk
The output and associated risk analysis justifying management in the clinical pharmacy field. Eur J Hosp Pharm
the approach should be documented and endorsed by the 20:218–222. doi:10.1136/ejhpharm-2012-0002542
organisation’s quality unit and senior management. Addi- 6. European Committee for standardization. EN15224 Health care
tionally, this information should be communicated to services – Quality management systems – Requirements based on
EN ISO 9001:2008. Annex B: Practical guide for the implementation
stakeholders for their information and to ensure their sup- of this standard in health care organizations.
port. Again reference is given to Sect. 2.2 for an example 7. Assessment of quality risk management implementation. PIC/S aide-
how to perform this for pharmacy preparations. memoire. PI 038–1. March 2012. http://www.picscheme.org.
A system of change control requires the repetition of risk Accessed December 2013
8. WHO guidelines on quality risk management. Annex 2, in: WHO
assessments because of new knowledge or if other relevant Technical Report Series No. 981, 2013: 73–4. http://www.who.int/
changes have happened. A Risk Review is therefore a natural medicines/areas/quality_safety/quality_assurance/Annex2TRS-981.pdf.
part of a quality system. WHO [8] states: “Appropriate Accessed August 2014
Stability
22
Daan Touw and Jean Vigneron
Contents 22.7 General Instructions for Storage Times . . . . . . . . . . . . . . 455

22.7.1 Shelf Life and Usage Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
22.1 Physical Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 22.7.2 Assignation System for Pharmacy Preparations . . . . . . . . . 456
22.2 Chemical Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 22.7.3 Storage Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
22.2.1 Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 22.8 What Should a Patient Know? . . . . . . . . . . . . . . . . . . . . . . . . . 459
22.2.2 Oxidation and Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
22.2.3 Isomerisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
22.2.4 Photolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
22.2.5 Degradation of the Protein Structure . . . . . . . . . . . . . . . . . . . . 443
22.3 Microbiological Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Abstract
22.3.1 Packaging Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 After manufacturing or preparation and during use,
22.3.2 Hygienic Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 medicines are subject to changes. Examples are a decline
22.3.3 Microbiological Vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 of the content, formation of degradation products,
22.4 Content Limits During Storage . . . . . . . . . . . . . . . . . . . . . . . . 447 changes in appearance and microbiological contamina-
22.4.1 Limits for Decline of Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 tion. In this chapter, physical degradation, chemical deg-
22.4.2 Limits to the Amount of Toxic Degradation Products . . 447
radation and microbiological aspects of the stability of
22.5 Stability Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 pharmaceutical preparations are discussed. The section
22.5.1 Method of Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 on chemical stability not only concerns hydrolysis, oxi-
22.5.2 Stability Parameters and Number of Samples . . . . . . . . . . . 449
22.5.3 Accelerated Stability Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 dation, isomerisation and photolysis but also structural
22.5.4 Long-Term Stability Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 changes of proteins. This basic knowledge leads to gen-
22.5.5 In-Use Stability Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 eral advice on how to improve the stability of pharmacy
22.5.6 Ongoing Stability Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 preparations. This is not only relevant for the formulation
22.5.7 Reaction Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
of medicines, but also for reconstitution and for the stor-
22.6 Stability Data in a Pharmacist’s Daily Practice . . . . . . 452 age in the pharmacy of licensed pharmaceutical
22.6.1 Storage at a Different Temperature . . . . . . . . . . . . . . . . . . . . . . 452
22.6.2 Shelf Life when Packaging has been Changed . . . . . . . . . . 453
preparations. If degradation reactions are sufficiently
22.6.3 Extension of the Shelf Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453 understood, the pharmacist may be able to solve every
22.6.4 Preventing Wastage and Saving Money by an Extended day’s stability problems. Examples are given.
Shelf Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 When performing stability studies on medicines to
22.6.5 Searching Information about Stability and Compatibility
for Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
determine shelf-life and usage periods, it is shown that
chemical degradation may be fairly predictable but shelf
life and usage periods may be influenced by less predict-
able causes. Changes that can be observed by the patient
Based upon the chapter Stabiliteit by Yvonne Bouwman-Boer and
Herman Woerdenbag in the 2009 edition of “Recepteerkunde”. offer another perspective. The last section of the chapter
provides advice on storage conditions, shelf life and
D.J. Touw (*)
Department of Clinical Pharmacy and Pharmacology, University usage periods of pharmacy preparations.
Groningen, University Medical Center Groningen, Groningen,
The Netherlands
e-mail: [email protected] Keywords
Stability Chemical degradation Microbial
J. Vigneron
CHU Brabois Service Pharmacie, 54511 Vandoeuvre, France degradation Shelf life Storage Hydrolysis
e-mail: [email protected] Oxidation Photolysis Stability testing Usage period

436 D.J. Touw and J. Vigneron
Physico-chemical degradation can be limited by a robust

22.1 Physical Degradation design, a suitable container, correct storage conditions and
good patient information.
Physical degradation is seen as a change in physical
characteristics without a change of the active substance mole-
cule itself. Physical changes usually concern the dosage form: 22.2 Chemical Degradation
resuspendability of suspensions, viscosity, phase separation of
emulsions, capsules getting sticky, alterations of friability, Upon storage of medicines, chemical reactions inevitably
disintegration, or dissolution rate of tablets. But taste, colour, occur. These reactions may proceed with a noticeable
smell or appearance of solutions of medicines can also alter. speed or unnoticeably slow. Degradation products of active
Changes may also mean the appearance of agglomerates and substances are usually inactive, although toxic degradation
particles or, crystallisation. These changes usually negatively products are sometimes formed.
affect the usability and efficacy of medicines.
Isoniazid degrades into hydrazine, which has carcino-

The subvisual physical degradation is an important genic properties.
aspect that cannot be ignored when studying the sta- When primaquine degrades under the influence of
bility of injectable medicines. An interesting example light (photodegradation) degradation products may be
is the stability of pemetrexed. The chemical stability formed that are more toxic than primaquine itself [5].
has been evaluated by various authors [1, 2] who Under the influence of light chloramphenicol
observed little change by HPLC after 1 month. How- degrades into p-nitrosanilline, which is carcinogenic.
ever, the turbidity measurement shows an increase of Paracetamol (acetaminophen) hydrolyses into
the NTU value (Nephelometric Turbidity Measure- aminophenol, which in turn oxidises into toxic
ment) when the solution is stored at low temperature chinonimines. These processes may occur in the raw
(refrigerator or freezer) [3]. This phenomenon can material [6].
provoke the occurrence of a visible precipitate.
Hydrolysis and oxidation are the most frequently occurring

As a rule, medicines need to comply with their physical degradation reactions, in addition to isomerisation and photol-
characteristics during their shelf life. ysis. For pharmaceutical proteins, degradation processes may
Physical changes probably indicate a problem with the lead to alteration of the tertiary and quaternary structure.
robustness of the design of the medicine. Another reason The development of a new medicine requires knowledge
could be that the pharmacist fails to realise the importance of about these degradation reactions, about the rate with which
a special container of the medicine. The latter may occur they occur, and about the factors that influence these pro-
when the pharmacist repacks for automated medicines dis- cesses. Formulation, production conditions, container and
pensing systems. Insufficient information to the patient on storage conditions should be optimised to minimise the
how to handle the medicine can also be the reason for degradation of the active substance within the medicine.
physical instability. When the patient usually stores his Section 22.6 describes how data on chemical stability at a
medicines in a refrigerator, this habit may be the cause of certain temperature and basic knowledge of reaction kinetics
the crystallisation of the active substance in an oral solution can be used when in daily practice a product’s stability has to
which should not be stored below room temperature. be re-estimated, because of a different storage temperature
Physico-chemical instability of emulsions (e.g. creams), or of a change in medium.
can be predicted with a test where the temperature is
changed with short cycles.
To get an idea of the stability of an extemporaneous 22.2.1 Hydrolysis
preparation the only possibility is to keep a part of the
preparation in the pharmacy in order to be able to recall if Hydrolysis is the cleavage of an ester, carbon amide or
necessary or to have some information in case of a second lactam bond by water. Therefore, hydrolysis of substances
prescription. For background information on the instability can occur in aqueous solutions, but also in solids when the
of disperse systems (suspensions, emulsions) and the ways relative air humidity is sufficiently high. The hydrolysis of
to overcome those stability problems, see Sect. 18.4. For a amide bonds in proteins is called proteolysis.
useful review about the changes in dissolution rate during Generally speaking, a fixed percentage of a substance is
shelf life and how to prevent them, reference is made to [4]. hydrolysed per unit of time when dissolved in water (a first
22 Stability 437
3 may shift when the temperature changes [13]. Heating of a

solution may thus influence the hydrolysis rate both through
temperature and pH. Changes in pH may also be important
during freezing and freeze-drying. Gradual freezing of an
aqueous solution results in the formation of ice crystals and
a concentrated salt solution, in which hydrolysis rates can be
4
increased due to a higher concentration or a pH shift, or both.
Therefore, freezing should be done as fast as possible.
Borate buffers show a minimal pH shift when the tem-

−log k (s-1)
perature increases (e.g. during heating or sterilisation) or

5 decreases (freezing) and the concentration that is required
to achieve an isotonic solution is relatively low. These
two factors contribute to this buffer’s suitability for oph-
thalmic solutions (see Sect. 10.6.1).
PRODUCT DESIGN
6 Hydrolysis of an ester can result in a substance with
reduced aqueous solubility; possibly leading to precipitation
even when relatively little degradation has occurred. An
example is the hydrolysis of prednisolone disodium phos-
phate and the formation of the poorly soluble prednisolone.
7
Examples of substances that are prone to hydrolysis are:
0 2 4 6 8 10 12 acetylsalicylic acid, ampicillin, barbiturates, chlorampheni-
pH col, chlordiazepoxide, cocaine, corticosteroid phosphate or
Fig. 22.1 pH stability relationship for acetylsalicylic acid solution [11]
succinate esters, proteins, folinic acid, indomethacin, local
anaesthetics, paracetamol (acetaminophen), pilocarpine,
tropa alkaloids (atropine, scopolamine), xylomethazoline
order reaction, see Sect. 22.5.7). The absolute amount thus and the antimicrobial preservatives methyl and propyl
depends on the concentration of the substance. This is in parahydroxybenzoate. In the field of oncology, melphalan
contrast to the process of oxidation, for which a fixed quan- and bendamustine hydrochloride are highly susceptable to
tity of the substance degrades per unit of time (a zero order hydrolysis with a shelf life of 1.5 h for melphalan and 3.5 h
reaction). for bendamustine at room temperature.
Hydrolysis is a pH-dependent process, which usually
proceeds more rapidly in either acidic or alkaline conditions.
Cocaine Eye Drops
Therefore, substances that are prone to hydrolysis have a pH
The hydrolysis of cocaine strongly depends on pH and
optimum. For example, the rate of hydrolysis of indometha-
temperature. To minimise degradation, the pH should
cin is the lowest at pH 4.9 and increases with higher and
not exceed 5.5. Therefore, a boric acid –
lower pH values [7–9]. For isoniazid, the stability optimum
benzalkonium solution is suitable for the preparation
regarding hydrolysis is pH 6 [10], and also here, hydrolysis
of iso-osmotic solutions, with a pH of 4.5–5 (see
increases with higher and lower pH values. A classic exam-
Table 22.1).
ple of an investigation of the influence of pH on hydrolysis is
that for acetylsalicylic acid [11]. Figure 22.1 shows the pH Table 22.1 Cocaine Hydrochloride Eye Drops 5 % [14]
stability relationship for acetylsalicylic acid that resulted Cocaine hydrochloride 5g
from that investigation. Benzalkonium chloride 0.01 g
Hydrolysis is not only dependent on the pH (catalysis by Boric acid 0.4 g
H+ or OH ions), but may also be catalysed by certain ions, Disodium edetate 0.1 g
such as phosphate and acetate. In general, higher ion Water, purified ad 100 mL
concentrations promote hydrolysis reactions [12]. In a buff-
ered solution, hydrolysis thus depends on the pH, the type of Cocaine may degrade into benzoylecgonine and
buffer and the concentration of that buffer. subsequently into ecgonine and benzoic acid [15]. The
Hydrolysis rates increase by 2–3 times for every 10 C
temperature increase. Note that the pH of a buffered solution (continued)
reactive, due to the presence of one or more unpaired

degree of degradation that results from heating the electrons. Free radicals exist as the superoxide anion
solution has been investigated. The unheated solution (•O ¼ O-), hydroxyl radicals (•OH) and carbon (chain)
(pH 5.0) contained 1.3 % benzoylecgonine, expressed radicals (•R). Many oxidation reactions are catalysed by
as percentage of the cocaine content. After 30 min of traces of heavy metals.
heating the solution at 100 C, the benzoylecgonine The mechanisms and kinetics of oxidation reactions are
content had increased to 2.1 % and after 15 min very complex, which makes it difficult to predict whether
at 121 C to 2.7 %. Due to the weak buffer in the oxidation reactions of organic molecules will occur and how
solution, the degradation resulted in a pH decrease to to prevent them from happening.
approximately 3. The oxidation reaction rate is usually not dependent on the
concentration of the substance (see Sect. 22.5.7). Therefore,
the content of low-dose preparations decreases relatively faster
The process of hydrolysis can be inhibited by using the by oxidation than that of high-dose preparations. This is in
right pH, by reducing the storage temperature, or by contrast to the process of hydrolysis, during which the percent-
processing the active substance in the solid state. Solid age of the substance that degrades is more or less constant per
state active substances and medicines should be stored unit of time. Like all chemical reactions, oxidation proceeds
under dry conditions to prevent hydrolysis. more slowly at lower temperatures. However, oxygen
The pH of a prednisolone oral solution (Table 22.2) is set molecules dissolve better in water and fats at lower
at 7–7.5 to limit the hydrolysis of prednisolone disodium temperatures, which implies that more oxygen will be present
phosphate. After 12 months of storage, no degradation is in the formulation to initiate oxidation reactions. The degree of
measurable. However, hydrolysis of the preservative methyl oxidation of many substances in aqueous solutions is depen-
parahydroxybenzoate limits the shelf life to 12 months, as dent on the degree of ionisation of the substance. Lowering the
the amount of preservative has then been decreased by 25 %. pH will lead to protonation of nitrogen atoms in amines and
blocking of easily excited electrons in several organic
molecules [17]. Those molecules will therefore be protected
by a low pH. This is only the case for basic substances.
22.2.2 Oxidation and Reduction An example of a simple oxidation reaction is the conver-
sion of Fe2+ into Fe3+. Examples of active substances that are
Oxidation is a chemical reaction during which a substance prone to oxidation are acetylcystein, adrenaline, apomorphine,
loses (donates) electrons, whereas during reduction an elec- clioquinol, dithranol, dobutamine, ergotamine, hydroquinone,
tron is taken up (accepted) by the substance. Active isoniazid, mesalazine, naloxone, neomycin, oxycodone, para-
substances are decomposed more often by oxidation than cetamol, peptides, salbutamol, phenothiazine derivatives
by reduction. Typical oxidation processes involve organic (promazine, promethazine, chlorpromazine), phenylephrine,
molecules that react with oxygen molecules that are physostigmine, tetracycline, tretinoin, the vitamins A and D,
dissolved in water or present in the air. The process usually and the excipients: flavouring agents, fragrances and unsatu-
consists of a cascade of reactions through the formation of rated fats (vegetable oils, suppository bases).
free radicals, which are molecules or atoms that are highly Reduction of active substances occurs more infrequently
than oxidation. Some examples are:
Table 22.2 Prednisolone Oral Solution 1 mg/mL (as disodium phos-
• The conversion of hydrogen peroxide into oxygen
phate) [16] • The reduction of methylthionine (in the solution for injec-
tion) into its leuco-form, which may be the active form
Prednisolone sodium phosphate 0.146 g
Bananas flavouring (local standard) 0.1 g
anyway
Disodium edetate 0.1 g • The formation of metallic silver in an aqueous solution of
Disodium phosphate dodecahydrate 1.9 g silver nitrate that is exposed to light and that contains a
Methyl parahydroxybenzoate 0.15 g trace of an organic substance to prime the reaction
Sodium dihydrogen phosphate dihydrate 0.21 g Oxidative reactions often proceed into polymerization
Sorbitol, liquid (crystallising) 25.8 g reactions, resulting in large molecules of which the complex
Water, purified 77.5 g structures can be difficult to determine. A well-known phar-
Total 106.8 g (¼ 100 mL) maceutical example is the brown discolouration of adrena-
line solution.
22 Stability 439
situations it is essential to add antioxidants, substances that

Upon degradation, adrenaline solution first turns reduce oxidation.
into pink, then red, and finally brown. Adrenaline
is first oxidised into adrenochrome, which is cons-
22.2.2.2 Antioxidants
ecutively oxidised into the fluorescent adrenolutin
Oxidation reactions can be inhibited by three types of
and brown melanin products [18]. The oxidation
antioxidants [20]:
rates increase with increasing pH. The stability is the
1. True antioxidants: these are thought to block chain
best at pH 3.2–3.6, by virtue of the relatively low
reactions by reacting with free radicals. The agent
reaction rate of the first step at this pH [19]. At
(e.g. DL-alpha-tocopherol, butylhydroxytoluene) donates
pH 7.4, the rate of the second step is relatively high,
electrons and hydrogen atoms, which are accepted by free
whilst at pH 6.9, accumulation of adrenochrome
radicals, more easily than the active substance itself.
occurs [18].
2. Reducing agents: these have a lower redox potential than
The raw material paracetamol may hydrolyse into
the active substance or excipient they are protecting. The
aminophenol at high relative humidity. Subsequently,
agent (e.g. sodium metabisulfite, sodium formaldehyde-
aminophenol is oxidised into toxic quinonimines and
sulfoxylate, ascorbic acid) is oxidised more easily than
PRODUCT DESIGN
related substances [6]. This process causes a
the active substance.
discolouration of the powder from white to pink,
3. Antioxidants synergists: these enhance the effects of
brown, and black. Discolouration of a paracetamol
antioxidants. For instance by the binding of copper or
solution may imply that the raw material was stored
iron ions, which catalyse the oxidation reaction. Usually,
under humid conditions. To be able to be aware of
complexing agents are used for this purpose
toxic degradation products, it is advised not to add a
(e.g. disodium edetate, citric acid).
coloured flavouring agent, like caramel, to a paraceta-
mol solution.
The mechanism of action of a substance that is
oxidised more easily than the active substance can be
Oxidation processes can be inhibited by limiting the
explained by Nernst’s law:
availability of oxygen and sometimes by the addition of
antioxidants. 0, 059 ½ox
E ¼ E0 þ log ð22:1Þ
n ½red
22.2.2.1 Limiting the Availability of Oxygen in which E ¼ redox potential

An effective way to prevent oxidation is to remove oxygen E0 ¼ standard redox potential
from the water that is used in the formulation and to prevent n ¼ number of electrons in the redox equation
the influx of oxygen after preparation. It is nearly impossible [ox] ¼ concentration of substance in oxidised form
to completely remove oxygen from water, oil or fat. [red] ¼ concentration of substance in reduced form
Preventing the influx of oxygen is only possible if the prep- This equation can be used for both the active sub-
aration is packed separately per dose. For injectable, oxygen stance and the antioxidant. The active substance is
sensitive substances, in ampoules, flushing with and packag- protected when the redox potential of the antioxidant
ing under an inert gas is a common and effective method to is several units lower than the redox potential of the
decrease the oxygen content. However, the transfer of a active substance, which is the case when both the
solution for injection from an ampoule into a syringe allows standard redox potential of the antioxidant is lower
oxygen to dissolve in the water. Therefore, it is usually not than that of the active substance and the antioxidant
possible to prepare the syringes far ahead when dealing with is mainly present in its reduced state. For a given
oxidisable active substances (for example at the Centralised oxygen load, protection against oxidation lasts longer
Intra Venous Additives Service (CIVAS)). when the initial concentration of the antioxidant is
In multidose containers, the ingress of oxygen can only higher. Some active substances have a very low stan-
be prevented marginally. For aluminium tubes, squeezing dard redox potential, which renders protection by the
them and rolling them up helps to a certain extent. For usual antioxidants ineffective. In these cases, elimina-
bottles, limiting the empty volume in the top may increase tion of oxygen is the only way to prevent oxidation.
the shelf life of the unopened container. By substituting a The Nernst equation can only be applied when the
part of the water in an aqueous solution for a concentrated redox potentials of both the active substance and the
sugar solution, glycerol or propylene glycol, the solubility of antioxidant are known.
oxygen is diminished, and thus oxidation. However, in many
Generally, the choice for an antioxidant or combination

of antioxidants and the required concentration are deter- of the medicine is not only limited by the require-
mined experimentally. This choice is also dependent on the ment of a maximum of 10 % decomposition of
phase that should contain the antioxidant, either the water acetylcysteine, but also by the unpleasant smell of
phase or the oil phase. The antioxidants that act via the first the sulfur-containing degradation products. By HPLC
mechanism are fat-soluble; those that act via the second and the effects of antioxidants on the formation of
third mechanism are water-soluble. Some examples follow N,N-diacetylcystin in acetylcysteine eye drops
showing the importance of actually testing the anticipated (Table 22.5) could be determined.
effect of an antioxidant.
Table 22.5 Acetylcysteine Eye Drops 5 % [25]
Acetylcysteinum 5g
Example 1. Blocking the Oxidation of Tretinoin Disodium edetate 0.1 g
Butylhydroxytoluene decreases oxidation of tretinoin Trometamol 5.3 g
both in an ethanol/propylene glycol mixture (Table 22.3) Water, purified ad 100 mL
and in cetomacrogol cream (Table 22.4).
Table 22.3 Tretinoin Cutaneous Solution 0.05 % [21]

It appeared that ascorbic acid, sodium metabisulfite
or sodium formaldehyde sulfoxylate had no effect or
Tretinoin 0.05 g
even increased the amount of N,N-diacetylcystin and
Alcohol denaturated 95 % V/V (local 40.4 g
standard) potentiated the smell of sulfur containing substances.
Butylhydroxytoluene 0.05 g
Total 92.5 g (¼ 100 mL)
Example 3. Dithranol Cream

Ascorbic acid has been added to a dithranol cream
Table 22.4 Tretinoin Cream 0.05 % [22]
(Table 22.6) following research results with similar
Tretinoin 0.05 g preparations [27, 28]. According to the literature [28]
Alcohol denaturated 95 % V/V (local standard) 12 g the combination of ascorbic acid and salicylic acid
Butylhydroxytoluene 0.04 g protects dithranol in a cetomacrogol cream better
Cetomacrogol cream FNAa 88 g
than salicylic acid alone. If ascorbic acid and salicylic
Total 100 g acid are omitted, the degradation of dithranol amounts
a
Cetomacrogol emulsifying wax (BP) 15 g, sorbic acid 200 mg, up to 40 % instead of 10 % within 1 month at room
decyl oleate 20 g, sorbitol, liquid (crystallising) 4 g, water, temperature.
purified 60,8 g. Total 100 g
Table 22.6 Dithranol Cream 0.05 % [26]
On the contrary, a different antioxidant, DL-alpha- Dithranol 0.05 g
tocopherol, increases oxidation in cetomacrogol Ascorbic acid 0.1 g
cream. This phenomenon is caused by peroxides, Salicylic acid (90) 1g
which originate from DL-alpha-tocopherol oxidation Lanette cream I FNAa 98.85 g
in the oil phase. The peroxides generate free radicals Total 100 g
that initiate the oxidation of tretinoin. a
See Table 12.34
Example 2. Instability of Acetylcysteine The concentration of the antioxidant is related to the total
Acetylcysteine decomposes in aqueous solution volume of the preparation instead of the active substance
by hydrolysis and oxidation. The oxidation into content, since the volume determines the oxygen content.
N,N-diacetylcystin is said to be predominant [23, When a preparation that contains an antioxidant has to be
24]. Furthermore, hydrogen sulfide and other sulfur diluted, caution should be exercised to ensure that the end
containing substances can be formed. The shelf life concentration of the antioxidant is not too low to be
effective.
(continued)
22 Stability 441
Table 22.7 Antioxidants with their E-number, ADI and Usual Concentrations
Antioxidant E-number ADI (mg/kg body weight) Usual concentration (%)
Ascorbic acid E 300 No limit 0.01–0.5
Butylhydroxyanisole (BHA) E 320 0.5 0.01–0.02, but less in i.v. injections
Butylhydroxytoluene (BHT) E 321 0.3 0.01–0.02, but less in i.v. injections
Sodium metabisulfite (sodium pyrosulfite, sodium hydrogen sulfite) E 223 0.7 0.01–0.2
a
Sodium formaldehydesulfoxylate 0.1
DL-alpha-tocopherol E 307 2 0.05–0.1
a
Not allowed in food
‘True’ antioxidants (type 1, see above) and reductants established for these substances. These limits are called
(type 2, see above) are used up during the shelf life, which Accepted Daily Intake (ADI) in the EU and Recommended
implies that their content is much lower at the end of the Dietary Allowance (RDA) in the US. In many countries,
shelf life than when the preparation was released. these limits also apply to pharmaceuticals. Table 22.7
PRODUCT DESIGN
Other aspects of antioxidants should be considered: summarises the antioxidants, their European identification
• Sodium metabisulfite reacts with oxygen with the forma- number, their ADI, and their usual concentrations in phar-
tion of sulfate, which results in a pH drop maceutical preparations according to [32, 33].
• Sodium metabisulfite may bind to certain active
substances, such as prednisolone disodium phosphate
and adrenaline tartrate 22.2.3 Isomerisation
Isomerisation is the transition of one isomer of a molecule

Adrenaline reacts in equimolar proportions with
into another isomer. During this transition, the configuration
sodium metabisulfite and is thereby inactivated [29a].
(spatial arrangement of molecular groups) around an asym-
Because of the equimolarity of this reaction, changing
metric carbon atom changes. Two types of isomerisation can
the concentration of either adrenaline or metabisulfite
be distinguished: racemisation and epimerisation. In the case
may change the shelf life of the preparation quite
of racemisation the molecule has one centre of asymmetry.
drastically. It is supposed that metabisulfite at first
In case of epimerisation the molecule has two or more
reacts with oxygen. Therefore, the availability of any
centres of asymmetry, of which one is involved in
metabisulfite that is left for the reaction with adrena-
isomerisation. Isomerisation is a reversible process; eventu-
line also depends on the amount of oxygen in the
ally equilibrium between both configurations is established.
preparation. Moreover, this reaction is influenced by
A solution of one of the configurations is optically active.
the pH, with a maximum rate at pH 2–3 [30].
Racemisation results in a racemic mixture without optical
To add to the complexity of the preparation, bisul-
activity. On the contrary, for epimerisation the optical activ-
fite has a negative effect on the stability of adrenaline
ity remains in equilibrium. In many cases pH influences the
in presence of light. Therefore, it may be necessary to
rate of isomerisation.
avoid the use of bisulfite if the solution is exposed to
A well-known example of isomerisation is the conversion
light during the administration, especially during con-
of ergotamine into ergotaminine and, if the other carbon
tinuous infusion [31].
atom also is affected, in aci-ergotamine. Other active
substances that degrade by isomerisation are adrenaline,
colecalciferol, ergometrine, pilocarpine and tetracycline.
Oxidation of ascorbic acid causes a yellow
discolouration. A preparation that contains this substance
can turn yellow, whilst the active substance may still be Racemisation of L-adrenaline is accelerated by light
unaffected. Therefore, masking the discolouration of and acid. At pH 4.5, racemisation is minimal. Temper-
ascorbic acid in a promethazine syrup with caramel is ature has a large influence: Q10 ¼ 2.8 (see
defendable. Sect. 22.5.7). The leftward rotating isoform is 15–20
Many of the antioxidants and complexing agents that are times more active than the rightward rotating isoform,
used in pharmaceutical preparations are also used in food so racemisation results in loss of activity.
products. Since food can be taken daily, limits have been
22.2.4 Photolysis accelerated by light. In oncology, carmustine, fotemustine

and dacarbazine are examples of active substances that
Photolysis is chemical degradation facilitated by light. The are very sensitive to light. Moreover, the degradation
standard reference on this topic is the book Photostability of products of dacarbazine are suspected of being toxic to the
drugs and drug formulations [17]. patient.
Light is a form of energy. When a molecule absorbs this Photolysis can be prevented or reduced in the following
energy, its energetic state is increased and in some cases, ways:
ionisation can occur. The molecule may return to its original • Prevent the light from reaching the medicine product.
stable state, or it may degrade. In principle, all types of • Exclude oxygen or add radical scavengers or UV absorb-
degradation can follow the absorption of light, but most ing substances.
often oxidation occurs. This combination of events is called • Reduce the exposure to light during manufacturing.
photo-oxidation. Light can also be absorbed by excipients that • Administer the medicine in subdued light or cover the
subsequently transfer a different kind of energy to the active skin with clothes after administration of a dermal
substance, which in turn may degrade. This process is called medicine.
photo-sensitisation. Examples of excipients that can act as A coating or protective secondary packaging can be used to
sensitizers are the antioxidant metabisulfite and furfural, prevent light from reaching the active substance.
which is the degradation product of glucose that is present A tablet coating can protect the core against photolysis if
in trace amounts in glucose 5 % infusion solutions [34]. this coating is not light transmissive, for example because it
The light spectra that can be absorbed by a substance can contains pigments. Suitable non-light transmissive second-
be determined from the substance’s absorption spectrum. ary packagings are carton boxes and aluminium tubes.
Coloured active substances absorb visible light; the light Brown glass may provide enough protection for its contents,
spectrum that is absorbed is complementary to the colour but not always.
of the active substance. White organic substances absorb UV
light, corresponding to their UV spectrum. The presence of
For coloured, light-protective glass, the Ph. Eur.
conjugated double bonds or an aromatic ring are an indica-
contains requirements on the transmittance of light
tion of the ability of the substance to absorb UV light and
with a wavelength of 290–450 nm. These requirements
thereby be susceptible to photolysis.
provide a certain standardisation of coloured glass, but
The most reactive part of the spectrum is UV-B
they do not guarantee that coloured glass protects
(280–320 nm), which is responsible for most direct photo-
against all kinds of photolysis. For example,
chemical degradation reactions of active substances. UV-A
phytomenadione in oily solution, colchicine tablets
(320–400 nm) is more likely to induce photo-sensitisation.
and tretinoin solution are not protected sufficiently
Infrared light is only relevant in the sense that it transfers
by brown glass or opaque plastics. In addition to the
heat, and may thus increase the reaction rate of degradation
brown bottles in which they are packaged, these
processes. Sunlight has a very broad light spectrum. Glass
products should be stored in the dark.
blocks most UV-B light present in sunlight, but still enough
may pass through to induce degradation of active substances
in glass containers, for example in a container that is kept on The disadvantage of an overwrap is that the patient or
the window sill, or in an infusion bottle hanging from the bed nurse may want to take it off and not put it back on, which
of a hospitalised patient. Fluorescent light, in some countries may result in problems in the following situations:
known as tube luminescent (TL-)light, contains a fraction of • For parenteral medicines that should be prepared for
UV light. administration and subsequently administered, wrapping
Some well-known photochemical degradation reactions the medicine conflicts with the desire to continuously
of active substances are: check the solution for clarity and volume. If a light-
• The formation of p-nitrobenzaldehyde from chloram- sensitive active substance is to be administered, the
phenicol duration of the administration should be limited.
• The formation of lumi-derivatives from ergotamine A nicardipine intravenous infusion can be exposed to
• The separation of a side chain from methotrexate light for up to 8 h, which is sufficient time for administra-
Also the oxidations of chlorpromazine, cyanocobala- tion [35]. A furosemide intravenous infusion can even be
mine, dithranol, nifedipine, tretinoin and primaquine are exposed to light for up to 24 h [36].
22 Stability 443
• Repackaging of solids in automated medicine dispensing 22.2.5 Degradation of the Protein Structure
systems should be done in such a way that the light
protective capacity of the original container is met. In Many of the newly licensed medicines are biopharma-
practice however, the new packaging material is often ceuticals, which either are proteins or contain protein
more transmissive to light than the original packaging groups. Such pharmaceutical proteins are expected to
material. Still, it is generally assumed that in most cases, become more and more available in the near future.
the shelf life in the dispensing bag is long enough to cover
the storage period of such bags, which is usually 1 week.
Examples of pharmaceutical proteins are: insulin,
An example of an active substance that requires specific
glucagon, somatostatin and analogues, erythropoeietin
attention in these situations is nifedipine.
and analogues, interferons, interleukins, monoclonal
Oxygen is usually involved in many photochemical
antibodies, gonadorelin and analogues, colony
reactions, thus the elimination of this substance is an effec-
stimulating factors, antithrombotic medicines,
tive means of protection against these reactions in many
vaccines.
cases. Radical scavengers can be used to reduce the reactiv-
ity (“quench”) of radicals or oxygen singlets. Ascorbic acid,
PRODUCT DESIGN
DL-alpha-tocopherol and butylhydroxytoluene are used for Proteins can be described by a primary, secondary, ter-
this purpose. Also lactose, mannitol, saccharose, starch and tiary and quaternary structure, all of which can be affected
povidone can have a quenching effect [17b]. Another strat- by degradation processes. See also Sect. 18.4.1.
egy is to add UV-absorbing substances, such as The primary structure of a protein consists of the arrange-
p-aminobenzoic acid, benzophenones or vanillin, to a light ment into chains of amino acids. The number of amino acids
sensitive active substance [17c]. per chain can vary from a few dozens to many hundreds.
Some active substances are so sensitive to light that light The secondary structure is created by hydrogen bonds
must be excluded to the highest possible extent during prep- between the carbonyl group of one amino acid with the
aration. In practice, this means that the preparation should amine group of another. This structure manifests itself as
not be done in the vicinity of a window and that artificial an alpha helix or in a beta sheet. Within one protein, both
lights should be switched off. Examples of pharmaceutical alpha helixes and beta sheets can occur.
preparations for which this may be necessary are dithranol The tertiary structure is formed by the folding of peptide
cream, phytomenadione oral solution and tretinoin solution. chains. Covalent and non-covalent bonds result in the posi-
The final question that should be raised is would it be tioning of the secondary structures in relation to each other.
necessary to protect light sensitive active substances if the Covalent bonds are disulfide bonds between two cysteine
patient uses the preparations on his skin or in the eye. The units in the protein. Examples of non-covalent bonds are
answer is that it depends on the rate of degradation and on hydrogen bonds, ionic bonds and hydrophobic bonds in the
the toxicity of the degradation products. protein. Which type of bond is formed, depends on the
length of the peptide chain, pH, electric charge, polarity,
and lipophilicity of (secondary) structural elements of the
As an example, the photodegradation products of protein.
chloramphenicol (nitroso-compounds and paranitro- A quaternary structure is the arrangement of two or more
benzaldehyde) are considered carcinogenic. These protein subunits into a complex. These subunits may be
products will be formed in vitro and in vivo and can identical but may also differ from each other. Interactions
reach the bone marrow in rats [37]. Chronic use of between subunits determine the three-dimensional orienta-
chloramphenicol has been connected with bone mar- tion towards each other and therewith the structure of the
row depression, not caused by chloramphenicol itself. whole protein (dimer, trimer, tetramer). The three-
Apart from the question if this risk is estimated well dimensional structure of proteins is essential for their
[38], it can be avoided completely if the patient covers biological efficacy and is highly sensitive to degradation.
his skin if a dermal preparation has been applied and The chemical bonds in proteins can be disrupted by:
only use chloramphenicol as eye ointment 1 % at • Hydrolysis of amide bonds (proteolysis)
night. See also Sect. 10.5. • Deamination (cleavage of an unbound amino group of an
amino acid)
If a light sensitive substance is administered via an infu- • Disulfide exchange (breaking of disulfide bonds and for-
sion administration system, this should be covered, or made mation of new disulfide bonds with other cysteine units)
from opaque or completely light-resistant material. These degradation reactions are influenced by pH, tempera-
ture, and the presence of light and oxygen.
The spatial structure of proteins (tertiary and quaternary) can A good microbiological quality can be achieved by using
be disrupted by: starting materials of the right quality, by working hygieni-
• Aggregation (coagulation of proteins) cally, by using germicidal treatments, and by using clean or
• Denaturation (unfolding of proteins) sterile packaging material (see Sect. 19.5.3).
• Precipitation The construction and volume of the stock packaging, the
• Adsorption (binding of lipophilic parts of the protein to patient packaging, and the hygiene during repackaging from
surfaces) stock packaging to patient packaging determine the chance
Many factors influence the disruption of the spatial structure. and amount of contamination. The formulation of the medi-
Changes in temperature and pH can induce aggregation. The cine and the storage conditions (temperature, humidity)
pH and ionic strength influence the charge of the amino acids determine the suitability for growth of micro-organisms.
and therewith the bonds and tertiary structure. In general, This is called the microbiological vulnerability (see also
the higher the ionic strength, the greater the influence is on Sect. 22.3.3).
the structure. However, the effect of specific ions on the The factors packaging, hygienic handling, microbio-
structure may vary. logical vulnerability, and storage conditions are discussed
In addition, the concentration of the pharmaceutical pro- separately in the next paragraphs, but for the determination
tein and the processes that they are subjected to, such as of a safe shelf life concerning the microbiological stability
dissolving, suspending, and diluting, can be of influence. the interdependence of these factors should be considered.
Shaking a vial can cause foam formation and denaturation. When for example a medicine is microbiologically vulnera-
Shearing stress, as with the use of peristaltic pumps, can ble, the requirements for the construction of the container
cause aggregation. Certain packaging materials are more and the storage conditions must be stricter.
absorbent than others.
Degradation of proteins can be prevented by not changing
the composition of the solution of the protein, by not
22.3.1 Packaging Material
repackaging, by not shaking but gentle swirling of the solution,
by not using peristaltic pumps, by avoiding large temperature
For the storage of medicines in the pharmacy, storage in the
differences, and by not heating the solution. Processes in the
primary container (as dispensed to the patient) is preferred
pharmacy in which proteins are involved are for example
over packaging in stock containers. The reason for this is
dissolving a freeze-dried pharmaceutical protein before use,
obvious, since a primary container will not be opened before
or the preparation with a protein raw material like polymyxin.
dispensing. Stock containers are frequently opened for
Stability studies have demonstrated that monoclonal
repackaging the contents, and thus subject to contamination
antibodies are chemically stable in daily practice. Rituximab
by the hands of the operator, utensils, and possibly by air-
and trastuzumab infusion are stable for 6 months when
borne micro-organisms.
stored between 2 C and 8 C [39, 40]. Bevacizumab
When the use of stock containers is inevitable, the vol-
repackaged in syringes is stable for at least 3 months [41].
ume should be restricted to limit the number of times that the
stock container will be opened. As a general rule, a stock
container should contain no more than ten times the amount
22.3 Microbiological Stability
that is dispensed to an individual patient.
A multidose container should also ensure a minimum
Medicines must have a low micro-organism content and for
chance of contamination. This is especially important when
some administration routes, the products have to be free of
the preparation is microbiologically vulnerable, or has
micro-organisms (sterile). The requirements are described in
stricter microbiological requirements (eye drops, creams)
Sect. 19.6.2. The microbiological quality of a preparation
than preparations that are less vulnerable, such as water-
can worsen after preparation despite a good starting quality.
free dermatological preparations.
This happens when micro-organisms that are present grow
(see Sect. 19.2) or when micro-organisms from the environ-
ment contaminate the preparation during storage in the
pharmacy or at home, and during use by the patient. The 22.3.2 Hygienic Handling
microbiological shelf life of a medicine depends on:
• The initial degree of contamination Hygienic handling means that contact of the medicine with
• The probability of contamination from the environment sources of microbiological contamination are minimised.
• The suitability of the preparation for growth of micro- Relevant sources of micro-organisms for pharmacy
organisms (see Sect. 19.4) preparations are the human body, dirty utensils, and moist
22 Stability 445
surfaces. These are more likely sources of contamination for presence or absence of antimicrobial agents, pH, environ-
medicines than airborne contamination. mental temperature and relative humidity. These factors are
The operator’s hands are an important source of discussed separately.
microbiological contamination, as such, but also as a
medium for transferring contamination coming from other
body parts. This can be limited by wearing gloves during 22.3.3.1 Water
preparation. However, a study into the contamination of hard The presence of water is a prerequisite for the growth of
gelatine capsules via handling with bare hands showed that micro-organisms (see Sect. 19.2). This implies that in dry
the contamination may be minimal in practice [42]. Despite pharmaceutical preparations no growth of micro-organisms
these findings, the use of gloves becomes more and more is to be expected, as spore forming micro-organisms reside
common practice, not only from a microbiological perspec- in their spore form, whereas non-spore forming micro-
tive but also from an occupational health and safety perspec- organisms die. A trace of water, e.g. condensed water, may
tive (see Sect. 26.4.3). be sufficient for revival of spores. For this reason, a preser-
Hygienic handling is the most important factor for good vative agent is sometimes added to tablets that are used in
aseptic handling, both in the pharmacy and during reconsti- tropical areas [45]. The chances of survival for various
PRODUCT DESIGN
tution on hospital wards (see Sect. 31.3.3). micro-organisms are dependent on the water content in the
Proper hygienic handling by the patient can be improved preparation. Some micro-organisms can only survive in a
with a well-constructed container, such as a tube for a cream, wet environment, whereas others are able to resist high salt
a Gemo® dropper bottle for eye drops, or a pump sprayer concentrations or even grow in a (moist) powder. This
for nose drops that uses air from the surroundings. In addi- knowledge is important for the investigation of the
tion, the patient should be informed clearly and sufficiently microbiological vulnerability of medicines. Preferably,
about the importance of hygienic handling of the medicine those micro-organisms with the highest chance of survival
(see Sect. 37.7.4). in the product are used in studies.
A measure for the water content in a preparation is the
water activity, as defined in the Ph. Eur. [46]. The water
22.3.3 Microbiological Vulnerability activity is the ratio between the water vapour pressure of a
preparation at a certain temperature and the water vapour
A preparation is microbiologically vulnerable when it pressure of pure water at the same temperature. Therefore,
facilitates microbiological growth. Microbiological vulnera- water activity is the reciprocal of the osmotic value.
bility can be investigated with a challenge test, a test for the Table 22.8 gives an overview of micro-organisms that can
effectiveness of the preservative. In this test, the degree of grow at a certain water activity, with pharmaceutical
growth or eradication of micro-organisms in a formulation is examples.
investigated. The predominant reason to perform challenge Micro-organisms cannot grow in a pharmaceutical prep-
tests is to test the effect of varying the formulation on the aration with a water activity below 0.5. Concentrated
microbiological vulnerability. However, firm statements on solutions, for example of saccharose, sorbitol, sodium chlo-
microbiological vulnerability are difficult to make. Only a ride and urea, give micro-organisms little chance to grow,
limited number of strains are tested and the question arises due to their low water activity. Simple syrup and sorbitol
whether a single inoculation with a large number of micro- solution basically need no preservation, but nevertheless this
organisms is representative for a real contamination. Still, is done for two other reasons. The first reason is that when
the Ph. Eur. contains requirements [43] for the minimal and simple syrup is used in oral mixtures, it is diluted. Preserva-
recommended eradication rate, depending on the tion then gives an extra microbiological protection of the
dosage form. mixture. The second reason is that in the stock bottle of
It is advised to test the microbiological vulnerability simple syrup condensed water can be formed at the surface
without the addition of a preservative. That way, it may be and the vacant sides of the bottle, in which micro-organisms
proven that the addition of a preservative is not always can grow.
necessary. An example is a diacetylmorphine injection for Besides the water activity, the size of the water droplets in
multiple uses for heroin addicts. A solution of 150 mg/mL the water phase of an ointment can be important. Butter,
diacetylmorphine without preservative complied with the which is not preserved, contains small water drops in which
Ph. Eur. test [44]. micro-organisms hardly grow, perhaps because the amount
Especially from research with food microbiology, knowl- of food for the micro-organisms is limited. However, this
edge is available of the factors that influence the theory does not apply to pharmaceutical preparations as
microbiological vulnerability of medicines. The most impor- well. In w/o ointment, growth of micro-organisms can
tant factors are the presence or absence of water, the occur when contaminated water is used (see Sect. 12.5.3).
Table 22.8 Water activity, micro-organisms and pharmaceutical preparations (From [47] with permission)
Water Examples of pharmaceutical preparations with this water
activity Micro-organisms that can grow at this water activity activity
1.00–0.95 Gram-negative rods, bacterial spores, some moulds Eye drops, water containing creams
0.95–0.91 Most cocci, Lactobacillus species, vegetative forms of bacillaceae,
some yeast
0.91–0.87 Most moulds Simple Syrup
0.87–0.80 Most yeasts, Staphylococcus aureus Sorbitol 70 % solution
0.80–0.75 Most halophile bacteria
0.75–0.65 Xerophile yeasts
0.65–0.60 Osmophile moulds Starch with 18 % water
0.50 Extractum glycirrhizae crudum
0.40 Sodium lactate 60 % solution
0.20 Milk powder
0.0 Dried lactose
22.3.3.2 Substances with an Antimicrobial Effect Table 22.9 Ferrous Chloride Oral solution 45 mg/mL [49]
Some active substances or excipients have an antimicrobial Ferrous chloride tetrahydrate (local standard) 7g
effect not only through reducing the water activity, but also Citric acid monohydrate 0.42 g
through a specific antimicrobial mechanism. The best- Sorbitol, liquid (crystallising) 10.6 g
known example is propylene glycol, but also ethanol, local Syrup BP 105 g
anaesthetics, chlorpromazine hydrochloride, promethazine Water, purified 8g
hydrochloride and essential oils exhibit a specific antimi- Total 131 g (¼ 100 mL)
crobial effect. In addition, the combination of weak antimi-
crobial effects of disodium edetate, borax, and boric acid
appeared to justify prolongation of the shelf life of Table 22.10 Theophylline Oral Solution for Children 30 mg/mL [50]
non-preserved eye drops over the standard limit of 24 h [48]. Theophylline-ethylenediamine, anhydrous 3.5 g
Lemon spirit BP 0.5 mL
22.3.3.3 pH Sodium hydroxide solution 2 M (local standard) 2.5 mL
Micro-organisms exist in numerous forms and shapes, so for Water, purified ad 100 mL
every (extreme) pH value, types can be found that are able
to survive and replicate under those specific conditions.
However, micro-organisms that are commonly encountered in fact no suitable preservative exists; only the use of high
during the preparation and use of pharmaceutical prepara- concentrations of parahydroxybenzoic acid esters may give
tions do not grow outside the pH range of 3–9. There are some level of preservation.
a few examples of preparations with a pH outside this range,
for example a ferrous chloride oral solution (pH 1.5) 22.3.3.4 Storage Temperature and Humidity
(Table 22.9) and a theophylline oral solution 30 mg/mL Most micro-organisms replicate more slowly in a refrigera-
(pH 9.5) (Table 22.10). Such preparations thus require no tor than at room temperature. Storage at a low temperature
preservation. generally improves the microbiological stability and slows
The pH is important for the preservative effect of sorbic down chemical degradation processes. Under freezer
acid and parahydroxybenzoic acid esters. These substances conditions, no growth takes place at all. A preservative
are most effective at pH <5. Since sorbic acid decomposes only has an antimicrobial effect when micro-organisms actu-
faster at low pH, pH 5 is used as a compromise (see Sect. ally grow. When a patient uses preserved eye drops, room
23.8.6). At a pH above 5.5–6.0, sorbic acid is not effective at temperature is therefore preferred over the refrigerator for
all. At pH 7–8.5, the effectiveness of the parahydrox- storage: micro-organisms that contaminate the eye drops
ybenzoic acid esters is strongly reduced, in part due to should be killed as quickly as possible.
their chemical instability. This implies that for dermatologi- Another concern is the effect of changes in temperature.
cal preparations with a pH > 7, or in case of hypersensitiv- Changes in temperature may lead to condensation of mois-
ity for parahydroxybenzoic acid esters already > 5, the ture from the air, which can form a thin layer of water on top
pharmacist has to resort to propylene glycol or probably of the pharmaceutical preparation. Micro-organisms that
phenoxyethanol. In case of an oral liquid with such a pH, were initially suppressed in the preparation can now grow
22 Stability 447
in this water layer. In addition, following adaptation to the Physical or microbiological changes usually lead to the
preservative, they may eventually be able to grow into the immediate expiration of the medicine but it is hard to
preparation itself. This effect is for example observed during predict when these, occur. Estimations can be made on
storage of syrups. Another, especially notorious, example is researched microbiological vulnerability of the product or
the growth of micro-organisms in tablets that are packed in a by reasoning by analogy, such as: if the maximum storage
strip impermeable to water, through which condensed water time for a chemically stable all-fatty ointment is 2 years,
cannot evaporate. Upon cooling of a tablet that was pro- then a water-containing ointment should not be stored that
duced under heated conditions, condensed water is formed. long. In fact the storage times for dosage forms given in
Covering during cooling and mixing after cooling are there- Table 22.15 are mainly based on analogy reasoning.
fore necessary precautions. Ideally, non-preserved pharma-
ceutical preparations should be stored as cool as possible and
preserved preparations should preferably be stored at room 22.4.1 Limits for Decline of Content
temperature, large temperature fluctuations should be
avoided. It is common practice to accept a decline of 5 % or 10 % of
the active substance. At the start of the shelf life, the content
PRODUCT DESIGN
22.3.3.5 Summary of the active substance is between 95 % and 105 % relative
This paragraph can be summarised as follows: to the declared content. At the end of the shelf life, the
• All preparations that contain water are microbiologically content should thus be between 90 % and 105 %
vulnerable. Dry formulations are therefore preferred from [51]. These limits are hardly attainable for the pharmaceuti-
a microbiological perspective. cal industry, as often an overage is needed to comply to the
• High percentages of propylene glycol, ethanol or sugar limits [52]. If too much of a toxic degradation product is
can reduce the microbiological vulnerability of a formed or the appearance has unacceptably changed before
preparation. the limit of the active substance has been reached, the shelf
• For the preservation of oral liquids and dermatological life of the product should be shorter.
preparations at pH <5, sorbic acid or methyl parahydrox- For pharmacy preparations, limits of 90–110 % apply to
ybenzoate is used, at pH 5–7 methyl parahydroxybenzoate, the entire shelf life (see Sect. 32.6). As an example: the shelf
and at pH >7–8.5 methyl parahydroxybenzoate, even life of the Dutch standardised preparations in the FNA is
though its preservative effect is weak. It is therefore based on a maximum content decline of 5 %. When 10 %
advised to reduce the pH or pay extra attention to the decline would be allowed, the chance on the active substance
prevention of contamination. content falling below the lower limit of 90 % would be
• The chance of microbiological contamination is reduced unacceptably high. If setting the limit for decline of content
by limiting the amount of the preparation that is dis- at 5 % would result in unacceptable storage conditions or an
pensed to the patient, by use of containers and dosage unacceptably short shelf life, it can be reasoned to accept a
devices with better protection against micro-organisms, decline of 10 %.
or by reducing the shelf life after dispensing and opening. During the preparation of medicines, content decline of
• Non-preserved preparations are stored in the refrigerator, the active substance can occur, especially by heat
preserved preparations are stored at room temperature. sterilisation. To compensate for this loss, an overage can
be added to the preparation, which means that more of the
active substance is put in the preparation to obtain a content
22.4 Content Limits During Storage of 100 % relative to declared content in the final product. In
general, the application of an overage is unattractive for
How much can a medicine be altered by instability before it pharmacy preparations. The amount to be weighed must be
cannot be used anymore? recalculated and the chance of preparation errors increases.
For medicines that show a gradual decline in content, a
limit can be determined for the decline of the active sub-
stance. Limits can also be determined for toxic degradation 22.4.2 Limits to the Amount of Toxic
products that are formed during storage. Such limits are Degradation Products
dependent on the toxicity of the degradation product. The
shelf life of a medicine can be determined by investigating A general approach, to determine limits to the concentration
the stability of the medicine under standardised and realistic of toxic degradation products, can be found in a CHMP
conditions. This paragraph discusses the norms for the guidance on impurities [53]. This directive states that if the
decline in active substance content, as well as the design of maximum daily dose is <1 g, impurities are limited to
stability studies required for determination of the shelf life of <0.1 %. At a daily dose of >1 g, impurities should be no
the medicine. greater than 0.05 %. The EMA requires a toxicological
evaluation on limits greater than these for licence

applications. For genotoxic impurities (see Sect. 26.3.3), An example is the establishment of the shelf life of
other limits apply. The applicable CHMP Guideline [54] an Isoniazid injection solution. Isoniazid when
states that if a limit is available, such as the Permitted dissolved in water, may hydrolyse and oxidise. Upon
Daily Exposure (PDE) or the No Observed Adverse Effect hydrolysis, isonicotinic acid, isonicotinamide,
Level (NOAEL), these can be used. If no limit is available, di-isonicotinoylhydrazine and hydrazine are formed
the Threshold of Toxicological Concern (TTC), which is [10, 29b]. The increase in hydrazine does not match
related to a life-long intake, can be used. A TTC value of a decrease of isoniazid content. Since hydrazine is
1.5 micrograms/day of a genotoxic impurity is defined as genotoxic, the shelf life of the product is limited to
leading to an acceptable risk for a given medicine, because it the formation of hydrazine, which is measurable even
is weighed against the benefit: the disease is considered to be before the degradation of isoniazid is measureable.
worse than the risk from the impurity in the medicine. With Neither the USP nor the BP give limits to the
this value and the expected daily dose, the maximal percent- amount of hydrazine in isoniazid oral solutions or
age can be calculated for genotoxic impurities. Higher isoniazid injection solutions. The amount in the
values than the TTC can be justified if: starting material is limited to 0.05 % by the Ph. Eur.
• The therapy with the medicine is of short duration as hydrazine sulfate relative to isoniazid, which equals
• A life-threatening condition is treated to 0.012 % hydrazine. Hydrazine may be present in
• The expected survival is <5 years the starting material following the synthesis.
• A person is exposed to the same impurity from other A PDE for hydrazine can be calculated from the
sources in higher quantities NOAEL [58], which is 1 microgram/day for life-long
• The genotoxic impurity is also a metabolite formed in exposure.
the body Using the general TTC approach, an acceptable
Since many medicines are used for only a short period of percentage of 0.00005 % or 0.5 ppm for long-term
time, the TTC concept has been expanded [55]. The amount use and of 60 ppm for short-term use can be calculated
of 1.5 micrograms/day is applicable for an exposure as isoniazid injection solutions usually contain
>12 months. For an exposure <1 month, the TTC limit is 100 mg/mL isoniazid and the daily dose is 300 mg.
120 micrograms/day. Since 3 mL is allowed to contain up to 1.5 micrograms
and 120 micrograms of hydrazine respectively, the
maximum allowable concentration in the injection is
A limit to hydrazine in Isoniazid Oral solution
0.5 microgram/mL equalling 0.00005 % or 0.5 ppm
(Table 22.11) and Injection solution (Table 22.12).
and 60 micrograms/mL equalling 0.006 % or 60 ppm.
Isoniazid injection solution FNA (Table 22.11) is
Table 22.11 Isoniazid Solution for Injection 200 mg ¼ 2 mL
(100 mg/mL) [56]
sterilised by autoclaving, which increases the amount
of hydrazine in the solution, for example from 0.02 %
Isoniazid 10 g
(relative to isoniazid in the starting material) to 0.1 %
(after autoclaving). During storage at 25 C, the
Hydrochloric acid (local standard) q.s.
amount of hydrazine increases with 0.1 % every
Water for injections ad 100 mL
3 months. These percentages are higher than calcu-
lated with the TTC concept, also if a higher limit is
applied because of short duration of the intravenous
Table 22.12 Isoniazid Oral Solution 10 mg/mL [57] therapy.
Isoniazid 1g However, based on the justifications described
Disodium edetate 0.1 g above, an exception to the general rule can be made
Glycerol 85 % 20 g for isoniazid as an injection. Firstly, the injection is
Methyl parahydroxybenzoate 0.15 g given as a treatment to a life threatening condition to
Sodium citrate 0.075 g very weak tuberculosis patients. Moreover, hydrazine
is also formed in the body upon the metabolism of
Total 105 g (¼ 100 mL)
(continued)
(continued)
22 Stability 449
22.5.2 Stability Parameters and Number

isoniazid in larger quantities than are formed during of Samples
storage of the injection solution [59, 60].
Should the limit be decreased, this means that the Directly at the start of a stability study, the parameters to be
injection cannot be autoclaved, which results in less determined and their limits for storage should be established.
certainty about sterility in the situation of small-scale Some parameters should always be determined (see further
preparation. Storage in the refrigerator would reduce Chap. 32):
the degradation rate, but then the concentration of the • Active substance content
injection has to be lowered to prevent precipitation. • Content of toxic degradation products
This would result in a larger volume to be • Appearance (colour, clarity, phase separation)
administered, which would be burdensome to the • Dissolution time and disintegration time of tablets and
already weakened patient. capsules
It is clear that Isoniazid injections should only be • pH of aqueous solutions
given if there are no therapeutic alternatives. Even • Resuspendability of suspensions
Isoniazid oral solution FNA (Table 22.12) is a better In addition, determination of the content of the preservative
PRODUCT DESIGN
alternative from a toxicological perspective. can be useful to detect degradation and adsorption. The
determination of the antioxidant may be useful in certain
cases, but a decrease of this substance is to be expected and
does not necessarily mean that the product cannot be used
anymore.
22.5 Stability Studies Since it is not always known beforehand which changes
occur, it is better to monitor a few parameters more instead
The following types of stability studies are described:
of less.
• Accelerated
The same holds true for the number of samples. This
• Long term or real time
number depends in the first place on the accuracy of the
• In use
assay [51], see also Sect. 20.4.4. However, to allow for
• Ongoing
repetition of assays or to determine samples at extra time
All types of stability studies require an analytical method
points that turn up during the study, it is advised to have an
that is specific for the active substance (stability indicating)
ample number of samples.
to allow for determination of the stability of the preparation.
The parameters to be determined should be defined beforehand.
For a stability study of a parenteral medicines
samples are scheduled at t ¼ 0, t ¼ 3 months, t ¼ 6
22.5.1 Method of Analysis months, t ¼ 12 months, t ¼ 18 months, t ¼ 2 years
and t ¼ 3 years. It was calculated that per sample
The method of analysis (assay) should allow for determina- point 5 vials should be tested. That makes 35 vials.
tion of the content of the parent active substance and, if Because of loss, more sample points or extra tests it is
necessary, the amount of degradation product that is formed. advised to store at least 42 or 49 vials (1 or 2 extra
Therefore, the assay should be specific, which means that it vials per sample point).
is able to quantify the parent substance in the presence of
degradation products and excipients (stability indicating).
The method has to be validated.
For the validation of analytical methods, an international
guideline applies [61] that has been elaborated by EDQM, 22.5.3 Accelerated Stability Testing
see Sect. 32.16.2. For stability studies on pharmacy
preparations, where there may be neither the equipment During the design phase of a medicine, stability studies are
nor the time available to develop and validate an analytical performed, to investigate the influence of variations of the
method, as an alternative approach [62–64] can be used. formulation and to determine under which circumstances the
The reduced reliability of the results of stability studies final stability study should be performed. To limit the time
on pharmacy preparations compared to the stability data of awaiting for the results, degradation reactions can be
licensed medicines can be compensated with a relatively accelerated by increasing the temperature. According to
short shelf life. ICH guidelines (see Table 22.13), the standard conditions
Table 22.13 Guidelines for long-term stability testing 22.5.4 Long-Term Stability Testing
ICH guidelines (www.ich.org):
Q1A Stability testing of new drug substances and products Long-term stability testing is used to determine the shelf life
(R2) of the medicine. Long-term stability studies should thus
Q1B Photostability testing of new substances and products show the latest time point on which the product still
Q1C Stability testing, requirements for new dosage forms complies with the specifications.
Q1D Bracketing and matrixing designs for stability testing of new For the execution of long-term stability studies, world-
substances and products
wide ICH guidelines, WHO guidelines and European CPMP
Q1E Evaluation of stability data
guidelines are followed. Table 22.13 gives an overview of
Q3A Impurities in new drug substances
the most important guidelines. These guidelines include the
Q3B Impurities in new drug products
Q5C Stability testing of biotechnological/biological products
following directions:
WHO guidelines (www.who.int/en/):
• Storage conditions for storage at room temperature are
WHO guidelines for stability testing of pharmaceutical products
25 2 C at 60 5 % relative humidity, for storage in
containing well established drug substances in conventional dosage the refrigerator 5 3 C, and for storage in the freezer
forms (http://whqlibdoc.who.int/hq/1994/WHO_PHARM_94.565_rev. 20 5 C.
1.pdf) • Sampling times are every 3 months for the first year,
European CPMP guidelines (www.ema.europa.eu/ema/): every 6 months for the second year and once yearly
Stability testing for applications for variations to a marketing thereafter.
authorisation
• At least three independent batches should be investigated
Stability testing of existing active ingredients and related finished
products in their final package, which are produced according to
In use stability testing of human medicinal products the final method of preparation.
Maximum shelf life of sterile products of human use after first opening • The batch size should relate to the final batch size.
or following reconstitution • Stability testing should be based on knowledge of the
Annex: declaration of storage conditions for medicinal products behaviour of the active substance and the dosage form.
particulars and active substances From the experience with stability testing of the Laboratory
of Dutch pharmacists some advice can be added:
for an accelerated stability study are 40 C 2 C at • Pharmacy preparations usually have a short shelf
75 5 % relative humidity. life; therefore, sampling times should be adjusted
However, the recalculation of the rate of degradation accordingly.
under accelerated conditions to the rate at the final storage • Keeping a constant temperature during long-term stabil-
temperature has its limits. This approach usually does not ity studies is important, not only to comply with the
apply well to heterogeneous systems like emulsions or regulations, but also for repeatability and interpolation
suspensions. An increase in temperature may result in a of the results. Refrigerators and incubators with tempera-
change of the nature of this kind of preparations, such as ture monitoring are therefore required.
the dissolution of dispersed ingredients, or the breaking of • Studies of preparations that are packed in water (semi)-
the emulsion. Moreover, at higher temperatures interaction permeable packaging material should be performed at
with the primary packaging material can take place in a constant relative humidity too. Ideal for such studies are
different way. Also for solutions, a rise in temperature can climate cabinets in which both the temperature and the
lead to important changes. The pH shift of buffer solutions is humidity can be controlled. Alternatively, saturated aque-
being discussed in Sect. 22.2.1, but also the activation ous solutions of salts can be used to control the relative
energy of a degradation reaction can change, meaning that humidity in air-tight cabinets [65, 66].
the Arrhenius equation (see Sect. 22.5.7) cannot be used to • Preparations that are packed in water (semi)-permeable
interpolate over large temperature intervals. packaging material should be checked for evaporation of
Another example of an accelerated stability study is the water by regular weighing.
acceleration of the rate of phase separation in emulsions by • Up to a shelf life of 3 years the so-called half-time rule
changing the temperature. To compare the stability of dif- can be applied. When after 1.5 years of stability testing
ferent formulations of emulsions, they are subjected to tem- the extrapolation of the results demonstrates that a shelf
perature cycles, for example 24 h refrigerator, 24 h room life of 3 years is justifiable, a shelf life of 3 years can then
temperature, 24 h refrigerator, etc. be attributed after 1.5 years.
22 Stability 451
22.5.5 In-Use Stability Testing stability data have to be interpreted from the product infor-
mation. Such examples are dealt with in Sect. 22.6.
For certain dosage forms, it is necessary to collect stability This chapter deals briefly with equations for the degrada-
data whilst the patient is using them. This is especially tion rate and their dependence on the temperature. For fur-
important for: ther study of this topic, reference is made to the textbooks of
• Medicines that are dispensed in packages for multiple Grimm [51] and Tønnesen [17].
use
• Medicines that require reconstitution or dilution prior
to use 22.5.7.1 Reaction Rate
When the primary packaging of a preparation has been In pharmaceutical practice, most degradation reactions
opened, oxygen, micro-organisms, water, and sometimes occur following a first order equation:
also light can enter. An in-use stability study thus focuses
dCt
on medicines that are sensitive to (photo-)oxidation and ¼ kCt ð22:2Þ
microbiological contamination. When the actual use is dt
simulated, relevant circumstances should be taken into
In which Ct is the concentration of the degrading active
PRODUCT DESIGN
account. For example, for a preparation in a 300 mL bottle
substance at any time point t and k is the reaction constant.
that is sensitive to oxidation, 10 mL should be taken, three
Suppose C0 is the concentration at time point 0, then
times a day, from that bottle, over a period of 10 days, to
integration of Eq. 22.2 gives:
simulate the influence of the remaining volume on the avail-
able amount of oxygen. Guidelines exist [67] for this type of C0
studies. However, the simulation of the expected behaviour ¼kt ð22:3Þ
Ct
of the patient has its limitations.
and:
C0 kt
22.5.6 Ongoing Stability Testing log ¼ ð22:4Þ
Ct 2:303
Even when the shelf life has been established stability testing This implies that a linear relationship exists between the
should be continued. This is called ongoing stability testing. A logarithm of the content and time. This is important, because
practical approach is to investigate the active substance at the it leads to a better interpolation and to more reliable results
end of the shelf life. It can be questioned whether the prepa- than non-linear interpolation of concentration-time data. In
ration always complies with the end-of-shelf life requirements addition, measurement of the content on only two time points
during routine production. Small deviations in the production is necessary to estimate the degradation (see Fig. 22.2).
process, starting materials, or packaging materials may influ-
ence the stability of the preparation.
22.5.7 Reaction Kinetics content (%)

100
Stability studies on degradation rate by chemical reactions
usually also include the investigation of the reaction kinet-
94
ics. It not only matters if a hydrolysis or an oxidation reac-
tion is taking place but also at which rate and which 90
dependency on pH or temperature is valid: reaction kinetics.
This science is only very modestly dealt with in this book,
just to serve practical purposes in case that a shelf life has to
time
be roughly re-estimated. Examples of those practical 80
0 1 2 3 4 5 (weeks)
situations are a patient who wants to take his medication
with him on a holiday to a tropical country, medicines in a Fig. 22.2 Determination of t90 by extrapolation from 102 % at t ¼ 0
doctor’s bag, or parenterals to be prepared for use for which and 94 % at t ¼ 3 weeks. t90 is almost 5 weeks
For t90 (the time point that 90 % of the content is still

present) Eq. 22.5 follows on Eq. 22.4: 22.6 Stability Data in a Pharmacist’s Daily
Practice
2:3log100 0:105
t90 ¼ 90
¼ ð22:5Þ In the pharmacy, shelf life is often only based on a specific
k k
temperature. For licensed medicines shelf life may be traced
from the product information by the manufacturer or
investigated by the pharmacist for pharmacy preparations.
22.5.7.2 Temperature Influence
Many situations in practice however require stability data at
The influence of the temperature on reaction kinetics has
different temperatures, different concentrations, solvents or
been described by Arrhenius:
containers. A justified extension of a shelf life could be very
helpful for the patient or the pharmacy’s logistics as well as
k ¼ Z:eE=R:T ð22:6Þ
saving a lot of money.
In which Z is a constant, E is the activation energy of the This section at first deals with examples of a different
degradation reaction, R is the gas constant and T is the storage temperature and secondly with the extension of shelf
temperature in Kelvin (¼ C + 273). lives for reconstituted parenteral solutions.
The logarithmic Eq. 22.6 is:
E 1 22.6.1 Storage at a Different Temperature

log k ¼ log Z ð22:7Þ
2:303:R T
Calculations to estimate a shelf life at a different temperature
The logarithm of the reaction constant k, plotted against T1 can only be made when the active substance is not subject to
gives a straight line. This way the reaction constant at a degradations other than chemical degradation, such as phys-
certain temperature can be calculated when it is already ical or microbiological degradation. In addition, calculations
known at two different temperatures. It is also possible to are only possible for relatively small differences in tempera-
plot the logarithms of t90 against T1 . Then t90 at the desired ture. Data from stability studies that have actually been
temperature can be read easily from the plot. performed are preferred over estimations. Moreover, the
From the Arrhenius equation and the activation energy equation for a first-order reaction can only be used for the
for various reactions, the following general rule is derived: first 10 % degradation for any other type of reaction.
with every 10 C temperature increase the reaction rate
increases 2–4 times. This factor is called Q10. 22.6.1.1 Patient Going on Holiday
When the reaction rate has to be estimated at an increased A patient plans to go on a holiday with a backpack (without a
temperature, a Q10 value of 4 is safe. On the contrary, when cool box) to a country with an average temperature of 30 C.
the reaction rate has to be estimated at a lowered temperature, The medicine he uses has a shelf life of 3 months in the
a Q10 value of 2 is safe. It is also possible to make calculations refrigerator due to chemical degradation. How long can the
using t90; a rise of the temperature with 10 C results in a t90 patient use the medicine on his holiday when the medicine is
that is four times shorter, whilst a lowering of the temperature freshly prepared?
with 10 C results in a t90 that is twice as long. Suppose: a refrigerator has a temperature of 5 C and the
For any change in temperature ΔT the following equation shelf life is based on a maximal degradation of the active
can be used: substance of 10 %. Because there is a rise of the tempera-
ture, a Q10 of 4 is used:
ΔT=10
kT 2 ¼ kT 1 Q10 ð22:8Þ
ΔT=10
Then Q10 ¼ 425=10 ¼ 32
or:

ΔT=10
ΔT=10 From Eq. 22.9 t90ðT2Þ ¼ t90ðT1Þ =Q10 it can be calcu-
t90ðT2Þ ¼ t90ðT1Þ =Q10 ð22:9Þ
lated that storage in a backpack results in a shelf life that is
22 Stability 453
32 times shorter than storage in a refrigerator, which is only 22.6.3 Extension of the Shelf Life
3 days.
Calculated in another way: from Eq. 22.5 Very short shelf lives limit the time frame for reconstitution,

t90 ¼ 2:3log100=90 ¼ 0:105 a k5 C of 0.001154 per day can aseptic handling, transport and administration of the medi-
k k
cine or do not allow for the preparation in advance for the
be calculated.
weekend. Using specific information sources [68–71] can be
ΔT=10
From Eq. 22.8 kT 2 ¼ kT 1 Q10 the k30 C can be very helpful to find justification for longer shelf lives. Some
calculated: k30 C ¼ 0:001154 425=10 ¼ 0:001154 32 ¼ examples:
0:037 per day.
For t90 in the backpack it follows then (Eq. 22.5): 22.6.3.1 Melphalan Injection Solution
0:037 ¼ 3 days
0:105 For example, the stability of melphalan injection solution is
It is clear that both the pharmacist and the patient have to 90 min at room temperature according to the manufacturer,
consider other options in this situation. as the active substance rapidly degrades by hydrolysis. How-
When the shelf life of a medicine is at least 3 years, a ever stability has been demonstrated for 4 h at 2–8 C and
journey of less than 6 months to a country with a warmer then 90 min at room temperature, provided that the prepara-
PRODUCT DESIGN
climate usually gives no stability issues for that specific tion is performed by diluting with an infusion solution in a
medicine. bag taken from the refrigerator [69]. The results were based
on a t90% value of melphalan content and the evaluation of
all degradation products. However, it has also been shown
22.6.1.2 Doctor’s Bag [69] that a shelf life of 5 h and 30 min instead of 90 min is
The temperature in a doctor’s car may fluctuate between possible and would be much more convenient for the prepa-
rather extreme values: heat as well as freezing. The required ration, transport, and administration.
storage conditions for the medicines in the doctor’s bag will
possibly not be met and the expiry date of many medicines
may not be valid anymore. In the Netherlands the doctors are 22.6.3.2 Clorazepate Injection Solution
advised: Dipotassium clorazepate is available as Tranxene®
• Not to leave their bag in the car, to avoid extreme containing 50 mg and the additives mannitol and potassium
temperatures (and to prevent theft) carbonate. According to the product information, the powder
• To refresh the medicines once a year, preferably just after should be dissolved in a phosphate buffer until a concentra-
summer season tion of 20 mg/mL at a pH of 6.7–7.2 is reached. How long
• To check the expiry dates and the appearance twice a year can the reconstituted solution be kept before administration
as injection solution? How long can a diluted solution as
infusion be kept before administration?
Dipotassium clorazepate degrades to nordazepam follow-
22.6.2 Shelf Life when Packaging has been ing a pseudo-first order reaction that accelerates when the
Changed pH is reduced and when the temperature rises [72]. Florey
[73] gives the relationship between reaction rate and pH.
If medicines are repackaged, especially into a medicines Using Eq. 22.4 ðt90 ¼ 0:105=kÞ it can be calculated that t90 at
dispensing system, the new primary package should protect 22 C and pH 7 is 12.5 h. For pH 6 t90 is 1.3 h. When
from degradation at least as well as the original package . knowing the t90 at 22 C, an estimation can be made for
This requirement will seldom be met. The new packaging of the t90 at storage in the freezer. This can be done by using the
a medicines dispensing system will usually be more trans- Q10. A freezer temperature of 4 C is about 2 x 10 C lower
parent to light and humidity for instance. The pharmacist than 22 C. Assuming a Q10 of only 2 (worst case) for 10 C
who repackages the medicine has to evaluate stability and temperature difference, would mean the reaction rate at 4 C
decide on the maximum storage period in the new package. being 2 x 2 times slower compared to 22 C. Then t90 at pH 6
Parenteral infusion solutions can be put into infusion bags of will be estimated at about 5 h and at pH 7, t90 is estimated at
different type of plastic (PE, PVC) which may lead to an about 2 days. In this way shelf lives for several usual
unexpected adsorption of the active substance. clorazepate preparations can be calculated, see Table 22.14.
Table 22.14 Chemical stability of dipotassium clorazepate From the SmPC medicines usually are advised to be prepared
preparations immediately before use. Usually some of the preparation will
Chemical stability be left over and has to be discarded. This can lead to a waste
Concentration Room temperature Refrigerator of precious active substances and inefficiency.
Reconstituted, 20 mg/mL 8h 2 days If the shelf life can be extended, for instance to 2 or
undiluted 3 months, preparation in advance will become possible,
Diluted with NaCl 0.1–0.4 mg/mL 8 h 2 days
thus also decreasing waste. As example, extended stability
0.9 %
has been demonstrated for carboplatin infusions (84 days)
Diluted with 0.1–0.4 mg/mL 2 h 8h
glucose 5 % [81], rituximab (6 months) [39], oxaliplatin (3 months) [82].
A successful example is also the study on the stability of
bortezomib. Bortezomib is available in lyophilised form in
22.6.3.3 Azacitidine Injection vials each containing 3.5 mg (Velcade®). However, the dose
Azacitidine is an active substance that is very sensitive to is 1.4 mg/m2. For a patient with a body area of 1.8 m2, the
hydrolysis. According to the SmPC, azacitidine has a 45 min dose is therefore 2.5 mg. The wastage will be 1 mg which
stability at room temperature after reconstitution, an 8 h represents almost 30 % of the cost of one vial of the medi-
stability after reconstitution and storage at 2–8 C, and a cine. Stability studies have demonstrated stability for at least
22 h stability if the reconstitution takes place with Water For 1 month for the 1 mg/mL or the 2.5 mg/mL solution [83,
Injections at 2–8 C and storage in the refrigerator. An 84]. This makes pooling of preparations for different patients
8 days stability of azacitidine at 20 C followed by an possible, and thereby diminishing wastage.
8 h stability at 2–8 C would allow the advanced preparation
for the weekend [74]. Furthermore an extended stability of
Dose Banding is an important way of diminishing
23 days has been demonstrated when the suspension is
those losses as well. Certain cancer chemotherapies
frozen [75].
are now more and more carried out with standardised
doses instead of with individual doses. This concept of
22.6.3.4 Patient Comfort at the VAD Regimen Dose Banding has been developed in the early 90s in
The VAD regimen combined vincristine 0.4 mg/day (V) and United Kingdom. If standardised doses can be
doxorubicin 9 mg/m2/day (Adriamycin®: A) as a continuous prepared in advance, many advantages occur such as:
IV for 4 days with oral dexamethasone (D). This regimen immediate availability for the patient, diminished
was a common treatment for multiple myeloma. The patient workload and occupational exposure for the pharma-
had to stay in the hospital to receive two continuous ceutical staff, possibility of quality control, less wast-
infusions a day. To avoid this, studies were performed to age of precious products.
demonstrate the stability of the mixture (vincristine and
doxorubicin with sodium chloride) to allow for it to be
given on an outpatient basis [76–78]. Today, this regimen
is less often prescribed, but these stability studies were of
great importance for the quality of life of the patient for 22.6.5 Searching Information about Stability
many years. and Compatibility for Practice
22.6.3.5 Facilitating Administration on the Ward Stability studies on medicines are often published in phar-
Knowing that mixtures such as cyclophosphamide and maceutical journals. Other sources for stability data could be
mesna [79] or cytotoxic and antiemetic medicines [80] are useful as well, such as the Pharmaceutical Codex [29],
stable enough for a suitable period (for instance several Kommentar zur Europäisches Arzneibuch [72] (see Sect.
days) to facilitate administration for nurses and patients. 39.4.8), Martindale [85] (see Sect. 39.2.4), Ophthalmika
[86], Connors [15] and Trissel’s Stability of Compounded
Formulations [70] (see Sect. 39.4.14). Additional informa-
22.6.4 Preventing Wastage and Saving Money tion can be found in Analytical and International Pharma-
by an Extended Shelf Life ceutical Abstracts. These can be retrieved by the search
engine OvidSP [87]. The German collection DAC-NRF
Many expensive parenteral medicines have to be dosed indi- [88] (see Sect. 39.4.2) also provides much information on
vidually and have to be reconstituted for only one patient. stability.
22 Stability 455
The stability of parenteral medicines is of great impor-

tance for practice, as explained in Sect. 22.6.3. For those 22.7 General Instructions for Storage Times
dosage forms stability data for numerous medicines have
been collected in specialised databases: Trissel’s Handbook For each medicine the storage conditions should be
on injectable drugs [71], the King Guide® to parenteral indicated, as well as the shelf life and the beyond-use-date
admixtures [68] and Stabilis® [69], see Sect. 39.2.6. The after opening. In this section it is explained how storage
last one is most explicit about the effect of various factors times are determined in general1. Secondly, a system is
(solvent, container, light, temperature, concentration, pH, introduced that can be used especially for pharmacy
filters) and most reliable as to the quality of the studies it preparations. Finally storage conditions are dealt with.
referenced. These databases are a considerable help for the
hospital pharmacist but are not the total solution. The user
can consider them a tool but should have sufficient back- 22.7.1 Shelf Life and Usage Period
ground knowledge of the design and applicability of stability
studies to make an informed decision about their applicabil- The label of any medicine meant for dispensing should
ity to the user’s particular circumstances. A particular aspect contain an expiry date, stating month and year, and storage
PRODUCT DESIGN
of information about stability of parenteral admixtures is conditions (see Sect. 37.3). This applies to licensed
whether or not a distinction between instability and incom- medicines as well as pharmacy preparations.
patibility has been made. Chemically, if two substances are A maximum of 5 years seems to be a sensible maximum
incompatible in solution they will form a precipitate sooner shelf life or turn-around time for licensed medicines
or later (see Sect. 18.1.6). When the precipitate will form, is [89]. For pharmacy preparations the quality of design and
difficult to predict. Basing a decision regarding stability on of production is less well controlled than in industrial pro-
say, 2 h without a precipitation, of two substances, is not duction. For this reason for pharmacy preparations a maxi-
justified. See further Sect. 13.8. mum shelf life of 3 years has become an acceptable limit in
Lawrence Trissel has written in the preface of his hand- many Countries. But for many preparations the shelf life will
book: “Users of the Handbook information should always be less than 3 years, because they are unstable in one way or
keep in mind that the information in the Handbook must be another.
used as a tool and a guide to the research that has been For industrially manufactured preparations the stability of
conducted and published. It is not a replacement for thought- the product in its (closed) package leads to an expiry date
fully considered professional judgement.” (exp.). This is the date after which the product is not to be
The users should particularly compare the differences used. The product information does not always make clear
between the preparation as it was studied and the preparation whether this date still applies after the package has been
as it occurs in their daily practice. opened. The indication “do not use later than . . ... after
As examples: opening” would give a decisive answer but is not very
• Is the same licensed product used to prepare the infusion common, except for certain categories of medicines
solution? Are there differences in the excipients? Cau- (e.g. eye drops).
tion: the same licensed product can have different In a number of preparations the package is of a type that
formulations in time. This is the case with Fluorouracil, makes storage after opening difficult or impossible
which was alkalised with trometamol but is now alkalised (ampoules, infusion bags, single-use vials). For this type of
with sodium hydroxide, which leads to a different (sterile) unpreserved preparations a Note for Guidance of the
stability profile. CPMP [90] states, that the shelf life after first opening or
• Is the concentration identical or comparable or are there reconstitution should not exceed 24 h at 2–8 C. This is an
big differences? A higher concentration can cause precip- example of a storage period determined by microbiological
itation at low temperature. factors. A longer shelf life is allowed if justified.
• Is the same material used for the container? Polyvinyl However also in many non-sterile medicines discrimina-
chloride (PVC) containers can cause sorption of the mol- tion between stability in the intact package and after opening
ecule to the plastic or the leaching of plasticizers. The is necessary, because by opening the package, in particular a
stability data for non-PVC containers cannot always be multidose package, certain conditions will undergo great
used for PVC containers, especially if there are lipophilic
excipients in the formulation.
• Is the same solvent used? Differences in pH or in chloride 1
This section has been supplied by Suzy Dreijer-van der Glas, Royal
ion concentration can be responsible for large stability Dutch Pharmacists’ Association KNMP, The Hague, The Netherlands.
differences. e-mail: [email protected].
change. These are conditions that can strongly influence Usage Period
stability: moist air, day light, oxygen, micro-organisms, The usage period is the time that a medicine, after opening of
evaporation of volatile solvents, etc. the package, can be used regarding the chemical, physical
Thus a great deal of pharmacy preparations will have a and microbiological quality. For an individual patient this
shelf life after opening that is shorter than in the intact applies to the period after opening of a package. It is the time
package, for two main reasons. A relatively large part of till the in-use date. In some cases these periods will differ
pharmacy preparations are vulnerable to microbiological from one setting to the other.
contamination, and caution in determining the shelf life is The clearest way of indicating the end of a storage period
the consequence of the often limited amount of research on for the patient is an actual date. On ampoules and other small
this subject. packages there is no room to print or write, for instance, a
In assigning shelf lives there are two possible situations: sentence “Not to be used after. . .”. In these situations the
• Preparations that are chemically stable, but can only be term “exp.” may be used. If the patient does not open the
stored for a limited period after opening, for the risk of package immediately after it is dispensed, both a shelf life
microbiological contamination or evaporation of volatile for the intact package and a storage period after opening are
solvents, or due to the influence of oxygen, moist air or needed on the label. Examples are situations where several
day light packages of the same medicine are delivered to the patient.
• Preparations that are not chemically stable, where it does In those cases the following text can be used: “Do not use
not make any difference for the (short) shelf life whether later than . . ... after opening, opened at. . .”.
the package is opened or not Chemical, physical and microbiological factors are
explicitly mentioned in the definitions of the storage periods,
indicating that therapeutic aspects have not been taken into
22.7.2 Assignation System for Pharmacy account. These aspects are no less important, but demand
Preparations quite different considerations. The active substance will
normally be the main factor, and not the dosage form.
In this section a general system is described for the assign-
ment of shelf lives, both for the intact package and after Administration Period
opening. In this system shelf lives are given which apply to The maximum time from start to the end of the administra-
specified types of package and storage conditions. The sys- tion, especially used with parenteral medicines.
tem has been used for about 25 years in Germany and the
Netherlands [91, 92]. The section starts with an outline of the
logic used followed by the starting points together with a 22.7.2.2 Starting Points and Flow Chart
flow chart to decide about maximum storage times for each The constructs of shelf life of the intact package and the
preparation and situation. usage period have been elaborated into concrete starting
points:
• The shelf life of a pharmacy preparation is 3 years at
22.7.2.1 Definitions and Labelling maximum.
The shelf life of a preparation is usually constructed of two • Maximum usage periods for patients after opening the
consecutive components: shelf life in the intact package and package, for medicines in multidose containers, with a
the usage period after opening of the package. Their standardised formula, are given in Table 22.15. These
definitions are: maximum usage periods are only valid within the shelf
life of the preparation.
Shelf Life of the Intact Package • At the time of dispensing in the pharmacy, the maximum
The maximum shelf life in the intact package is the shelf life usage period must be sufficient for the duration of the
of that medicine (in the original intact package) with respect prescribed therapy.
to the chemical, physical and microbiological quality. This • Medicines with limited stability have a specific shelf life,
shelf life is the same as that which applies to industrially often distinguished between before and after opening of
manufactured preparations (time up till the expiration date, the package. After passing a renewed quality test, an
the “not to be used after. . .” date.) extended shelf life can be specified.
22 Stability 457
Table 22.15 Assigned usage periods for dosage forms Table 22.15 (continued)
Maximum usage period for the Maximum usage period for the
Dosage form patient Dosage form patient
Sterile forms Gargle, preserved 6 months
Bladder irrigation Do not store Gel for dental use 3 months
Dusting powder, sterile 24 h Gel with alcohol >15 % m/m, in tube 3 months
Ear drops for middle ear, preserved 1 month Hydrogel, in jar 1 month
Eye drops, not preserved 24 h Hydrogel, in tube 3 months
Eye drops, preserved, at home 1 month Mouth paste 6 months
Eye drops, preserved, at the ward 1 week Mouth wash, not preserved 2 weeks
Eye ointment, anhydrous 1 month Mouth wash, preserved 6 months
Eye ointment, containing water 1 month Nasal drops, not preserved 2 weeks
Eye wash, not preserved 24 h Nasal drops, preserved 3 months
Eye wash, preserved 1 month Nasal gel, in tube 3 months
Intravesical solution Do not store Nasal ointment, in tube 6 months
Irrigation, sterile (apart from bladder 24 h Nasal spray, not preserved 2 weeks
PRODUCT DESIGN
irrigations) Nasal spray, preserved 3 months
Solution for injection, not preserved 24 h Oral drops, not preserved 2 weeks
Solution for injection, preserved 1 month, refrigerated Oral drops, preserved 6 months
Solution for intravenous infusion 1 week Oral solution, not preserved 2 weeks
Solution for nebuliser, not preserved 24 h Oral solution, preserved 6 months
Solution for nebuliser, preserved 1 month Oral suspension, not preserved 2 weeks
Dosage forms without water, not Oral suspension, preserved 6 months
sterile Oromucosal solution, preserved 6 months
Capsules in tablet container 12 months, keep dry Ovules, hydrogel base, not in strip 1 month
Collodium 6 weeks Paste containing water, in jar 1 month
Dusting powder 12 months Shampoo 6 months
Ear drops without water 6 months Syrup, not preserved 2 weeks
Ovules, fatty base, not in strip 12 months Syrup, preserved 6 months
Paste, anhydrous, in jar 6 months Vaginal solution, preserved 6 months
Powders for oral use, (un)divided 12 months, keep dry Vapour with alcohol >15 % m/m 3 months
Suppositories, in strip 12 months W/o cream, not preserved, in jar 1 month
Suppositories, not in strip 12 months W/o cream, not preserved, in tube 3 months
Tablets 24 months, keep dry W/o cream, preserved, in jar 6 months
Dosage forms containing water, not W/o cream, preserved, in tube 12 months
sterile
Cream, not preserved, in jar 1 month
Cream, not preserved, in tube 3 months • Extemporaneous preparations, with unknown or uncer-
Cream, preserved, in jar 3 months tain chemical or physical stability, cannot be kept on
Cream, preserved, in tube 12 months stock in the pharmacy. They have a maximum usage
Cutaneous emulsion, not preserved 2 weeks period according to Table 22.15, but this period is not
Cutaneous emulsion, preserved 6 months more than 1 month for liquid and semisolid preparations,
Cutaneous solution, not preserved 2 weeks and not more than 6 months for dry forms. If the formula
Cutaneous solution, preserved 6 months is similar to a standardised one, the maximum shelf life of
Cutaneous solution, with alcohol 3 months that standardised formula can be used.
>15 % m/m
• The length of the administration period depends on the
Cutaneous suspension with alcohol 3 months
>15 %
conditions under which the medicine has been
Cutaneous suspension, not preserved 2 weeks reconstituted or adapted for administration (see Sect.
Cutaneous suspension, preserved 6 months 31.3.6).
Dental solution 6 months In Table 22.15 actual usage periods are given for the most
Ear drops for external ear 6 months popular dosage forms and their containers. Depending on the
Enema, not preserved Do not store dosage form, these usage periods may vary between 24 h and
Enema, preserved Do not store 24 months. The flow chart (Fig. 22.3) makes it easier to
Gargle, not preserved 2 weeks determine a usage period, depending on the dosage form
(continued) and the nature of the preparation.
Fig. 22.3 Flow chart for the

assignation of usage periods of
dosage forms in multidose
containers
22.7.2.3 Storage of Semi-Finished Products Table 22.16 Usage periods in the pharmacy of Stock packages of
Starting materials in pharmacy preparation sometimes are cutaneous bases
semi-finished products, e.g. cream bases for cutaneous Usage period in
preparations, concentrated solutions of preservatives or Type of semi-finished product pharmacy
triturations of active substances. Usually this type of Ointment bases not containing water
products will be kept in stock in jars. They may be prepared Bases with mainly paraffins, pastes 3 years
Bases containing wool fat 2 years
in the pharmacy, or bought from a wholesaler. These
Hydrophobic cream bases (w/o bases, not 3 months
products can be considered as raw materials for a
preserved)
preparation. Hydrophilic ointments (macrogol) 3 years
In both cases there will be an expiry date on the label for Hydrophilic cream bases (preserved) 6 months (in jar)
the intact package. But also for these preparations the 12 months (in tube)
conditions of storage will change after opening the package, Hydrophilic emulsions (preserved) 6 months
more or less in the same way as discussed above for Hydrophilic gels (preserved) 3 months (jar)
packages for the patient. Therefore the shelf life of these 12 months (tube)
semi-finished products after opening will often be shorter
than that of the intact package. Microbiological factors play ten times before it is empty. When a semi-finished product is
an important role, in particular in water containing used as the starting material for a stock preparation in the
preparations. In concentrated solutions evaporation of sol- pharmacy, it should be taken from a new package, thus not
vent may be the reason for a short usage period. Apart from from a jar that has been opened before. In that case the shelf
the time, the number of openings of the stock package may life of the pharmacy stock preparation will be the same as if
influence the quality of its content. it had been prepared from raw materials only.
In general it is recommended to choose the volume of the Usage periods (in the pharmacy) of stock packages for
‘stock jar’ in such a way that it only has to be opened about different types of cutaneous bases are given in Table 22.16.
22 Stability 459
The periods given by [93] have been used. In these cases the • Changes in the disintegration time of tablets
usage period must lie within the shelf life. • Microbial growth, resulting in decay
For concentrated solutions or triturations the maximum Patients will often notice these changes and return the medi-
usage period depends on the type of preparation. For cine to the pharmacy. In some cases the changes are such
instance, if the solvent is water, the risk of microbiological that the medicine cannot be used any more. But sometimes
contamination will play a role. In case of volatile solvents changes in appearance do not mean that the content of the
evaporation is the most important factor. When defining active substance has decreased. Any change in appearance
maximum usage periods for this kind of preparations, the may undermine patients trust in the medicine, which is
pharmacist has to keep in mind the factors that influence the sufficient reason to consider them unacceptable. If such
storage conditions after opening the stock package. changes are unavoidable and harmless, it is better to inform
and reassure patients in advance.
Patients should also be instructed on the importance of
22.7.3 Storage Temperature refrigerating some kinds of medicines: maintaining the cold
chain, see Sect. 37.5.
The following labelling statements are required for licensed
PRODUCT DESIGN
preparations:
• Store in a freezer (below 15 C). References
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Analysemethode en referentiestandaarden. (deel 2). Validatie Pharm 56:875–881
analysemethode en stabiliteitsonderzoek. Pharm Weekbl. 81. Kaestner S, Sewell G (2007) A sequential temperature cycling
140:659–661 and 899–901 study for the investigation of carboplatin infusion stability to facili-
63. Yska JP, Maring JG, Dekens KG (2005) Het uitvoeren van tate ‘dose-banding’. J Oncol Pharm Pract 13(2):119–126
stabiliteitsonderzoek (deel 2). Validatie analysemethode en 82. Junker A, Roy S, Desroches MC, Moussay C, Berhoune M,
stabiliteitsonderzoek. Pharm Weekbl 140:899–901 Bellanger A et al (2009) Stability of oxaliplatin solution. Ann
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70. Trissel LA (2009) Trissel’s stability of compounded formulations, Wissenschaftliche Verlagsgesellschaft, Stuttgart
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73. Raihle JA, Papendick VE. Clorazepate dipotassium. In: Florey K Stuttgart, p 146
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San Diego, London, vol 4. pp 106–107 human use after first opening or following reconstitution. CPMP/
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12(1):10–12
Raw Materials
23
Roel Bouwman and Richard Bateman
Contents 23.7 Viscosity Enhancing Substances . . . . . . . . . . . . . . . . . . . . . . 484

23.7.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
23.1 Label, Identity and Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . 464 23.7.2 Gel Preparation Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
23.1.1 Pharmacopoeial Designation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464 23.7.3 Details of Viscosity Enhancers . . . . . . . . . . . . . . . . . . . . . . . . . 487
23.1.2 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
23.1.3 Other Designations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 23.8 Preservatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
23.1.4 Water Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 23.8.1 Hypersensitivity and Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . 490
23.1.5 Salt-and Ester Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 23.8.2 Activity, Concentration and Applicability . . . . . . . . . . . . . 490
23.1.6 International Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 23.8.3 Quaternary Ammonium Compounds . . . . . . . . . . . . . . . . . . . 492
23.1.7 Microbiological Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 23.8.4 Mercury Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
23.1.8 Physico-chemical and Functionality-Related 23.8.5 Hydroxybenzoic Acid Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 23.8.6 Sorbic Acid and Benzoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . 493
23.1.9 Mix-Up of Names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 23.8.7 Chlorhexidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
23.8.8 Phenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
23.2 Quality, Stability and Shelf Life . . . . . . . . . . . . . . . . . . . . . . 471 23.8.9 Alcohols, Di- and Trioles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
23.3 Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 23.8.10 Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
23.3.1 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 23.9 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
23.3.2 Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
23.3.3 Glycols and Glycerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 23.10 Complexing Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
23.3.4 Macrogols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
23.3.5 Fatty Oils, Fat, Waxes and Paraffin Waxes . . . . . . . . . . . . 476 23.11 Colouring Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
23.3.6 Acetem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 23.12 Herbal Raw Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
23.4 Filling and Disintegration Agents . . . . . . . . . . . . . . . . . . . . 478 23.13 Medical Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
23.4.1 Starch and Microcrystalline Cellulose . . . . . . . . . . . . . . . . . . 478
23.4.2 Polyols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
23.4.3 Calcium Hydrogen Phosphate Dihydrate . . . . . . . . . . . . . . . 479
23.4.4 Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
23.5 Lubricants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Abstract
23.6 Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 Raw materials for pharmaceutical preparations are either
23.6.1 Anionic-active Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
23.6.2 Cationic-active Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 active substances (or active pharmaceutical ingredients:
23.6.3 Amphoteric Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 APIs) or excipients. The choice of excipients and the
23.6.4 Non-ionic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 quality of all raw materials determine the quality of a
medicinal product. In addition to purity and content,
physical properties such as particle size can influence
Based upon the Chap. 20 Grondstoffen by Roel Bouwman and Suzy the manufacturing process and the therapeutic effective-
Dreijer in the 2009 edition of Recepteerkunde. ness. Changes in quality can have unforeseen
R. Bouwman (*) consequences.
Central Hospital Pharmacy of The Hague, Escamplaan 900, Active substances have to be manufactured according
NL-2547 EX The Hague, The Netherlands
to EU GMP. When manufactured outside the European
Union, USA, Japan, Australia or Switzerland, they need a
R. Bateman
‘written confirmation’ from the manufacturing country’s
East and South East England Specialist Pharmacy Services, Guys
Hospital, London SE19RT, UK authorities that they are manufactured in compliance with
e-mail: [email protected] the EU-GMP.

464 R. Bouwman and R. Bateman
The general properties of raw materials will be preparation. For the use of a raw material that is not
discussed: identity, physical, chemical and described in one of the mentioned pharmacopoeias therefore
microbiological quality, nomenclature, labelling, stability it may be necessary for the preparing pharmacist to take
and shelf life. Main excipients and groups are discussed, personal responsibility for the use of a raw material, without
for their quality properties as well as their applications: being able to establish that it fully complies with the mono-
solvents such as water, ethanol, glycols, fatty oils, filling graph Substances for pharmaceutical use. This is acknowl-
agents for capsules and tablets, surfactants, viscosity edged by a statement in the section Active substances and
enhancers, preservatives, antioxidants, complexing excipients of the monograph: “Where no specific
agents and herbal raw materials. monographs exist, the required quality must be defined,
taking into account the intended use and the involved risk”.
Keywords Most raw material suppliers indicate the source of the
Active substances Quality Excipients Application quality specifications on the label. However, it may occur,
Raw material Labelling Pharmacopoeia FRC that despite there being an entry in the Ph. Eur., suppliers,
Solvents Surfactants Viscosity enhancers perhaps due to market conditions, will sell substances that
Preservatives Colouring agents Herbal meet the requirements of a foreign pharmacopoeia or other
standard. Some suppliers may allow the download of a
certificate from their website or supply a certificate with
each delivery. In other cases it may be necessary to contact
23.1 Label, Identity and Quality
the supplier to request the certificate to be sent. Such a
certificate should refer to which pharmacopoeia or standard
The structural formulas of substances not shown in this
the raw material complies. It should also list the pharmaco-
chapter, can be found in the monographs of the Ph. Eur. or
poeial analytical data of the raw materials including relevant
Clarke’s [1] or Florey [2]. Data on excipients and substances
quantifiable impurities such as bacterial endotoxins. A cer-
that are not included in the Ph. Eur. can be found in
tificate of analysis is signed, or refers to the authorisation by
references [3–5].
the quality officer of the supplier.
23.1.1 Pharmacopoeial Designation 23.1.2 Sources
Each substance in a pharmacy preparation must meet the Active substances should be manufactured in accordance
requirements of the latest edition of the Ph. Eur. For the with the GMP guidelines (part II) [6]. In industry, when
monograph Pharmaceutical Preparations states: “Active using raw materials in a licensed product, the qualified
substances and excipients used in the formulation of phar- person releasing the final product is also responsible for
maceutical preparations comply with the requirements of ensuring that the active substances used are manufactured
relevant general monographs.” in accordance with the GMP guidelines. EU-legislation that
When a raw material is not described in the Ph. Eur., a came into force in July 2013 [7] prescribes that each delivery
raw material may be used with reference to the British of an active substance that is manufactured in a country
Pharmacopoeia (BP), the German Pharmacopoeia (DAB), outside the European Union must be accompanied by a
the Deutsche Arzneimittel Codex (DAC) or, if that is not declaration of the authorities of that country that the sub-
possible, a recent edition of a well-known non-European stance is manufactured according to the European GMP
Pharmacopoeia, such as the Japanese Pharmacopoeia (a “written confirmation”). Excluded from this obligation
(JP) or United States Pharmacopoeia (USP). Sometimes an are the ‘third countries’, that have proven to have a legisla-
older edition of the European Pharmacopoeia or the other tive framework for the inspection and enforcement of
pharmacopoeias may be the sole reference. GMP-compliant production of active substances. So far
In any case, the raw material has to comply with the these countries are: United States, Japan, Australia and
general monograph Substances for pharmaceutical use of Switzerland. The implementation of this system in the qual-
the Ph. Eur.; this monograph applies to all raw materials ity system of community and hospital pharmacies is prob-
intended for processing in pharmaceutical preparations, lematic. In the (hospital) pharmacy raw materials are bought
regardless of whether they have a monograph in the from wholesalers and for the individual hospital pharmacist
Ph. Eur. or not. However the requirements of this mono- it is often difficult to find out the manufacturer of the raw
graph on related impurities, residual solvents and material. Since many raw materials are now manufactured in
microbiological quality are too general as well as too China or India, monitoring the GMP compliance is very
detailed to be implemented in daily practice of pharmacy difficult to achieve, so the declaration of the authorities is
23 Raw Materials 465
Table 23.1 Different Forms of Codeine

Substance Bruto formula Molecular mass 1 mg substance ¼ base (mg)
Codeine (pure substance) C18H21NO3 299.4 1
Codeine. H2O (Ph. Eur.) C18H21NO3.H2O 317.4 0.94
Codeine phosphate.½H2O (Ph. Eur.) C18H24NO7P.½H2O 406.4 0.74
Codeine phosphate. 1½ H2O (Ph. Eur.) C18H24NO7P.1½H2O 424.4 0.71
Codeine HCl.2H2O (BP) C18H21NO3Cl.2H2O 371.9 0.81
indispensable. On occasion it will be necessary to balance, 23.1.4 Water Content

based on a risk assessment, the benefits of providing a
product to a patient with the level of assurance of GMP Some raw materials are described with different water con-
compliance of the raw material. The risk assessment should tent. Different Pharmacopoeias may use the same name for
consider both the clinical consequences of not supplying the raw materials with different water content. This is found
product and the degree of knowledge of the manufacture and between different editions of the subsequent Ph. Eur. The
supply chain of the raw material and its degree of compli- historical changes are described in the introduction of each
ance with EU GMP. edition of the Pharmacopoeia under ‘Hydrates’.
For example, if codeine phosphate sesquihydrate, codeine
hydrochloride or codeine base is processed instead of
codeine phosphate hemihydrate, this leads at standard
An example of what can happen with raw materials formulations to a different codeine content. Table 23.1
that are insufficiently controlled by foreign authorities exemplifies this. Therefore, it is advised to use in preference
occurred in China with heparin. The raw material was the form of codeine phosphate hemihydrate, as this is the
intentionally adulterated with over-sulfated chondroi- form that is used in most standard formulations.
tin sulfate (OSCS). Heparin injections prepared from In addition to water of crystallisation, where the water
this raw material in the United States have led to molecules are in stoichiometric proportion to the substance,
severe hypersensitivity reactions in patients [8]. The water also appears as adsorbed water, such as in the case of
Ph. Eur. monograph has been revised with a test to prednisolone disodium phosphate.
detect this impurity, on recommendation of the
EMA/CHMP assessment report about this topic
[9]. In June 2013 the FDA issued a Note for Guidance
PRODUCTION
for Industry about this subject to manufacturers taking
23.1.5 Salt-and Ester Forms
steps to ensure that the heparin supply chain is not
Many substances appear either as unconjugated or as salt or
contaminated with OSCS [10].
ester form. If the substance is a salt or an ester of the
substance to be processed, it will be seen from the dosage
specified whether or not there is a need for a conversion
factor to be applied.
23.1.3 Other Designations Exchanging a base/acid with the corresponding salt, or an
alcohol/acid with an ester almost always has biopharmaceu-
Some raw materials such as for clinical research or experi- tical, pharmacokinetic or pharmacodynamic consequences
mental treatments, are not available by the regular pharma- of clinical importance. Sometimes these are desirable, but
ceutical chains. In such cases, it may be necessary to buy most often they are not. Be guided by the biopharmaceutical
them from wholesalers in chemicals [11]. Such a trader often information in reference books (such as Martindale [3]) or
puts the phrase on the label “not for human use”. The the composition of the licensed medicine. Some examples:
pharmacist himself must, either on the basis of a Pharmaco-
poeia monograph, or on the basis of his in house quality 23.1.5.1 Corticosteroids
system, assess whether the raw material is suitable for phar- The esters of monovalent fatty acids (triamcinolone
maceutical application. acetonide) are usually used in cutaneous preparations. Free
The analytical grade designation that is sometimes given corticosteroids can usually be administered orally. When a
to this category of substances is not a formalised quality solution in water is needed the esters of a multivalent acid in
indication in pharmaceutical meaning, but substances with the salt form (-disodium phosphate, disodium succinate)
this quality designation are often sufficiently pure for use in should be used. This also applies to processing
pharmaceutical preparations. corticosteroids in a lipid based suppository.
23.1.5.2 Excipients i.e. chlorhexidine acetate that is insoluble in water but solu-
It is also important, with regard to excipients as to what ble in propylene glycol.
chemical form is used. DL-alfa-Tocopherol acts as antioxi-
dant in an alcohol-water mixture; the esters have no effect.
23.1.6 International Units
23.1.5.3 Label Claims
In many cases the labelling of the strength indication is clear, International units are used for the strength indication of raw
but errors can easily occur. Some examples to illustrate how materials where this is not possible with units of mass. This
label claims should be interpreted: will be the case, for example, if the raw material consists of a
• Garamycin® ampoule: according to the label it contains long chain with a varying number of functional groups, if the
10 mg per mL gentamicin base as sulfate. Thus the raw material consists of a mixture of substances with differ-
ampoule contains gentamicin sulfate and the indication ent mass per functional group or if for any other reason the
of the strength relates to gentamycin ion. mass is not strictly proportional to the strength of the raw
• Erythrocin® -suspension and tablets: according to the material. Often the content of such substances must be
label the content is related to erythromycin base. determined with biological methods.
• ‘Ritalin capsules’; when these are to be prepared from If a substance that is prescribed in international units
methylphenidate hydrochloride it is simple, since the (IU) needs to be weighed, the amount of substance is calcu-
strength of Ritalin® tablets relates to methylphenidate lated with the conversion factor that is listed on the label or
hydrochloride. in the analytical report. For vitamins A and D the number of
• Bethamethason cream: in this case however there is international units per gram is standardised. Other well-
firstly the choice between valerate and dipropionate, known examples are polymyxin and vitamin E. Prescribers
each of which represents a different corticosteroid activ- often continue writing in units, even when, for the relevant
ity class. Then in both cases the desired concentration in active substance, a known chemical content has existed for a
relation to the amount of free betamethasone has to be long time.
calculated. The strength of the authorised products is In some cases, the number of international units is
specified respectively as valerate or dipropionate. indicated per packaging unit, for example, per ampoule of
• Iodinated povidone is a colloidal complex and problems benzylpenicillin sodium. In that case, dilute the contents of
can arise with the content indication of iodinated the vial to a known volume and take back a calculated
povidone solution. Betadine® contains 10 % iodinated volume.
povidone complex, corresponding to a concentration of In Table 23.2 are some commonly used raw materials
approximately 1 % iodine. listed with, as far as is known, the equivalent amount of mass
• Neomycin: Still more unclear is the issue of the interpre- per unit.
tation of label claims with neomycin sulfate. Neomycin
sulfate Ph. Eur. is “a mixture of sulfates or substances”.
The sulfate content may vary between 27 % and 31 % 23.1.7 Microbiological Purity
calculated on the dried substance and the water content
can be up to 8 %. It is therefore not possible to derive an 23.1.7.1 Micro-organisms
exact conversion factor when a neomycin preparation is For a number of raw materials Ph. Eur. has microbiological
prescribed. In practice no difference is made between quality criteria for Total Aerobic Microbial Count (TAMC)
prescribing neomycin or neomycin sulfate, as neomycin and Total combined Yeast and Mould Count (TYMC) (see
as such is not available and the dose cannot be based on Sect. 19.6.3) and for absence of specific micro-organisms
experience with that substance. So it turns out from the (see Sect. 19.6.4). Theoretically it would be logical to apply
context that there is no need for conversion. one requirement for all substances which are used in
An important point can be the difference in application of non-sterile preparations, but the approach should take into
certain salts. An example is chlorhexidine digluconate, that account the use of the final product. The General monograph
is available as 20 % solution (Hibitane®). Chlorhexidine Substances for Pharmaceutical use applies a general recom-
chloride is not water-soluble and is available as dry powder mendation with regards to the microbiological contamina-
(under the same brand name Hibitane®). If in the doctor’s tion of the raw material and the microbiological
request the brand name is used, it will be seen from the requirements for the finished product. This contamination
context what salt is intended and, in the case of the gluco- mainly refers to substances of vegetable, animal or mineral
nate, whether the strength indication relates to the origin (see also Table 9.1 in Sect. 19.6.2). Even if such
digluconate as such or to the 20 % solution. To complicate substances are not listed in the pharmacopoeia, it is
the matter even more, a third variant is available, recommended that microbiological contamination should
Table 23.2 Substances of which the strength is expressed in IU

Substance 1 IU ¼ 1 mg ¼ Remarks
Bleomycin 0.00067 mg 1500 U Clinical damage has been published [12]
(Ph. Eur.) (Ph. Eur.)
0.67–0.5 mg (USP) 1.5–2 U
(USP)
Heparin 0.0057 mg 173 IU Theoretical value
Heparin calcium/sodium Ph. Eur. For parenteral use: 150 IU 1. The exact amount of conversion should be
<0.0066 mg mentioned on the label;
2. Other standards apply for low molecular
heparins;
3. Values apply to dried substance;
4. The tolerance in comparison to the declaration is
90–111 %;
Not for parenteral 120 IU 5. IU are not the same as USP units; However, the
use: <0.0083 mg difference is not clinically relevant [4]
Neomycin sulfate Ph. Eur <0.00154 mg 680 IU Value applies to dried substance
Nystatin Not oral: 4400 IU Value applies to dried substance
<0.227 microgram
Oral: 5000 IU
<0.20 microgram
Polymixin B 0.1 microgram 10,000 IU Theoretical value
Polymixin B sulfate 0.12 microgram 8304 IU Theoretical value
Polymixin B sulfate Ph. Eur, commercially available <0.167 microgram 6000 IU 1. Value applies to dried substance
2. Ph. Eur. no longer applies IU
Protamin sulfate 0.01 IU heparin 100 IU 1. Theoretical value
heparin 2. Usually, the value is expressed in amount
percentage
Vitamin A as all-trans Retinol 0.3 microgram 3333 IU 1. Theoretical values
Vitamin A as all-trans Retinol palmitate 0.55 microgram 1818 IU 2. The format in IU has already been left in 1956
Vitamin A as all-trans Retinol propionate 0.36 microgram 2786 IU
Vitamin A concentrate synthetic (oily form) Ph. Eur. <0.002 mg 500 IU The format in IU has already been left in 1956
(Vitaminum A densatum oleosum)
PRODUCTION
Vitamin A concentrate synthetic (powder form) Ph. Eur. <0.004 mg 250 IU
(Vitaminum A pulvis)
Vitamin A concentrate, synthetic, solubilisate/emulsion <0.01 mg 100 IU
Ph. Eur. (Vitaminum A in aqua dispergibile)
Vitamin D as Cholecalciferol (D3) or Ergocalciferol (D2) 25 ng 40,000 IU Theoretical value
Cholecalciferol concentrate (oily form) Ph. Eur. <0.002 mg 500 IU
(Cholecalciferolum densatum oleosum)
Cholecalciferol concentrate (powder form) Ph. Eur. <0.01 mg 100 IU
(Cholecalciferolum densatum pulvis)
Cholecalciferol concentrate (water-dispersible form) <0.01 mg 100 IU
Ph. Eur. (Cholecalciferolum in aqua dispergibile)
Vitamin E as d-alfa-Tocopherol 0.67 mg 1.49 IU The format in IU has already been left in 1956
Vitamin E as dl-alfa-Tocopherol 0.91 mg 1.1 IU
Vitamin E as d-alfa-Tocopheryl acetate 0.74 mg 1.36 IU
Vitamin E as dl-alfa-Tocopheryl acetate 1.00 mg 1.00 IU
Vitamin E as d-alfa-Tocopheryl hydrogen succinate 0.83 mg 1.21 IU
Vitamin E as dl-alfa-Tocopheryl hydrogen succinate 1.12 mg 0.89 IU
Vitamin E as d-alfa Tocopheryl polyethylenglycole- 2.58 mg 0.39 IU
1000- succinate
be investigated; especially with herbs which can often be Since vegetable raw materials with a sufficient
heavily contaminated. Examples of substances of which microbiological quality are sometimes difficult to obtain,
batches with questionable microbiological quality have methods to sterilise them have been investigated. Gamma
been found are tragacanth gum, corn starch, kaolin and radiation, ethylene oxide or microwaves have been used.
alginic acid [13]. Viable organisms are successfully killed but spore-forming
bacteria especially may remain intact when radiation doses manufacturers can display a TSE certificate for the requested
are used that do not adversely affect the active substances. substance [14].
The microbiological quality requirements of water are
described in Sect. 23.3.1.
23.1.8 Physico-chemical and Functionality-
Related Characteristics
23.1.7.2 Bacterial Endotoxins and Pyrogens
Microbiological contamination of raw materials can lead to
The Ph. Eur. monograph Pharmaceutical Preparations
a finished product that does not meet the requirements for
states: “When physico-chemical characteristics of active
microbiological purity and in addition a high endotoxin level
substances and functionality-related characteristics (FRCs)
can be found leading to a pyrogenic response after intrave-
of excipients (e.g. particle-size distribution, viscosity, poly-
nous injection.
morphism) are critical in relation to their role in the
manufacturing process and quality attributes of the pharma-
The terms pyrogens and endotoxins (bacterial) are ceutical preparation, they must be identified and controlled.”
often used interchangeably. However, the Ph. Eur. Ph. Eur. contains a monograph on FRCs. The chapter is
makes a clear distinction between them: not mandatory, neither is the FRC-section in specific
• Pyrogens are substances that cause a febrile monographs. But that does not mean that FRCs are unim-
reaction. portant. Especially in pharmaceutical development FRCs
• Endotoxins are lipopolysaccharides of the cell wall determine the design space of a medicinal product. Many
of gram-negative bacteria that causes fever when excipients are manufactured by industries other than the phar-
injected intravenously. maceutical industry, so in many cases the excipient manufac-
So not all pyrogens are endotoxins, see Sect. 19.3.4. turer has little knowledge about the pharmaceutical use of an
Endotoxins are however the most common cause of excipient. Several methods to determine FRCs are described
toxic reactions that are attributed to contamination of in Ph. Eur. e.g. Particle-size determination, Specific surface
pharmaceutical products with pyrogens; their pyro- area by gas adsorption, Powder flow, Bulk density and tapped
genic activity is much greater than that of most other density, Wettability of porous solids including powders.
pyrogenic substances. Two FRCs will be dealt in more detail: particle size and
viscosity.
For approximately 80 raw materials the Ph. Eur. has set
23.1.8.1 Particle Size
limits for endotoxin levels if they are intended for parenteral
Particle size is an important physical quality property of raw
dosage forms. These include among others: dextran, sorbitol
materials. With regards to particles in this section a distinc-
and mannitol, sodium chloride, trometamol, water for
tion is made between firstly loose crystals (primary particles)
injections.
and secondly agglomerates: coagulated small particles (sec-
ondary particles) that have such a strong cohesion that they
23.1.7.3 Prions resist normal dispersion techniques and therefore are not
Raw materials especially of animal origin, or produced using easy to disperse in the production process.
reagents of animal origin, can be infected with prions, some The particle size determines to a large extent the dissolu-
of which are the cause of transmissible spongiform enceph- tion rate and later in the use of the final product may deter-
alitis (TSE). See Sect. 19.3.1 for information about the mine the bioavailability of poorly soluble compounds. The
nature and pathogenicity of prions. Examples of raw stability of suspensions and the homogeneity of powder
materials that may be infected with prions are gelatin and mixtures may also be influenced. For a detailed description
fatty acids and fats of animal origin: oleic acid, magnesium of the importance and reduction of particle size we refer to
stearate, glycerol, sorbitane esters, polysorbates and Sect. 29.2. If a substance does not have the required degree
wool fat. of fineness for the intended process then it will be necessary
The deactivation of prions, if it can be achieved, requires to bring it to that degree.
aggressive interventions on the material, see also Sect. The Ph. Eur. sets requirements for the particle size of raw
19.3.1. Therefore it is essential to obtain the raw materials materials in eye ointments and suspensions for injection.
from a supplier that delivers a certificate, certifying that the When the particle size is important for a raw material, it is
raw material is free from TSE risk material. One can consult common to display it in micrometres between parentheses
the EDQM site by the material name (through the field after the name of the substance. The Ph. Eur. states in the
Databases and the Certification button) where monograph Sieve test that the fineness of a powder is
Table 23.3 Terminology concerning the degree of fineness of raw materials

Ph. Eur.: 95 % m/m smaller than 40 % m/m smaller than
Coarse 1,400 μm 355 μm
Moderately fine 355 μm 180 μm
Fine 180 μm 125 μm
Very fine 125 μm 90 μm
In BP [15] additionally:
Moderately coarse 710 μm 250 μm
Microfine 90 % m/m smaller than 45 μm
Superfine 90 % m/m smaller than 10 μm
expressed by the two sieve numbers, where at least 95 % of It is possible but not easy to describe semi-quantitatively
the powder passes the higher sieve size and not more than the particle size of a raw material by a microscopic method
40 % the lower sieve size (see Table 23.3), unless otherwise [16]. But generally other methods are used for the
prescribed in the monograph. In the case of a single number, characterisation of powder fineness like sieving, air perme-
the Ph. Eur. means that at least 97 % of the powder passes ability or gas adsorption.
the sieve size. Sieving gives a visual check of the size by what passes
The monograph Sieves of the Ph. Eur. has a table with through the sieve holes, in dry form or suspended in a liquid
sizes and tolerances of a series of 18 sieves. The smallest (wet sieving), under the influence of gravity or possibly
sieve has (square) holes with sides of 38 μm, the largest using vacuum. The sieving result and its reproducibility
holes with sides of 11.2 mm. The result of a sieve analysis is not only depends on the particle size but also on the crystal-
indicated as the percentage by weight of the substance that line form, the degree and strength of agglomeration, the
passes the sieve. Many raw materials are naturally fine (talc, shape of the sieve openings, the flow properties, the sieve
starch) or will be delivered in the required degree of fine- technique, the duration of the sieving process and the
ness, such as paracetamol (45) and salicylic acid (90). sample size.
Highly active substances are in most cases available In addition to the afore mentioned methods there are still
sufficiently fine. The designation ‘micronised’ is not special instrumental techniques applied such as the laser
standardised, but a very good description is given by diffraction method for the determination of the particle size
Møller [16]: 90 % of the number of particles <5 μm and and the gas permeability method for the determination of the
all <25 μm. In this area of fineness, the given ‘particle size’
PRODUCTION
specific surface of a powder [17]. A further discussion of
depends strongly on the method of measurement. these methods is beyond the scope of this book. More infor-
The particle size measurement of the raw materials is mation is available in textbooks [18].
usually done by the supplier or the manufacturer. For the Some substances are available in several degrees of fineness.
interpretation of those results it is necessary to know the The raw material triamcinolone acetonide is available as a
principles of some methods. In the design phase, during micronised powder, to be used if triamcinolone acetonide is
in-process controls and at final testing, it is important to dispersed in a base. The micronisation may increase dissolution
choose the particle size measurement method that is relevant rate and hence bioavailability. It has, however, a strong agglom-
to the property for which the particle size is investigated. eration tendency and therefore cannot be processed as such.
Next to the determination of the particle size, a description The 1 to 10 dispersion with rice starch contains micronised
of the nature of particles (crystals, agglomerates or triamcinolone acetonide, whose particles don’t agglomerate
aggregates) may be recommended. any more due to the presence of rice starch and it may be
As with all methods caution must be exercised to take a preferred for the preparation of creams. Triamcinolone
representative sample, both in terms of sampling location acetonide (crystalline form) as such can be used if it is dissolved
and size, for both the raw material and the product. A good in propylene glycol (for ointments) or in ethanol (for ear drops).
overview of the different sampling methods is available in To improve the absorption and bioavailability, paraceta-
the literature [16]. mol in suppositories is processed as particles < 45 μm. In
With microscopy both the form (crystal, agglomerate) powders because of the greater density and better flow
and the dimensions of a particle can be determined. The properties paracetamol (500–90) is used and for solutions
microscope must be equipped with ocular micrometers. either product can be used.
With a normal light microscope dimensions can be deter- Microcrystalline tetracycline hydrochloride in
mined for crystals or agglomerates of 5 μm to a few 100 μm. micronised or microcrystalline form is applied in ointments,
creams and eye ointments, while the coarser (‘heavy’) tetra- 23.1.9 Mix-Up of Names
cycline hydrochloride is applied in capsules because of the
greater density and in suspensions because of the greater If names of substances are similar they can easily lead to
chemical stability. mistakes. Well-known examples are: promazine and
Microcrystalline cellulose (Avicel®, Pharmacel®) also promethazine, salicylic acid and acetylsalicylic acid, sorbic
exists as many variations of particle size. See Sect. 23.4.1. acid and ascorbic acid, xylocain and xylometazolin, tetracy-
Lactose has many variations in terms of particle size as cline and tetracain, Aerosil® and Avicel®, Oleum soya
well, each with their specific application in the food indus- emulgatum and Oleum soya raffinatum etc.
try. The products for pharmaceutical use reflect only a small A notorious source of confusion and ambiguity are the
portion of the total volume of lactose produced by multina- phosphates and their different ways of naming. Mistaking
tional companies worldwide. These multinationals indicate one for another in buffer solutions will lead to unexpected
the particle size by using mesh seizes, as is usual in the food pHs. Mistaking the calcium phosphates may lead to wrong
industry. The mesh size gives the number of openings per strengths in preparations. A short overview of the structural
linear inch on a screen, see Table 23.4. Suppliers of pharma- formula, name in Ph. Eur. and much used other names is
ceutical grade lactose usually specify their products based on given in Table 23.5.
sieve analyses, so expressing the result in μm. New names in the Ph. Eur. also provide for confusion
such as the two known forms of Cera lanette N and SX. Cera
lanette N is now called Cetostearyl alcohol (type A)
23.1.8.2 Viscosity
emulsifying (Alcohol cetylicus et stearilicus emulsificans
Chemical quality indications are for instance important for
A). Cera lanette SX is now called Cetostearyl alcohol (type
cellulose derivatives. The quality depends on the length
B) emulsifying (Alcohol cetylicus et stearilicus emulsificans
of the polymer chain and is usually indicated by the
B). The mix-up is easily made with Cetostearylalcohol
viscosity that is achieved in a 2 % solution. An example is
(Alcohol cetylicus et stearilicus, a mixture of equal parts
hypromellose 4000 mPa.s. This quality is a highly viscous
cetyl-and stearyl alcohol).
form. A 2 % solution of medium viscous forms of the
Ph. Eur. will change names from time to time. Sometimes
cellulose derivatives usually have a viscosity of some
it is quite obvious and there is no ambiguity between the
hundreds and the low viscous quality of 10–100 mPa.s.
old and the new name, just a shift in the alphabetical order
(examples are sodium diclofenac which has become
Table 23.4 Conversion table suitable for some commonly used lac- diclofenac sodium, ethyl parahydroxybenzoate sodium that
tose types has become sodium ethyl parahydroxybenzoate). But some-
Mesh size Approximate size of opening times, especially with hydrates (ferrous sulfate is now fer-
80 177 μm rous sulfate heptahydrate), the substance is a different one
100 149 μm and sometimes the name will change completely but the
200 74 μm substance remains the same e.g. Glycerol triacetate becomes
325 44 μm Triacetin, Chloramine becomes Tosylchloramine sodium.
400 37 μm Differences in numbers and figures in the name can cause
450 32 μm confusion. Cetostearyl alcohol (type A) differs from
Table 23.5 Overview of phosphates used in pharmaceutical practice

Structural formula Name in Ph. Eur Synonyms
CaHPO4 Calcium hydrogen phosphate anhydrous Calcium phosphate, dibasic anhydrous
CaHPO4.2H2O Calcium hydrogen phosphate dihydrate Calcium phosphate, dibasic dihydrate
Ca3(PO4)2 Calcium phosphate Calcium phosphate, tribasic
Calcium orthophosphate
KH2PO4 Potassium dihydrogen phosphate Potassium phosphate, monobasic
K2HPO4 Dipotassium phosphate Dibasic potassium phosphate
NaH2PO4.2H2O Sodium dihydrogen phosphate dihydrate Sodium phosphate, monobasic
Na2HPO4 Disodium phosphate anhydrous Disodium hydrogen phosphate
Na2HPO4.2H2O Disodium phosphate dihydrate Sodium phosphate, dibasic (anhydrous, dihydrate, dodecahydrate)
Na2HPO4.12H2O Disodium phosphate dodecahydrate
Na3PO4.xH2O – Tribasic sodium phosphate
Cetostearyl alcohol (type B) concerning the emulsifier (type standardised storage conditions for this raw material, in an
A: sodium cetostearyl sulfate; type B: sodium lauryl sulfate). unopened packaging. If these storage conditions are not
The macrogols are followed by a number, which indicates maintained in practice, or when the packaging is opened
the average molecular mass of the chain. frequently, it is likely that the label claim is no longer
Vitamin A (Retinol) and Vitamin A acid (Tretinoin) are applicable for the content. This phenomenon occurs espe-
different substances and cannot be used instead of each other cially in efflorescing or strongly hygroscopic substances and
because they have a different pharmacotherapeutic applica- also substances sensitive for oxidation such as fatty oils with
tion. Folic acid (Acidum folicum) and Folinic acid (Acidum many unsaturated fatty acids.
folinicum) are closely related substances but differ signifi-
cantly in effective strength. Tocopherol esters are applied as
Prednisolone sodium phosphate and dexamethasone
vitamin E; tocopherol itself is especially applied as
sodium phosphate are examples. They always contain
antioxidant.
a quantity of water and ethanol which is factorised in
It is necessary to be alert to the existence of different
the standardised worksheets. Both substances can
esters or ethers of a substance and different amounts of water
attract more moisture than specified according to the
of crystallisation. The availability of two or three different
label. In addition, the attracted moisture accelerates
forms of a raw material can easily lead to mix-ups. For
the decomposition. For small scale preparation raw
examples refer to Table 23.1 and to Sect. 23.1.5.
materials suppliers sell these substances in small
Sometimes the name of a raw material is incomplete and
quantities in a well closed container, sometimes filled
therefore not unambiguous. Polymyxin can be polymyxin B
under a nitrogen atmosphere, in order to remain com-
or polymyxin E (colistin). If the designation vitamin D is
pliant to the specifications during the listed shelf life.
used, it may be assumed that cholecalciferol, vitamin D3, is
Within a few weeks after opening the container in the
meant and not the less effective ergocalciferol, vitamin D2.
pharmacy the substance will no longer meet the
specifications as a result of degradation, unless the
substance is stored in a desiccator in the fridge. It is
23.2 Quality, Stability and Shelf Life therefore recommended to process the whole pack into
the final product at one time.
Some raw materials degrade or otherwise lose quality. This
The water content of zinc sulfate.7H2O can
may be the result of:
decrease by efflorescence. The water may condense
• Hygroscopicity; for example calcium chloride, docusate
at the top of the container and to the inside of the lid.
sodium
PRODUCTION
This water can be reabsorbed by shaking well.
• Efflorescence, which is losing crystal water; it occurs
Both forms of calcium chloride (CaCl2.6H2O and
especially with sulfates and in particular with zinc sulfate,
CaCl2.2H2O) can attract water by hygroscopicity and
and with substances with a high crystal water content
subsequently dissolve in the attracted water.
such as disodium phosphate dodecahydrate
Water is able to evaporate from chlorhexidine
• Oxidation: for example cholecalciferol, ferro compounds,
digluconate solution 20 %. This may lead to a high
tretinoin, and catecholamines, fatty oils
content in chlorhexidine creams and mouthwashes. An
• Microbiological spoilage: for example water, starch,
use-by period of 1 year is therefore recommended for
paracetamol, amphotericin
this raw material.
The purity of the raw material will affect the active
substance content of the finished product and requires
factorisation. This means: correcting the quantity of a raw Caution must be exercised with these kinds of substances
material to be weighed for the active substance content and they need to be stored properly and not being used if the
deviating from 100 % in the raw material. The content expiry date is exceeded. The influence of light should not be
requirements of the finished product and the underestimated. The Ph. Eur. states for many substances, for
recommendations concerning factorisation can be found in example tretinoin, phytomenadione, corticosteroids and
Sect. 32.4. benzodiazepines that they must be protected against light.
The pack sizes of raw materials are often such that the In oils and fats oxidation and peroxide formation is
contents will not be used in its entirety, but in parts. Along increased by light. Sorbic acid in solution (so also in
with the substance’s properties, its packing, storage and use preparations) is sensitive to light.
determine the shelf life of the raw material in the pharmacy. Proteins is a group of active substances that will be used
The shelf life of a raw material is displayed on the package increasingly in the future. Proteins are large vulnerable
by an expiration date. This applies to the shelf life at the molecules with a complex structure. Their many functional
groups render proteins very sensitive to chemical and physi- 23.3.1.1 Potable Water
cal degradation. These can lead to disintegration of the Potable water (Tap water, Aqua, Aqua communis, Water for
molecule or may cause a change in the tertiary structure. In human consumption) is as such a raw material for purified
both cases, the biological activity is lost, see Sect. 18.4.1. water in small-scale preparation and it may be used for the
The chemical processes that can play a part are: oxidation, early stages of cleaning pharmaceutical equipment. It has the
hydrolysis, desamidation, disulfide conversion, beta- advantage that, if there is a good flow rate through the pipes,
elimination, racemisation. Physical processes that may in most European countries it usually has a reasonable
occur are: precipitation, adsorption, absorption, aggregation microbiological quality.
and denaturation. This means, that many factors can influ- Potable water contains as additives sodium, calcium,
ence the stability of proteins. Acidity, oxygen and light are magnesium, chloride and carbonate ions and a number of
known factors or catalysts of degradation reactions. Temper- other ions in very low concentrations. The bivalent ions of
ature plays a part in many of degradation processes. Freeze- calcium and magnesium are the cause of hardness in water.
thaw cycles may greatly affect the material. In addition, the The hardness of water is specified as hardness degrees, see
type of degradation reaction will depend on the temperature. Table 23.7.
Hard water will form precipitations of calcium and mag-
nesium salts of the anions that are dissolved in the water. The
hardness can be subject to regional differences. The water
23.3 Solvents company should be consulted (or the internet searched) for
the hardness of the water it is providing.
23.3.1 Water Among the trace ions, the heavy metals ions are of par-
ticular pharmaceutical interest. For instance copper and lead
Various water qualities that are used in the preparation or can occur in potable water, since pipes can be made of these
reconstitution of medicinal products are described in the materials. To limit the electrolytic formation of these ions,
Ph. Eur. and in an EMA Note for Guidance [19]. See for the pipes are now often made of plastic (PVC) and the earth
the overview Table 23.6. The production of water for phar- wire is no longer connected to the water pipe.
maceutical purposes is described in Sect. 28.3 and storage The common air gases, carbon dioxide, oxygen, and
and distribution in Sect. 27.5.2. nitrogen, are also dissolved in water. The dissolved oxygen
Table 23.6 Constituents and impurities which, as a result of the preparation method and storage conditions, may be found in the different types of
water
Heavy Micro- Organic
Type of water Subcategory Minerals metals Gases organisms substances*
Potable water (tap water) + + + + +
Water, purified Ph. Eur. (Aqua purificata) in two forms: Demineralised water – +() + ++ +
Purified water in bulk Distilled water – – + + +
Purified water in containers Reverse-osmosis water – – + + +
(RO-water)
Water, highly purified Ph. Eur. (Aqua valde purificata) – – + –(+) –
Water for injections Ph. Eur. (Aqua ad iniectabile) Water for injections in bulk – – – –(+) –
(WFI) Sterilised water for injections – – – – –
*incl. pyrogens
+ and – will indicate the presence or absence of the concerned materials
Table 23.7 Water hardness and corresponding calcium salt concentration

mg Ca/L mg CaCO3/L English degrees French degrees German degrees Hardness
<30 <75 <5.3 <7.5 <4.2 Very soft
30–50 75–125 5.3–8.8 7.5–12.5 4.2–7.0 Soft
50–100 125–250 8.8–17.5 12.5–25.0 7.0–14.0 Moderately hard
100–150 250–375 17.5–26.3 25.0–37.5 14.0–21.0 Hard
>150 >375 >26.3 >37.5 >21.0 Very hard
may decrease the stability of oxidisable active substances. adds limit tests for acidity or alkalinity, chlorides, sulfates,
Carbonic acid will form poorly soluble carbonates with oxidisable substances (mandatory, no choice of TOC),
many bivalent positive ions. ammonium, calcium and magnesium, residue on evapora-
Fresh draught potable water meets the following tion and microbiological contamination. The Ph. Eur. also
microbiological quality requirements, provided that it flows requires that the conductivity is measured. At 20 C the
well through the pipes and that there is no holding tank: not conductivity may not exceed the value of 4.3 microS.cm1.
more than 100 micro-organisms per mL, and Escherichia The measurement may be in-line or off-line. In-line mea-
coli <1 per 100 mL. In practice the contamination of fresh surement (see Sect. 27.5.2) enables a quick and permanent
potable water will not exceed 10 CFU/mL (CFU ¼ colony monitoring of the removal of sufficient minerals. If the water
forming units1). This means that fresh draught potable water complies with the requirement for the conductivity for Water
in microbiological terms is suitable for the manufacture of for Injections (1.1 microS.cm1) the test for heavy metals
non-sterile medicinal products; the Ph. Eur. limit for these does not need be carried out.
products being 100 CFU/mL. Do not use hot water from the Measuring the pH with a pH meter is only possible if the
tap, because it might come from a holding tank; prepare it by conductivity is increased by the addition of a little potassium
cold potable water and heat if necessary. chloride. Distilled water has a low pH, which quite often is
It is necessary to check occasionally the quality of potable caused by dissolved carbon dioxide. This is removed during
water. Especially in hospital pharmacies one should antici- the distillation process but it can re-enter by diffusion. This
pate the presence of still water, due to the presence of is a strong acid with a limited solubility. It is partly the cause
holding tanks. In those circumstances, germ growth will of distilled water’s aggressiveness towards base metals
occur such that the limit value of 100 CFU/mL may be (beware with aluminium). Dissolved gases may also be
exceeded. Pharmacy should have access to water supplied found in demineralised water since the process is not
directly from the mains supply. Nevertheless the quality of designed to remove them. neither is the demineralisation
the water supplied by the water company is not under the process designed to remove heavy metals, so also these can
control of the pharmacy. be found.
Potable water can be used for the various antibiotic oral
mixtures that are reconstituted from the dry granulate.
Carbon dioxide dissolves mainly in the form of the
carbon dioxide monohydrate (CO2.H2O) which is in
23.3.1.2 Purified Water
equilibrium with carbonic acid (H2CO3). The balance,
Purified water is water that has been purified from the hard-
however, lies predominantly to the hydrate side. Inso-
ness minerals by one of the methods mentioned by Ph. Eur.
PRODUCTION
far as carbonic acid is formed, this is fully split into
Ph. Eur. has two types of Purified Water: Purified Water in
ions and thus a strong acid. However, it usually
bulk and Purified Water in containers. It is used in the
behaves as a weak acid because of the natural shift to
pharmacy in several ways: as a raw material for the manu-
the hydrate side.
facture of non-sterile medicines, sterile medicines that are
not necessarily free of endotoxins, in water baths, as cooling
water for steam sterilisers, and sometimes for rinsing glass-
ware or packaging material. For Highly purified water
Microbiological Purity
Ph. Eur. the microbiological and endotoxin requirements
In the monograph for Water, purified a specification for the
are the same as for Water for injections.
microbiological quality is included: not more than 100 CFU/
mL (TAMC, see Sect. 19.6). This corresponds to the strictest
Chemical Purity
requirement for the microbiological contamination of
The monograph Water, purified of the Ph. Eur. set limits for
preparations. In general the requirements for raw materials
total organic carbon (TOC) or oxidisable substances,
are stricter than those for the preparations, but not in this
endotoxins (if intended for dialysis solutions), conductivity
case. The absence of E. coli is essential, but the starting
and the following ions: nitrates, aluminium (if intended for
material (potable water) has been checked already and the
dialysis solutions) and heavy metals. In addition it is neces-
growth of these organisms in the systems of water purifica-
sary to perform microbiological monitoring during produc-
tion is unlikely. For measuring the microbiological quality
tion and storage. For purified water in containers, the Ph.Eur.
of water the method (the nutrient medium and the tempera-
ture), should be chosen, see Sect. 19.6. The requirement of
microbiological purity is to be met at start of production by
1
Colony Forming Unit ¼ One or more micro-organisms that produce a
visible, discrete growth entity on a semisolid, agar-based distillation but if this water is prepared by demineralisa-
microbiological medium. tion or is kept longer than 24 h after production, then a
Table 23.8 Guidelines for keeping water for non-sterile medicines

Method of preparation + way of storage: Storage temperature: Storage period:
Distillation
Storage in closed bottle 2–8 C 2 weeks
Bottle after opening 15–25 C 24 h
Vessel from which it is tapped 15–25 C 24 h
Demineralisation plus boiling 15–25 C 24 h
Demineralisation with membrane filtration 15–25 C None: use immediately
Sterile purified water
Closed bottle 15–25 C 3 years
Sterilised water for injections
Closed bottle, sterilised 2–30 C 3 years
microbiological reducing treatment by heating or filtration is Purification should therefore only take place in this case
necessary. by distillation because demineralisation and reverse osmo-
A test on bacterial endotoxins is also included in the sis, as purification processes, are considered too risky from a
Ph. Eur. because of water for the production of dialysis microbiological point of view and because of the risk of
preparations. developing bacterial endotoxins. However, in the Japanese
For applications requiring water of high microbiological Pharmacopoeia reverse osmosis is now an accepted method
quality the Ph. Eur. includes the monograph Water, highly and in Europe there are ongoing discussions to accept
purified. The ‘requirement’ (the pharmacopoeia states an reverse osmosis after all [20].
action limit to production) is 10 CFU/100 mL. This require- When collecting and storing water, the growth of micro-
ment corresponds to that of Water for injections; yet Highly organisms and the increase of endotoxins as bacterial waste
Purified Water is considered unacceptable for use as Water products must be prevented. That means it is either collected
for Injections. It can be used when medicinal products and kept at a temperature higher than approximately 70 C
administered by nebulisation are required to be sterile and until it is processed (Water for injections in bulk), or it is
non-pyrogenic and for the final rinse of equipment, sterilised, either directly or after filling into vials or
containers and closures for sterile products [19]. The Phar- ampoules (Sterilised water for injections, Aqua ad
macopoeia lists it as one of the types of water that can be iniectabile sterilisata). See further Sect. 27.5.2.
used in gene transfer. Purified water can also be purchased. In that case Sterile
purified water or Sterilised water for injections is
recommended because of the insecure shelf life and usage
23.3.1.3 Water for Injections
period of non-sterile water. Table 23.8 provides practical,
Water for injections is prepared according to the Ph. Eur. by
not official, guidelines for keeping water in small-scale
distillation of potable or purified water from a device of
situations without a storage and distribution installation.
neutral glass, quartz or a suitable metal. The device must
be fitted with an anti-splashing device to prevent contamina-
tion of distilled water with non-distilled water. A special quality of water is described in addition in
Water for injections in bulk must comply with the the Ph. Eur.: Water for the dilution of concentrated
requirements as formulated for Purified water. It must haemodialysis preparations. This monograph is
also be produced free of bacterial endotoxins and stored included for information purposes and does not have
such that it remains free of them. It can be used for paren- the same legal force as the other pharmacopoeial
teral products and irrigations that are terminally sterilised. monographs. Nephrology associations may have
Water for injections, sterilised, must meet the requirements elaborated supplementary guidelines, such as in the
of sterility (sterility test) and the bacterial endotoxin con- UK [21] and ISO13959:2009. See also Sect. 14.5.
tent must not exceed 0.25 IU per mL. This is used for Special technical demands are applied to water
parenteral products and irrigations that are not terminally which is used as cooling water for sterilisation equip-
sterilised and for dissolving powders for injection immedi- ment and other devices used in health care.
ately before use.
23.3.2 Ethanol
bergamot oil to 1 L alcohol 96 % V/V. The methyl-
In pharmacy ethanol is usually used as a solvent and some- ethylketone renders the solution azeotropic thereby
times as a preservative. It can also be used as a disinfectant, making re-distillation of pure ethanol impossible.
mainly in a concentration of 70 % V/V in water. The excess Denatonium benzoate has an intensely bitter taste,
use of alcohol as a cleaning agent has been reduced after it thus creating an unpalatable drink. A similar method
was registered as being mutagenic on inhalation. Although of denaturating ethanol with methylethylketone and
the Occupational Exposure Limit (OEL) of ethanol is rather sometimes addition of a dye occurs in Switzerland,
high in many European countries: about 1,000 mg/m3 as Poland, Norway, and Czech Republic. In Kosovo and
Time Weighted Average (TWA)-8 h and 1,900 mg/m3 as Turkey denaturating is not common nor is it carried
TWA-15 min, this level can be easily exceeded in a small out in Croatia, where ethanol used in pharmacies is
room, see Sect. 26.7.2. free of tax.
The concentration of ethanol in water is still given in After denaturation the alcohol is of course unfit for
volume/volume percentage. When adding a mL ethanol to use in oral preparations.
b mL of water the final volume of the solution is smaller
than the sum of a + b. This phenomenon is called contrac-
The alcohol denatured with methylethylketone cannot be
tion. The alcoholimetric tables of the Ph. Eur. provide
used as a solvent for iodine spirit because methylethylketone,
sufficient information to prepare a variety of concentra-
like acetone, will complex with iodine. This complex irritates
tions. Next to the described concentrations in Ph. Eur.
the eyes of people using it or applying it on the skin.
(absolute and 96 %), ethanol 70 % V/V (62.4 % m/m) is
The addition of 5 % methanol may be considered by
used for preparation purposes.
authorities to be sufficient to denaturate ethanol. Ethanol
Ethanol as such is not automatically sterile. 50–70 % V/V
denaturated with 5 % methanol is commonly used in
ethanol/water is maximally bactericidal. Higher concen-
cosmetics despite the fact that methanol (and also
trations can cause some micro-organisms to transform into
methylethylketone) is, according to the H-statements (see
spores, which are able to survive. If the ethanol concentra-
Sect. 26.3.2) considered to be too toxic when regularly
tion of a liquid is higher than 15 % (V/V) in combination
applied to the skin of workers.
with a pH lower than 7, or if the concentration is higher than
18 % (V/V) in combination with a pH higher than 7, no
preservative needs to be added. These conditions make the
liquid self-preserving. Alcohol 96 % V/V can be sterilised 23.3.3 Glycols and Glycerol
PRODUCTION
by distillation. Filtration by ethanol-resistant membrane
filters with pore size 0.2 μm will reduce the number of Glycols are diols (alcohols with two hydroxyl groups). Eth-
micro-organisms considerably. Mixtures with sufficient ylene glycol has no pharmaceutical application. It is toxic
water content can be sterilised by autoclaving. Hydrogen because it strongly binds calcium.
peroxide may be added as a sporicide. Propylene glycol is a diol (propane-1, 2-diol). It is in use
in cutaneous preparations, dissolved in the aqueous phase, as
a humectant, to slow down a dehydration process. Other
23.3.2.1 Denaturated Ethanol
applications are the use as softening agent and as vehicle
In most countries excise duty must be paid on pure ethanol.
for ear drops intended for the external auditory meatus (see
Therefore in some countries alcohol that is intended for
Sect. 9.5.3).
external application or disinfection purposes (including dis-
In mixtures with ethanol and water it is a solvent for
infection of skin) is usually denaturated: rendered unsuitable
active substances with low water solubility such as digoxin,
for consumption. When denaturated, the duty can (partly) be
diazepam, barbiturates and phenytoin (see also Sect. 18.1.3).
exempted. The exemption of duty may be bound to licenses
The ratio water - ethanol - propylene glycol (or glycerol)
stating the amount of ethanol that is bought through the year
depends on the substance to be dissolved. Propylene glycol
and the agents used to denaturate.
concentrations higher than approximately 15 % are self-
preserving. Depending on the formulation of the preparation,
In Netherlands a usual way of denaturating alcohol is concentrations from 13 % may be sufficient for preserva-
the addition of 5 mL of methylethylketone, 25 mg tion. Mixtures with water can be sterilised by steam
denatonium benzoate and 2.5 mL of synthetic sterilisation. Propylene glycol is toxic in (chronic) oral use
by children and patients with poor renal function [22].
(continued)
Table 23.9 Some commonly used fats and oils

In 1937 the Elixir Sulfanilamide disaster occurred, Vegetable, unsaturated, liquid Almond oil
one of the most consequential mass poisonings of the Arachis oil
twentieth century. This tragedy occurred when propyl- Olive oil
ene glycol was used as the diluent in the formulation of Rapeseed oil
Elixir Sulfanilamide. More than 100 patients died. At Sesame oil
that moment premarketing toxicity testing was not Soya-bean oil
required. In reaction to this calamity, the Vegetable, unsaturated, solid Cocoa butter
U.S. Congress passed the 1938 Federal Food, Drug Animal, saturated,a solid Lard
and Cosmetic Act, which required proof of safety Synthetic, saturated, liquid Triglycerides, medium chain
(Miglyol 812®)
before the release of a new drug [23]. The FDA was
Synthetic, saturated, solid Hard fat
established. a
Read the concept of saturated as saturated or nearly saturated
Glycerol is a triol (propane-1,2,3-triol) and very hygro-

scopic. Glycerol 85 % is less hygroscopic and thus less 23.3.5 Fatty Oils, Fat, Waxes and Paraffin
perishable. The applications are similar to those of propyl- Waxes
ene glycol. When used in oral liquid preparations the taste is
slightly sweet and better than that of propylene glycol. Oils and fats are triglycerides (esters of glycerol with three
Glycerol is more hydrophilic than propylene glycol; self- fatty acids, mainly palmitic acid, stearic acid and oleic acid).
preserving concentration is higher than approximately 30 %, The melting point and consistency decrease with decreasing
so significantly higher than that of propylene glycol. Glyc- degree of saturation and increase with larger chain length.
erol/water mixtures are sterilised by steam sterilisation. The melting point of a saturated substance is higher than that
of the corresponding unsaturated substance.
Esterification of glycerol with saturated short chain fatty
23.3.4 Macrogols acids and unsaturated short-and medium chain fatty acids
usually results in (at room temperature) liquid oils; longer
Macrogol (polyethylene glycol, PEG) is a polymer of ethyl- fatty acids give hard fats. Table 23.9 shows several examples
ene oxide, see Fig. 23.1. of natural and synthetic oils and fats.
The chain length and the molecular mass depend on the Rapeseed oil and sesame oil, given their sensitising
polymerisation degree n. Macrogol 400 has a molecular properties, are no longer applied in cutaneous preparations.
mass of 400 in a polymerisation degree n ¼ 8. Below a They can cause contact allergy. Groundnut oil is made from
molecular mass of 700 the macrogols are liquid, above peanuts and may cause, when in non-purified form, peanut-
1000 they are solid. Macrogols are used as a basis for allergy. When using the purified, pharmaceutical form, aller-
hydrophilic ointments (Sect. 12.7.8) and as water-soluble gic reactions will not occur [24].
suppository bases (Sect. 11.4.5). During storage macrogols Hard Fat consists of a mixture of mono-, di- and
can be slightly oxidised by oxygen from the air. For that triglycerides. It is used as a lipid suppository base. More
reason they are incompatible with oxidisable active information can be found in Sect. 11.4.4.
substances, especially if those are applied in low
concentrations (e.g. ergotamine). Ph. Eur. contains assays, for acid, hydroxyl, iodine
Macrogols with a low degree of polymerisation(<2000) and peroxide values, to determine the qualities of oils
are hygroscopic [5]. and fats.
The acid value is a measure of the amount of free
fatty acids in the fat. An appropriate acid number, so a
correct amount of free fatty acids, of groundnut oil is
important in the preparation of Zinc oxide calcium
hydroxide weak paste FNA (see Table 12.39). The
Fig. 23.1 The formula of
macrogol H O CH2 CH2 OH (continued)
n
obtain a suppository that melts as soon as it is inserted,

ideal is 0.25–0.5. If the acid value is low (e.g. 0.06, for creating a soothing layer for haemorrhoids. This liquid fat
a just opened package) then free oleic acid must be can also be used for the preparation of oily injections, for
added. At too high an acid number the emulsion cutaneous and for oral preparations.
breaks. Waxes are esters of higher fatty acids and fatty alcohols.
The hydroxyl value is a measure of the number of Pharmaceutically important examples are the liquid Decyl
acylable places and thus the content of mono-and oleate (unsaturated; Cetiol V®), the semisolid Wool fat
diglycerides. A suppository base (Hard fat) with a (Adeps lanae) and the solids Yellow wax (Cera flava),
low hydroxyl value (<15) is less damaging to the Bees wax, white (Cera alba, white wax) and Cetyl palmitate
stability of acetylsalicylic acid and ergotamine tartrate (Cetaceum). The solid waxes are mainly used to increase the
than bases with a higher hydroxyl value. Witepsol H15 consistency of semisolid skin preparations (see Sect. 12.5.2).
has a sufficiently low hydroxyl value (5–15) for this Waxy liquid compounds are ethyl oleate, isopropyl
preparation. Bases with a high hydroxyl value (up to myristate and benzyl benzoate. In the first two cases the
50) have a better emulsifying ability and can include fatty acid is esterified with a short-chain alcohol.
aqueous systems in the form of a water-in-oil- Decyl oleate is used as lipid phase in hydrophilic cream
emulsion. bases (see Sect. 12.7.7).
The iodine value is a measure of the number of Wool fat (Adeps lanae; this is a wax and not a fat) is used
double bonds. For Hard fat the Ph. Eur. requires a in ointments and in eye ointments and increases the penetra-
value 3.0. tion ability of lipophilic ointments. A drawback is the chance
The peroxide value is a measure of the number of of contact allergy. Due to the presence of free surface active
peroxide bridges in the fat. Fats or oils with a low lanolin alcohols Wool fat has a greater power to absorb
peroxide number (0.5) are used for the processing water than the other waxes. Lanolin (Adeps lanae cum
of easily oxidisable substances. Examples are ergota- aqua) is an emulsion of 25 %water in 75 % Wool fat.
mine tartrate and chlorpromazine hydrochloride in Cetyl palmitate (Cetaceum) is no longer used because of
fatty suppositories. the endangered status of the sperm whale from which it
The saponification value is a measure of the number originates. There is a little used synthetic variant on the
of available saponifiable ester bonds. Also the market. It consists of a mixture of cetylesters with fatty
unsaponifiable matter may still be used as a property. acids in the order size C14 to C18.
For each fatty oil or fat the requirements are Paraffin waxes are hydrocarbons with short (<C15) and
specified in the relevant monograph. long (>C15) carbon chains. In pharmacy preparation the
PRODUCTION
solid (Hard paraffin), liquid (Liquid paraffin and Light liquid
paraffin) and soft type (White soft paraffin and Yellow soft
Unsaturated fats (high iodine value: >4) are sensitive to
paraffin) are used. They have a role in cutaneous
oxidation by peroxides; becoming rancid. Adding
preparations (see Sects. 12.7.9, 12.7.12, and 12.7.13) and
antioxidants (radical scavengers, examples: butylhydrox-
eye ointments (see Sect. 10.7.3).
yanisole and butyl hydroxytoluene, see Sect. 23.9) will
prevent this.
In addition to long chain triglycerides, liquid medium The liquid paraffin waxes are distinguished by viscos-
chain triglycerides may also be used. These are available ity. Liquid paraffin has a viscosity between 110 and
under the brand name Miglyol®, of which the most impor- 230 mPa.s, Light liquid paraffin between 25 and
tant are Miglyol 810 and 812. They differ slightly in compo- 80 mPa.s. In small-scale preparation liquid paraffin is
sition and viscosity. Miglyol 812 (Medium chain mainly used.
triglycerides, Triglycerida media saturata Ph.Eur.) is added Soft paraffin behaves rheologically as a gel (plas-
to Hard fat in zinc oxide suppositories (see Table 23.10) to tic). In a physical sense it is described as a colloidal
system (hydrocarbon gel) of long chains colloidally
dispersed in shorter chains.
Table 23.10 Zinc Oxide Suppositories 10 % [25]
For a suppository mold of any volume
Zinc oxide (90) 10 g Oil for injections originates from olive oil, sesame oil or
Triglycerides, medium chain (Myglyol 812) 20 g another suitable oil. The oil must be acid-free, dry and sterile.
Hard fat 70 g To achieve this, in the past, the olive oil was shaken with
Total 100 g
magnesium oxide and water (binding of the free fatty acids)
and then filtered and dried on anhydrous sodium sulfate. The
current commercially available oil is sufficiently acid-free and polymerisation degree of 800–3000, and of amylopectin:
dry. The general monograph Vegetable fatty oils Ph. Eur. 1,4-α-glucosidic connected chains branched with
states that vegetable oils may be used only in parenteral 1,6-α-sidechains. There are starches of different origins
preparations when they are alkali purified (no physical purifi- with different particle sizes and other properties. The Ph.
cation). The oil can be sterilised by dry heating or by filtration. Eur. lists (in descending order of fineness): Rice starch
Ethyl oleate and some other liquid waxy compounds are also (Oryzae amylum), Corn starch (Maydis amylum), Wheat
in use as a solvent for oil-based injections. starch (Tritici amylum) and Potato starch (Solani amylum).
In the monographs many other characteristics, for example
the grain sizes, are described. Starch is used as a filling agent
23.3.6 Acetem for capsules and tablets, as a disintegration agent in tablets
and as a moisture-absorbent ingredient in cutaneous pastes.
Acetem (E472a) is a mixture of acetylated monoglycerides Wheat starch can contain gluten, which makes the medicines
of fatty acids, an oily substance, which is mainly used in the unsuitable for coeliac patients (who are prescribed a strict
food industry. Acetem is allowed in food, also for babies, gluten-free diet). For this reason, corn starch is favourite for
and there is no restriction on the daily intake [26] Acetem processing in solid oral dosage forms.
can be used as a solvent for non-water soluble substances in Sodium starch glycolate (Carboxymethylamylum
oral preparations if ethanol or propylene glycol is not advis- natricum) is the sodium salt of the carboxymethylether of
able (for example, in case of paediatric use). For phenobar- potato starch. The Ph. Eur. describes three variants: type A
bital in a liquid oral dosage form, acetem seems an option. In and B contain 2.8–4.2 % sodium and type C 2.8–5.0 %
Netherlands acetem is used for dissolving phenobarbital in a sodium. In small-scale preparation the A type is mainly
liquid oral dosage form for children (see Table 5.7), as an used (trade name Primojel®). The starches are used as filling
alternative to an alkaline solution, an alcoholic solution or a agents and as disintegration agents. Sodium starch glycollate
suspension in water. Be aware of huge pharmaceutical avail- variants are, in a concentration of 2–8 %, almost exclusively
ability differences and hence unexpected pharmacodynamic used as disintegration agent.
effects of active substances dissolved in acetem, compared Cellulose is beta-glucosidic polymerised glucose with a
with their suspension in water. Acetem is incompatible with polymerisation degree of approximately 3000, see Fig. 23.2.
PVC, so it cannot be used with feeding tubes. Microcrystalline cellulose is crystalline, partially
Acetem is available under the brand name Myvacet. depolymerised cellulose. It is available in different qualities
There are two qualities, Myvacet 9–08 and 9–45, both of with particle sizes ranging between 20 and 200 μm. The
which are useful. Myvacet 9–08 has a lower solidification most suitable quality for the production of tablets, capsules
point, which in practice can be helpful. A disadvantage is and powders has an average particle size of 100 μm and is
that the substance is not explicitly described in any pharma- available under various brand names including Pharmacel
copoeia, which makes quality control difficult. There is only 102® and Avicel PH102®. It is a chemically inert substance,
a fairly general monograph Mono-and diglycerides in the has reasonably favourable flow properties and is almost
USP/NF [27]. Another drawback is the unpleasant taste. insoluble. The particle size of 100 μm corresponds to that
23.4 Filling and Disintegration Agents

HO
Filling agents are inert substances to be added to increase the

O
mass of solid and semisolid preparations. Disintegration HO OH
agents promote the disintegration of tablets and capsules. OH
O O
OH OH
23.4.1 Starch and Microcrystalline Cellulose
O
Starch (Amylum) and cellulose are polysaccharides. Starch H OH
n/2
consists of amylose, chains of glucose units: –
1,4-α-glucosidic connected, long unbranched chains with a Fig. 23.2 The formula of cellulose, powdered
of many active substances being processed, which promotes 23.4.3 Calcium Hydrogen Phosphate Dihydrate
good and stable mixing.
Calcium hydrogen phosphate dihydrate is a neutral and water-
insoluble substance, which in its non-ground form is used as
filling and binding agent for directly compressed tablets. It is
23.4.2 Polyols
available under the proprietary names Emcompress and
Di-Cafos DC92. It is also known as ‘heavy’ calcium hydrogen
The most important polyols used in the small-scale prepara-
phosphate dihydrate. It is, in case where the more universal
tion are the hexoles sorbitol and mannitol, (see Figs. 23.3
filling agents cannot be used, also used as filling agent for
and 23.4). They are obtained by reduction of the corres-
capsules. Capsules containing calcium hydrogen phosphate
ponding keto- or aldomonosaccharides with corresponding
dihydrate do not disintegrate spontaneously, despite the
steric configuration. They have a sweet taste.
hydrophilic character of the substance, so the addition of a
The absorption of polyols is slow and incomplete. High
disintegration agent is necessary. This is contrary to capsules
doses, administered orally, therefore have a laxative effect.
containing microcrystalline cellulose, lactose or mannitol as a
They find an application as oral laxatives. The use of more
diluent that disintegrate easily. The Dutch Formulary FNA
than 20 g per day for adults is undesirable unless an osmotic
uses a Primojel capsule diluent for processing corticosteroids
laxative effect is required.
(see Sect. 4.4.3). This diluent contains, in addition to calcium
Besides the use as filling agents and laxatives the hexoles
hydrogen phosphate dihydrate, sodium starch glycolate A
are used as humectants (e.g. sorbitol in creams), for taste
(Primojel®) as disintegration agent and colloidal anhydrous
correction (e.g. sorbitol in oral liquids), to get iso-osmotic
silica as lubricant, see Table 23.11.
solutions (e.g., mannitol in eyewashes, see Sect. 10.6.2), as
diuretics in parenterals and as a cake stabilising agent in
freeze drying.
23.4.4 Sugars
The Ph. Eur. describes two qualities of the 70 % solution
of sorbitol: Sorbitol, liquid (crystallisable) and Sorbitol,
In the group of the sugars mainly lactose and sucrose are
liquid (non-cristallisable). The solution is supersaturated
used as filling agents. Both are disaccharides, respectively
(see Sect. 18.1.6). The crystallisable solution has the disad-
galactose-glucose and glucose-fructose. Lactose is much
vantage that during storage sorbitol may crystallise. The
less sweet and less hygroscopic than sucrose. These sugars
non-crystallisable solution has a higher percentage of
are soluble and lactose is used as filling agent in powders,
allowed impurities. Therefore the crystallisable form is pref-
tablets and capsules. If suppositories contain less than 50 mg
PRODUCTION
erable for pharmaceutical preparations. The solution can
active substance, then 100 mg lactose monohydrate (180)
only be used after any crystals have been redissolved by
will also be added to improve processing. Sucrose is espe-
gentle heating.
cially used to correct the taste, in oral mixtures for instance
as sugar syrup, and in chewable tablets. For the latter xylitol
can also be used. It has a sweetness value comparable with
Fig. 23.3 The formula of OH sucrose but it does not cause a pH dip in the mouth.
sorbitol HO H When using an effective mixer sugars can be dissolved in
H water without heat. Dissolving by heating is faster and has
OH
HO the advantage that the vegetative micro-organisms, which
H may be present in the raw materials, may be killed. Con-
HO H
stantly stirring during heating prevents local overheating,
HO and thus yellow discolouration (caramellisation) [29].
Table 23.11 Primojel Capsule Diluent [28]

Fig. 23.4 The formula of OH
mannitol Calcium hydrogen phosphate dihydrate, heavya 94 g
HO H
Silica, colloidal, anhydrous compressed 1g
H
H Sodium starch glycolate (type A),b compressed 5g
HO Total 100 g
OH
HO H a
Di-Cafos® DC 92-14
HO b
Primojel®
preparations, lactose monohydrate (180) is used. Lactose is

Sucrose in solution is converted by hydrolysis into functioning as a filler and binder in tableting applications;
the reducing sugars fructose and glucose (inversion). the applied process (wet granulation, dry granulation, direct
There are several reasons to set a limit to the degree of compressing) may require a choice for more specialised
inversion of sugar syrup. The most important seems to grades. In formulation of dry powder inhaler preparations
be the formation of these reducing sugars which have very specific lactose products are used as a carrier for the
an aldehyde group and are thereby much more reactive active substance.
than sucrose. Because sugar syrup is mainly used as
part of other preparations this reducing activity can be
Lactose for pharmaceutical preparations is supplied
a problem. However if a high concentration of glucose
by, for instance, Meggle and DFE Pharma. The
and fructose is required just because of their reducing
website of both firms provide extensive decision
properties, then invert sugar syrup or glucose syrup,
trees for helping you to choose the optimal form of
with known levels of fructose and glucose may be used
lactose (sieved, milled, spray dried, anhydrous) for
intentionally.
your application. In some countries the original sub-
The inversion may also reduce the syrup’s ability to
stance may be supplied by brokers, whereas you have
inhibit the growth of micro-organisms due to the
to ask for the source of it.
decrease of the sucrose content. This is controversial
as sugar syrup inhibits growth due to the high osmotic
value, which increases due to inversion. Micro- Aldehyde-sugars (glucose) and derived disaccharides of
organisms that are able to survive under these it (lactose) in solid form are, in contrast to the keto-sugars
circumstances can generally use both sucrose and glu- (fructose), incompatible with strongly alkaline compounds
cose or fructose as carbon source. The inversion will and primary amines (ethylenediamine). A brown
also reduce the sweetness of the product. discolouration (caramellisation) takes place. In the case of
Fast heating and cooling limits the inversion. primary amines is this called the Maillard reaction. In
Research has shown that in the preparation of 500 g mixtures of solid (anhydrous) substances these reactions
Sugar syrup, heating caused no additional inversion. proceed very slowly and they occur only on the surface of
Heating at 100 C for 1 h caused about 1 % inversion. the sugar particle. Thus they may be irrelevant in practice.
Decreasing the pH, for example by carbonic acid in However, because of this incompatibility the WHO formu-
using water that has been boiled for too short a time, lation for the oral rehydration salts prescribes anhydrous
accelerates inversion. glucose, which moreover is not combined with sodium
bicarbonate but with sodium citrate. It is preferable not to
use lactose in capsules with primary aliphatic amines. A
Lactose occurs in several forms: alfa-lactose
more recently reported Maillard reaction is that between
monohydrate Ph. Eur., (see Fig. 23.5) and water free beta-
lactose and fluoxetine [30].
lactose (Lactose anhydrous Ph. Eur.). In small-scale prepa-
In solutions (intravenous solutions) the yellow
ration only alfa-lactose monohydrate is used. This is usually
discolouration is more manifest. An intermediate in the
called just lactose or lactose monohydrate. It is available in
reaction is a furan derivate (5-hydroxymethylfurfural) that
different qualities (sieved, milled, spray dried) and in a
is toxic (see Sect. 13.6.4). In glucose containing intravenous
variety of particle sizes. For most small-scale pharmacy
solutions the Pharmacopoeia specifies a limit test for this
impurity.
HO
23.4.4.1 Syrups
O Syrups are mentioned in Ph. Eur. as a dosage form, but in
HO
OH this book they are considered a raw material.
, H2O Syrups are a very commonly used form of sugars. They
HO O O OH contain approximately 45–65 % of sugar, water and a pre-
OH OH servative. Sometimes a flavouring is added. The preservative
is most often methyl parahydroxybenzoate 0.1–0.15 %.
Syrups can be very useful for improving the taste of oral
OH liquid preparations and sometimes they can be used to
stabilise a solubilisate of oil and polysorbate, e.g. in a vita-
Fig. 23.5 The formula of alfa-lactose monohydrate min A micellar solution (Table 23.12).
Table 23.12 Vitamin A Oral Aqueous Solutiona 50,000 IU/mL [31] “Inhalation of colloidal silicon dioxide dust may cause irri-
Vitamin A concentrate (oily form), synthetic 5g tation to the respiratory tract but it is not associated with
1,000,000 IU/g fibrosis of the lungs (silicosis), which can occur upon expo-
Citric acid monohydrate 0.24 g sure to crystalline silica” [5]. The main issue appears to be
Polysorbate 80 12.5 g whether the silica is crystalline or not. Colloidal anhydrous
Potassium sorbate 0.3 g silica Ph. Eur. is however amorphous. The irritation of the
Star anise oil 0.22 g throat, eyes etc. is an issue though and because of lesser dust
Syrup BP 12.5 g generation at weighing and processing the ‘pressed’ anhy-
drous form (Aerosil 200 V®) is preferred.
Total 104 g (¼ 100 mL) Magnesium stearate can adversely affect the disintegra-
a
This solution is actually a solubilisate tion time and dissolution rate and should therefore be used
only if these properties can be checked.
Lubricants can counteract the formation of agglomerates
This stabilising effect is achieved by the following prep- of small particles and disperse pre-existing agglomerates.
aration method: Colloidal anhydrous silica is added for this purpose in the
• Dissolve while heating potassium sorbate in 50 mL preparation of suppositories (see Sect. 11.4.6) and in the
purified water and citric acid in 15 mL purified water. preparation of oral suspensions (see Sect. 5.4.6).
• Cover the inside of the mortar or bottle with polysorbate
80.
• Mix vitamin A and anise oil with the polysorbate 80. 23.6 Surfactants
• Solubilise the vitamin A mixture by mixing with sugar
syrup. Surfactants is the name given to those substances whose
• Mix this mixture with potassium sorbate solution in one surface activity is the main reason for their use. Surfactants
go and with the citric acid solution in parts. (see also Sect. 18.3) are used to stabilise emulsions and
• Add purified water and mix again. suspensions, as wetting agents (see Sect. 5.4.6) as micelle
When a syrup is used in a formulation, it must be taken into makers for the preparation of solubilisatesons (see Sect.
account that syrups already contain a quantity of methyl 5.5.6 and Table 23.12) and to influence the flocculation-
parahydroxybenzoate. and deflocculation behaviour of dispersed systems (see
Syrups can be prepared by dissolving sucrose and methyl Sect. 18.4.2.2). Orally they can only be used in small
parahydroxybenzoate in purified water with heating (but quantities or low concentrations because of their irritating
PRODUCTION
mind inversion) but they are usually bought as such, as an properties and bad taste.
intermediate. Many other excipients and active substances that are
mainly used for another purpose, also exhibit surface activ-
ity. Examples can be found in the group of viscosity enhanc-
ing substances (see Sect. 23.7). In particular the low viscous
23.5 Lubricants methylcellulose is used for this purpose. Examples of active
substances that have surface activity are the tricyclic
Colloidal anhydrous silica (colloidal silicon oxide) and mag- antihistaminics and antidepressants, and the local
nesium stearate are used as lubricants in the preparation of anaesthetics (e.g. lidocaine).
capsules, tablets and powders (see Sect. 4.4.3). Addition of Another term for surfactants is emulsifiers. This designa-
lubricants in the preparation of capsules, powders and tablets tion is functional but has a limited distinctive character.
usually leads to a smoother fill of the capsules, or the Viscosity enhancing substances, which also stabilise
moulds. An additional advantage is the reduction of the emulsions and suspensions (see Sect. 18.4) are also
losses as a result of the elimination of the static charge of associated with this term. The preferred name in this book
the powder mixture. is the physical qualities characterising ‘surfactants’.
In the preparation of powders and capsules colloidal The next sections deal with four types of surfactants:
anhydrous silica (Aerosil®) is used as lubricant. There is a anionic-active, cationic-active, amphoteric and non-ionic.
water containing and an anhydrous type Aerosil. There is More information on surfactants is to be found in Sect.
discussion about the possibility that Aerosil causes silicosis. 18.3, in Martindale and other literature [3, 4, 32]. Table 23.13
The occupational disease silicosis is as a result of long-term gives an overview of the main surfactants that are used in
inhalation of siliceous dust. But in [5] it is concluded: small-scale preparation.
Table 23.13 Main surfactants

Type of surfactant Subtype Substances used in pharmacy preparations
Anionic-active substances Alkali and amine soaps Sodium stearate
Ammonium oleate
Triethanole amine stearate
Trometamol stearate
Earth alkali soaps (w/o) Calcium oleate
Magnesium stearate
Alkyl sulfates (o/w) Sodium lauryl sulfate
Sodium cetostearyl sulfate
Alkyl sulfonates (w/o) Sodium dioctyl sulfosuccinate
Cationic-active substances Quaternairy ammonium salts Benzalkonium chloride
Cetrimonium bromide
Amphoteric substances Betain compounds –
Phospholipids Lecithin
Non-ionic substances Higher alcohols Cetylalcohol
Stearylalcohol
Cetostearylalcohol
Cholesterol
Esters of fatty acids (w/o) Glycerol monostearate (monostearin)
Glycerol mono oleate (monolein)
Sorbitan mono oleate (Span 80)
Triglycerol diisostearate
Macrogol fatty alcohol ethers (o/w) Cetomacrogol 1,000
Macrogole sorbitan ethers (o/w) Polysorbate 20 (Tween 20)
Polysorbate 80 (Tween 80)
Aliphatic aromatic macrogol ethers (o/w) Nonoxynol-9
Octoxynol-9
Poloxamers –
23.6.1 Anionic-active Substances Fig. 23.6 The formula of OH

trometamol
NH2
The main anionic-active components are the alkali, earth
HO OH
alkali, ammonium and amine salts of fatty acids, and the
sulfated and sulfonated components. The first four types are
also called soaps. Soaps are created by alkaline hydrolysis of
natural fats and oils (saponification). This results in produc- not associated with nitrosamine creation. Secondary amines
ing palmitic, stearic and oleic acid as fatty acids and sodium can create nitrosamines, as can tertiary amines as they
(hard soap) and potassium (soft soap) as alkali-ions. always contain a small amount of secondary amines. For
The univalent alkali-, ammonium- and amine soaps dis- most preparations in which amine soaps are used they can be
sociate completely in water and are therefore predominantly substituted. Experts don’t consider substitution relevant for
hydrophilic. As a result they create oil-in-water (o/w-, high administration routes other than the oral one [35].
HLB-) systems (HLB ¼ hydrophilic lipophilic-balance, see Anionic-active substances are incompatible with strong
Sect. 18.3.1). The bivalent earth alkali- or polyvalent metal acids (pH 4) because the hydrophilicity of the acid group
soaps dissociate little in water and are therefore predomi- will decrease due to lower dissociation. There is also the risk
nantly lipophilic. The earth alkali soaps form water-in-oil of insoluble ion pairs when anionic-active substances are
(w/o-, low HLB-) systems, see Sect. 18.4.3. and [4]. combined with cationic-active ones such as neomycin
Trometamol and tri-ethanolamine stearate are amine sulfate.
soaps, formed from stearic acid and separately added
tri-ethanolamine or trometamol (see Fig. 23.6). The use of 23.6.1.1 Examples with Anionic-active Substances
amines is often avoided because of the association with In the Zinc oxide calcium hydroxide weak paste FNA (see
nitrosamine creation [33, 34]. Primary amines are however Table 12.39) a calcium soap and a zinc soap is created from
Fig. 23.7 The formula of CH3

docusate sodium O SO3Na
* O CH3
H3 C O * *
O
H3C
lime water and zinc oxide and the free fatty acids in the oil 23.6.3 Amphoteric Substances
used. By these soaps the (lime) water is emulsified in the oil
to create a cream. Amphoteric surfactants possess both an anionic and a cat-
Sodium cetostearylsulfate and sodium lauryl sulfate ionic function. In small-scale preparation they are little used
forms, both in a concentration of 10 % with 90 % cetostearyl but their role may increase in the future. Examples are long
alcohol the so-called self-emulsifying waxes Alcohol chain betains and phospholipids (e.g. lecithin).
cetylicus et stearylicus emulsificans A and Alcohol cetylicus Phospholipids play an important role as emulsifiers and
et stearylicus emulsificans B (see Sect. 12.5.4). Both are micelle formers for parenteral emulsions (see Sect. 13.5.7)
emulsifying agents in which the excess of cetostearylalcohol and micellar solutions and also in liposome technology.
is also the lipophilic phase. There are many other
representatives of this group with industrial applications.
The sulfonates possess, as the reactive part, a sulfone
23.6.4 Non-ionic Substances
group. Also this group of substances has many examples
with industrial applications.
The group of the non-ionic compounds includes the aliphatic
Docusate sodium (Sodium dioctyl sulfosuccinate, see
alcohols, the polycyclic alcohols, mono-and diglycerides, the
Fig. 23.7) is used as laxative in a 0.1 % concentration.
sorbitanesters, the macrogol compounds and the poloxamers.
Cholesterol and lanolin alcohols are examples of alcohols
with cyclic carbon structures (w/o). Cholesterol is used as
23.6.2 Cationic-active Substances such. It is suitable in combination with the phospholipids as
an emulsifier for the preparation of parenteral emulsions and
In small-scale preparation the quaternary ammonium in liposome technology. The lanolin alcohols are found in
PRODUCTION
compounds containing an alkyl chain are the most impor- wool fat (Adeps lanae) and Eucerinum® anhydricum. They
tant. Cetrimide (Cetrimonium bromide, see Fig. 23.8) is used are present as w/o-emulsifier in cutaneous preparations.
in a concentration of 0.5–2 % as emulsifier in creams. Qua- The monoglycerides of fatty acids (monostearin, monolein)
ternary ammonium compounds of this type are used from a and diglycerides are examples of partially substituted glycerol
concentration of 0.004 %. They also exhibit antiseptic and esters (w/o-type). These substances are found in the synthetic
preservative properties. Notably benzalkonium chloride, as suppository bases Hard fat (see Sect. 11.4.4). The hydrophilic
well as being a surfactant of the oil-in-water emulsifying part of the molecule consists of the non derivatised
type, is also important as a preservative in for example eye OH-groups. The presence of mono-and diglycerides explains
and nose drops. Cationic-active compounds are often incom- the emulsifying function of some forms of Hard fat. The
patible with anionic substances such as sulfobituminose polyglycerol derivate triglycerol diisostearate is used for
ammonium due to the risk of the formation of insoluble example in a concentration of approximately 5 % as w/o
ion pairs. Since it is often difficult to estimate this risk, it is emulgator in hydrophobic creams (see Table 12.26) [36].
better to avoid these combinations. The fatty acid sorbitan esters, are often used cyclic polyol
esters (w/o). The best known example is sorbitan mono-
oleate (Span 80) (Fig. 23.9).
Fig. 23.8 The formula of The main characteristic of non-ionic o/w emulsifiers is a
H3C CH3
cetrimide + macrogol group (¼ polyethylene glycol, PEG-group) in the
H3C N Br- molecule. This group makes the molecule predominantly
n CH3
hydrophilic (high HLB).
O CH3
CH2O C CH2(CH2)5CH2CH=CHCH2(CH2)6CH3 O O
HO O H
HO C O X X
Y
H
Fig. 23.12 The formula of a poloxamer
HO OH
Fig. 23.9 The formula of sorbitan mono-oleate

compatibility with phenols, tannins and heavy metals. Gener-
ally it is better to avoid such combinations.
Poloxamers are copolymers and consist of a core of
CH3-(CH2)x-(OCH2-CH2)y-OH
relatively hydrophobic polypropylene oxide surrounded by
Fig. 23.10 The formula of cetomacrogol 1000, x ¼ 15 or more hydrophilic polyethylene oxides; their molecular
17, y ¼ 20–24 weight is about 12,500 (see Fig. 23.12).
The substances have unique properties that show up espe-
Cetomacrogol 1000 is a cetyl-macrogolether, see cially well in pharmacy preparations and dosage forms with
Fig. 23.10. sustained release characteristics. For application possibilities
The name includes the average molecular mass of the see Sect. 18.4.1. The waxy, white and free flowing granules
chain length: 1,000 (corresponding with approximately are almost odourless and tasteless and are soluble/miscible in
20 glycol units). Cetomacrogol emulsifying wax is an emul- aqueous, organic polar and nonpolar solvents.
sifier (see Sect. 18.4.3) and consists for 80 % of cetostearyl
alcohol and 20 % from cetomacrogol 1000. The substance is
incompatible with phenolic compounds (phenol, resorcinol)
23.7 Viscosity Enhancing Substances
but low concentrations may be tolerated (see Sect. 12.5.7).
Polysorbates (Tweens) are esters of fatty acid macrogol-
23.7.1 Overview
sorbitanethers with as main representative Polysorbate
80 (see Fig. 23.11).
Gel formers (viscosity enhancers, thickeners) are primarily
These substances have a high HLB value, i.e. they are
used for their viscosity enhancing effect in liquid
predominantly hydrophilic by the prominent role of the
preparations. In low concentrations they stabilise
macrogol-sorbitan-group. So they cause the formation of
suspensions and emulsions and in high concentrations they
o/w-systems and are in use as emulsifiers, wetting agents
are used for gel formation.
and also as solubilisators.
The aliphatic-aromatic ethers are represented with the
macrogol-octyl-and nonylphenyl ethers (octoxynols: Triton- In the nomenclature for pharmaceutical preparations
X® and nonoxynols). Nonoxynol-9 has a macrogol chain of such as standardised in the Ph. Eur. the term of gel is
9 units. These substances are used as powerful detergents in, reserved for higher concentrations of hydrogel
for example, cleaning fluids for contact lenses and as germi- formers, with a semisolid consistency. But in practice
cidal substances in spermicide gels and pessaries (see Sect. the concept of gel is also used if hydrogel formers are
11.14.3). These kinds of compounds also have a powerful used in lower concentrations as thickener in
antimicrobial and antiviral effect. Surfactants with a macrogol suspensions and emulsions for oral use.
group (PEG-chain) in the molecule have a limited
HO(CH2 CH 2 O)W (OCH2CH 2)XOH
O CH(OCH2CH 2)YOH O
CH 2O (CH2CH 2O)Z-1 CH 2CH 2O C CH 2(CH2)5CH 2CH=CHCH 2(CH2 )6 CH 3
W+X+Y+Z=20
Fig. 23.11 The formula of polysorbate 80, W + X + Y + Z ¼ 20

Table 23.14 Viscosity enhancing substances 23.7.2 Gel Preparation Methods

Origin Non-ionic Anionic Amphoteric
Natural Starch species Acacia Gelatin Several different gel preparation methods exist, based on spe-
Agar cific qualities of viscosity enhancing substances. Six of them
Carrageenan that are most used are described in this section: dispersing by
Pectin hand in hot water, dispersing by hand in a viscous fluid, pH
Sodium change, dispersing mechanically, use of classic hydrogel
alginate formers and the ‘corpus emulsi’ (specific emulsifying) method.
Tragacanth
Semi- Hypromellose Sodium carmellose
synthetic 23.7.2.1 Disperse by Hand in Hot Water
Hydroxylethylcellulose
Methylcellulose
The physico-chemical method of temperature change uses
Xanthan gum the fact that many hydrogel formers are hydrophobic in hot
Synthetic Polyvidone Carbomer salts water and therefore form no gel but still get wetted. The gel
Polyvinyl alcohol former is sprinkled on hot water and stirred for only a short
Mineral Bentonite time. After wetting and spontaneously cooling down the gel
Colloidal aluminium is formed and homogenised. After that the gel often has to
magnesium silicate rest in the fridge for further gelling. The method is used for
Colloidal anhydrous silica substances that form no or bad hydrogels in hot water, such
as the cellulose derivatives and Al-Mg-silicate. The prepara-
tion of a lidocaine hydrochloride gel 2 % (see Table 23.15)
illustrates this method.
Some gel formers, for instance some of the cellulose Preparation method:
derivatives, also exhibit a degree of surfactant activity. • Dissolve the sodium monohydrogen phosphate
Others, particularly mineral viscosity enhancing substances, dodecahydrate and the lidocaine hydrochloride in a part
can also show dispersing (see Sect. 18.4.2) characteristics of the purified water.
through the release of ions (aluminium-magnesium silicate) • Mix in the glycerol 85 %.
that improve dispersion by influencing the zeta-potential. • Dissolve, whilst heating, the methyl parahydroxy-
This group consists of linear macromolecules of natural, benzoate and the propyl parahydroxybenzoate in the
semi-synthetic or synthetic nature and of inorganic colloids. main part of the purified water.
A further subdivision is that of non-ionic, anionic and • Disperse the hypromellose in the hot solution.
PRODUCTION
amphoteric substances (Table 23.14). • Mix the hypromellose dispersion with the lidocaine-
For pharmacy preparations the (half) synthetic gel glycerol solution.
forming agents are generally preferred. Caution should be • Keep the dispersion homogeneous during cooling down.
exercised with natural gel forming agents due to the varying • Supplement to weight with purified water and mix.
quality and the presence of micro-organisms. • Dissolve the hypromellose by placing the gel at 2–8 C
The ionic viscosity enhancing substances are usually for 12 h and mixing at regular intervals.
much more sensitive to pH-changes than the non-ionic.
However, the addition of electrolytes, and also of acids and 23.7.2.2 Disperse by Hand in Viscous Fluid
bases, affect thickeners as a result of increasing ionic The physico-chemical method of changing the solvent uses
strength or influencing the zeta potential (see Sect. 18.4.2). the property that many hydrogel formers do not form a
Viscosity enhancing substances not only increase the hydrogel in a non or slightly aqueous environment such as
viscosity but also introduce rheological qualities such as ethanol, a di-, tri, or poly-ol or a syrup. Triturating the
(pseudo) plastic, dilatant and thixotropic behaviour (see
Sect. 18.2.1). Table 23.15 Lidocaine Hydrochloride Gel 2 % [37]
Further details on substances are given in Sect. 23.7.3.
Lidocaine hydrochloride 2g
A problem with the processing of hydrogels or viscous
Disodium phosphate docecahydrate 0.1 g
systems is that many substances get slower wetted than they Glycerol (85 %) 20 g
form gels. This can easily lead to lump formation which has Hypromellose (4000 mPa.s) 3g
to be taken into account in the method of preparation. Methyl parahydroxybenzoate 0.0875 g
Physico-chemical means or mechanical methods may be Propyl parahydroxybenzoate 0.0125 g
necessary to slow down gel formation and thus to avoid Water, purified 74.8 g
formation of lumps. The main gel preparation methods in Total 100 g
small-scale preparation are dealt with in Sect. 23.7.2.
Table 23.16 Tetracycline Mouthwash 5 % [38] Table 23.17 Carbomer Gel [39]
Tetracycline hydrochloride 5g Carbomer 974P 1g
Methyl parahydroxybenzoate 0.1 g Disodium edetate 0.1 g
Sodium citrate 6.5 g Propylene glycol 10 g
Sorbitol, liquid (crystallising) 65.5 g Trometamol 1g
Tragacanth 0.5 g Water, purified 87.9 g
Water, purified 40.6 g Total 100 g
Total 118.2 g (¼ 100 mL)
hydrogel former with the non-aqueous, though water- Table 23.18 Sulfasalazine Oral Solution 100 mg/mL [40]
dilutable, fluid moistens it. After that the resultant mixture Sulfasalazine 10 g
can be diluted with water, which starts gel formation. The Aluminium magnesium silicate 0.54 g
method is applicable to substances that do not form a gel Carmellose sodium M 0.54 g
with the mentioned fluids, e.g. cellulose derivatives. The Citric acid monohydrate 0.63 g
method has the disadvantage that it takes quite some time Methyl parahydroxybenzoate 0.07 g
to reach the final viscosity (Al-Mg-silicate). The preparation Raspberry essence (local standard) 0.3 g
of a tetracycline mouthwash 5 % illustrates this method, see Sodium citrate 4.7 g
Table 23.16. Syrup BP 30 g
Preparation method: Water, purified 66.2 g
• Dissolve the methyl parahydroxybenzoate in the purified Total 113 g (¼ 100 mL)
water and cool down.
• Dissolve the sodium citrate in the methyl parahydroxy-
benzoate solution.
23.7.2.4 Dispersing Mechanically
• Mix the tetracycline hydrochloride with the tragacanth.
The mechanical method, such as with a rotor-stator mixer, is
• Disperse in an equal volume of sorbitol solution.
performed by dispersing the hydrogel forming agent in the
• Mix with the remaining part of the sorbitol solution.
vortex of the solution (water). The method is generally appli-
• Mix the sodium citrate solution in portions with the
cable especially for diluted hydrogels. However this method is,
tetracycline suspension.
as a result of foaming, less suitable for hydrogel formers that
• Add purified water to volume if necessary.
also have surfactant properties such as many cellulose
derivatives, and there is a risk of air being incorporated.
23.7.2.3 pH Change Some (long chain) hydrogel formers are sensitive to mechani-
The chemical method of pH change: some hydrogel formers cal shortening of the chains. In that case, the resulting viscosity
are wettable at a pH where the hydrogel is not formed. After might be lower than with other methods. In small-scale prepa-
changing the pH the hydrogel forms. Polyacrylic acids ration practice this phenomenon has not proved to be relevant.
(carbomers) for example have to be wetted with water and This method is exemplified by the preparation of a
then neutralised with a base. If in ethanol they have to be sulfasalazine oral solution 100 mg/mL, see Table 23.18.
neutralised with an amine. The preparation of a carbomer gel Preparation method:
is given as an example, see Table 23.17. • Use a rotor-stator mixer.
Preparation method: • Dissolve, whilst heating, the methyl parahydroxy-
• Dissolve the disodium edetate in the largest portion of the benzoate in 50 mL purified water.
purified water. • Disperse the colloidal aluminium magnesium silicate in
• Mix the disodium edetate solution with the propylene the hot solution.
glycol. • Disperse the carmellose sodium in this suspension.
• Disperse (preferably with a mixer) the carbomer in the • Mix with the sugar syrup.
solution. • Dissolve the citric acid monohydrate and the sodium
• Dissolve the trometamol in 10 times the amount of citrate in about 15 mL purified water, heat if necessary.
purified water. • Mix this solution and the suspension.
• Mix, with a spoon, the trometamol solution with the • Disperse the sulfasalazine.
carbomer suspension. • Mix the raspberry essence with the suspension.
• Mix in the remaining purified water. • Add purified water to volume and homogenise.
23.7.2.5 Classic Hydrogel Formers suspensions they are often combined with aluminium mag-
Some classic hydrogel formers (starch and gelatine) can be nesium silicate. In cutaneous hydrogels the concentration is
dissolved in hot water and form the hydrogel after usually 2–6 %. However, they cause a tightening sensation
cooling down. by xerogel forming.
23.7.2.6 Specific Emulsifying Method

Xerogel: from some gels the hydrogel former remains
A specific method was used with some classic hydrogel
if the solvent evaporates, as a membrane. In such cases
formers such as tragacanth and Acacia. By using a specific
it is described as a xerogel. For example, gelatin is
and exactly defined ratio of hydrogel agent to water, a thick
available as a powder as well as in sheets, thus: a
gel was created. By further diluting with water the desired
xerogel. The cellulose derivatives also form a xerogel
gel was obtained. This method is largely abandoned.
on drying. On the skin, preparations based on a cellu-
lose derivative therefore cause a sensation of tighten-
ing. For cutaneous preparations therefore the mineral
23.7.3 Details of Viscosity Enhancers
hydrogel colloidal aluminium magnesium silicate is
usually preferred, which does not form a xerogel. For
Table 23.14 gives an overview of the main groups of viscosity
the same reason the carbomer gels are often used on
enhancers. In this section the following groups are discussed
the skin.
in detail: natural gel formers, cellulose derivatives, povidone,
carbomers, mineral viscosity enhancers.
To enhance the viscosity of eye and nose drops
23.7.3.1 Natural Gel Formers hypromellose 4000 mPa.s at a concentration of 0.5 % is used.
Acacia (Gum Arabic) consists of the K-Ca-Mg-polyarabinic Cellulose derivatives degrade in aqueous solutions by
acid salts. It may contain peroxidases which can be opening of the glycosidic bonds. Increasing the temperature
inactivated by heating. Tragacanth consists of Na-Ca-salts and decreasing the pH speed up this process. In acidic
of galacturonic acid. The final viscosity is reached only after solutions (pH < 3) the viscosity will decline during storage.
a few days’ rest. Carrageenan, a hydrocolloid obtained by Hydroxyethylcellulose is known to get wetted faster than to
purification of red seaweed, is an anionic thickening agent. It form a gel, thus lumps are slowly generated which makes it
needs calcium ions to get an established gel [5]. It is used in easier to handle, cold and warm, than the other cellulose
Ora-Plus ®, a commercial available base for oral liquids (see derivatives.
Sect. 5.4.6) Sodium alginate consists of sodium salts of Further accelerated wetting and reduction of lump gener-
PRODUCTION
polymannuglucuronic acid. Gelatin is a polymerisate of ation can be accomplished by dry mixing in advance with
amino acids. The gel formation occurs after heating, opti- other substances, in particular poorly soluble substances, by
mally at a pH just outside the iso-electric zone. using a higher temperature and by using a neutral or higher
pH. Table 23.19 gives an overview of the main properties of
23.7.3.2 Cellulose Derivatives the cellulose derivatives.
A chemical definition of cellulose can be found in Sect. 23.4.1.
Carmellose sodium is the sodium salt of the polycarboxyl-
methylether of cellulose which is, as an anionic compound, 23.7.3.3 Xanthan Gum
usually incompatible with cationic compounds (lidocain, Xanthan gum (derived from corn sugar) is a polysaccharide
benzalkonium, chlorhexidine). There is a risk of the formation consisting primarily of the hexose units d-glucose and
of ion pairs, resulting in precipitation or inactivation. d-mannose and glucuronic acid. It is usually a sodium,
The Ph.Eur. uses different measurement methods for their potassium or calcium salt and soluble in cold water, in
viscosity, sometimes even at different temperatures. Usually both acid as alkaline environment. Xanthan gum is compati-
a concentration of 2 % is used, although for one substance ble with high salt concentrations, but not with polyvalent
this is a concentration level where deviations are easily metal ions such as magnesium and aluminium ions in alka-
noticed whereas for another substance viscosity hardly line environment by the negative charge. Solutions retain
depends on concentration at this level [41]. their viscosity in a wide pH-range of 3–11, are little sensitive
Cellulose derivatives, especially methylcellulose and to temperature differences and are miscible with up to an
hypromellose, usually cause a strong foam at preparation equal weight of ethanol. Xanthan gum is processed in
because they also possess surfactant activity. For the formu- suspensions in a concentration of 1–3 % [5].
lation of settling suspensions they are often unsuitable as
they create a sediment that is difficult to disperse. They are 23.7.3.4 Povidone
used in suspensions and emulsions for oral use (see Sects. Povidone (polyvinyl pyrrolidone, see Fig. 23.13) only
5.4.6 and 5.4.7) at concentrations of 0.25–2.5 %. In creates an increased viscosity at concentrations higher than
Table 23.19 Cellulose derivatives’ properties

Tolerance
towards
Incompatible with Swelling ethanol Details
Carmellose sodium and Polyvalent positive Not in strong acid environment; precipitates Bad Hardly decreasing the surface tension
mixed esters with ions: precipitation; at pH < 2
carboxy methyl groups also with cationic
substances
Methylcellulose Salts: flaking; In cold water methylcellulose swells and Well Strong surfactant (foam forming)
hydroxypropylcellulose hydroxybenzoates; disperse slowly to form a viscous dispersion;
strongly oxidising hydroxypropylcellulose forms a clear liquid
substances in cold water [5]
Hydroxyethylcellulose Sulfates: flaking Little tendency to generate lumps Moderate Hardly decreasing the surface tension;
is hydrophilic and by that no reversible
coagulation by heat. It is specifically
compatible with aluminium chloride
and surfactants
Hypromellose (mixed Salts: flaking; High concentrations of silver ions (.30 mg Moderate Quite strong surfactant; generates a
ether) oxidising substances per litre) enhance the viscosity [5] clear solution or gel
Fig. 23.13 The formula of H When the acid groups are neutralised the viscosity
povidone increases rapidly. The viscosity enhancement effect by the
H
hydroxyl group donors occurs slowly and is only completed
N O after a few hours.
Next to enhancing the viscosity a small amount of
n carbomer added to the water phase can stabilise creams;
the emulsion becomes much more stable but the cream is
still spreadable [42].
approximately 10 %. At lower concentrations it may be used The type of viscosity of a (partially) neutralised carbomer
though because of the favourable impact on resuspendability hydrogel is plastic: a (large) yield value and a decreasing
of suspensions. viscosity with increasing shear stress; a carbomer gel is not
thixotropic (see Sect. 18.2). Carbomer hydrogel is not com-
23.7.3.5 Carbomers patible with a number of active substances because of the pH
Carbomers are acrylic acid polymers with cross-linking by (about 6.5) that is needed for the gel formation. For instance
allylethers of sucrose or penta-erythritol. They have a pKa of salicylic acid is ionised at this pH and hence not effective as
6 0,5. In dry form the molecule has a compact folded a keratolytic. Weak base salts (e.g. alkaloid, chlorhexidine,
conformation. By interaction with the environment in aluminium and zinc salts) will precipitate at this pH.
which carbomers are dispersed a conformational change
can occur. By wetting with water the molecules are slightly Carbomer is available in several types. Carbomer
stretched; the dispersion in water is thus already a little 974 (Carbopol 974®) is produced using ethyl acetate.
viscous. In water and strong hydrophilic environments the In the production of Carbopol 980® ethyl acetate and
interaction is strengthened as is the conformational change, cyclohexane are used. These types are preferred over
when the acid groups of polyacrylic acid are ionised by a the types of Carbopol 940 and 934P®. Carbopol 940 is
basic substance. If the molecule is stretched even further, it produced using benzene; it has been demonstrated that
will lead to a higher viscosity. The resulting pH of a 0.2 % benzene may be present in the raw material. In
carbomer gel is usually about 6.5. The addition of sodium Carbopol 934P, allowed for oral use, traces of ben-
edetate ensures that bivalent ions such as calcium and mag- zene, about 60 ppm may be found as well.
nesium are bound. Cross linking these ions hamper the Suitable neutralising, alkaline reacting substances
conformation change that is needed for gel formation. Also for gel formation are sodium hydroxide, ammonia and
the formation of hydrogen bridges between the hydroxyl and the amines trometamol or possibly tetrahydroxypropy-
carboxyl groups of the carbomer leads to conformational lethylenediamine (Neutrol TE®). Triethanolamine
change and thus increased viscosity. Examples of such (a tertiary amine) and secondary amines can generate
hydroxyl group donors are propylene glycol, macrogol and
non-ionic surfactants. (continued)
Table 23.20 Zinc Oxide Cutaneous Paste [43]

nitrosamines and for that reason should not be used. Zinc oxide (90) 60 g
Sodium hydroxide creates gels in which no more than Arachis oil, refined 39.3 g
30–35 % ethanol can be processed. Carbomer gel that Oleic acid 0.7 g
is neutralised with ammonia can include 45 % ethanol Total 100 g
without the gel structure being lost. A gel with
trometamol is also resistant to approximately 45 %
ethanol and a gel with Neutrol TE can include 75 % Adding a small amount of cations enhances viscosity.
ethanol. However, a large amount of cations causes flaking and
sedimentation of aluminium magnesium silicate, this is floc-
culation of the hydrogel by cations that influence the zeta-
potential. The viscosity strongly decreases. This tendency is
23.7.3.6 Mineral Viscosity Enhancers even stronger as the added cations have a higher valence.
Bentonite and colloidal aluminium magnesium silicate are Colloidal anhydrous silica is used to enhance the viscos-
of mineral origin and do not exhibit all colloidal ity of oily and fatty systems such as suppositories (see Sect.
characteristics. They exhibit rheological properties such as 11.4.6). The result is an oleogel.
becoming more fluid under stress but they are not always Another oleogel is created when zinc oxide is mixed with
transparent. The colloidal systems of silicates have thus oil. The result is basically a cutaneous oleogel of zinc oleate
characteristics transitional to the coarser disperse systems. in arachis oil in which the excess zinc oxide is suspended
They hardly dissociate and are generally not split into ions. (Zinc oxide Cutaneous paste, see Table 23.20), see also Sect.
Therefore they are categorised (Table 23.14) under 12.7.13 for its use.
non-ionic viscosity enhancers, despite the fact that some Zinc stearate and other zinc salts find application as
dissociation occurs. thickening agents in oily injections.
Colloidal aluminium magnesium silicate (Veegum ®)
and bentonite are both aluminum silicates, but in Veegum
According to Ph. Eur. definitions (Semisolid
a much higher percentage aluminium is substituted by mag-
preparations for cutaneous application) gels consist
nesium. Because of the constant quality aluminium magne-
of liquids gelled by means of suitable gelling agents.
sium silicate is preferred to bentonite.
Lipophilic gels (oleogels) are preparations whose
The solid aluminium magnesium silicate has the shape of
bases usually consist of liquid paraffin with polyethyl-
flakes; these flakes are constructed of a number of layers. The
PRODUCTION
ene or fatty oils gelled with colloidal silica or alumin-
flat sides have a negative charge while the corners are weak
ium or zinc soaps.
positive. The resulting load of the layers is negative and is
Hydrophilic gels (hydrogels) are preparations
offset by Na+-ions and smaller quantities of other cations.
whose bases usually consist of water, glycerol or pro-
When dispersed in water the flakes become hydrated, the
pylene glycol gelled with suitable gelling agents such
positively charged corners focus on the negatively charged
as poloxamers, starch, cellulose derivatives,
flat sides of other particles and a hydrogel is formed.
carbomers and magnesium-aluminium silicates.
Because of this structure the liquid is viscous and thixotro-
Collodion can be considered as a oleogel of cellu-
pic. Aluminium magnesium silicate therefore is often used
lose nitrate in a mixture of ether and alcohol to which
to stabilise emulsions and suspensions.
castor oil is added. Collodion dries in on the skin to a
The speed of hydration of the aluminium magnesium
kind of lipo-xerogel that sticks like a capping mem-
silicate depends on the amount of energy (mechanical
brane. Collodion is therefore used to apply salicylic
energy and heat) that is supplied during dispersing. A better
acid on warts.
hydration results in a higher viscosity. After dispersing the
hydration increases in the course of time until this is com-
plete. If well dispersed, the maximal hydration is largely
achieved after about a day at room temperature.
Adding substances that mix with water or dissolve in 23.8 Preservatives
water before aluminium magnesium silicate is dispersed,
inhibits hydration, sometimes so strongly that no more Preservatives are substances that, usually in low
hydration occurs. When substances such as acids, alkalis, concentrations, are added to preparations because of their
electrolytes and solvents are added after hydration, the vis- antimicrobial action. Adding preservatives is one of the
cosity reaches its final value faster. methods to keep the microbiological contamination of
preparations within limits, especially during storage and use. Because of the possible occurrence of hypersensitivity
Sterile preparations in multidose containers need reactions the name of the preservative should be listed on
preservatives to control the microbiological contamination the label and on the instruction for the patient, see Sect. 37.3.
occurring during use. Preservatives are also sometimes used
to reduce microbiological count at a sterilisation or thermal 23.8.1.2 Toxicity
process (see Sect. 30.7). Toxicity of preservatives is especially important in oral
Preservatives must never serve to compensate for inade- preparations if a large amount is taken at one time (oral
quate preparation procedures, such as poor hygiene or the rehydration fluids, tube feeding, osmotic laxatives). Propyl-
use of raw materials of insufficient microbiological quality. ene glycol is toxic with oral use in children and in patients
Moreover, adding preservatives to contaminated raw with poor renal function [22].
materials creates the risk of the development of resistance, For chronic oral use of preparations which are used in
especially if the concentration of the preservative is low. small quantities the dose must be checked on the basis of the
Resistance against preservatives is found especially with Acceptable Daily Intake (ADI) as for foodstuffs. Problems,
gram-negative bacteria. It has also been reported that however, are unlikely to be met in these cases because of the
customised strains of Brevundimonas (Pseudomonas) species relatively small quantities that are used. The ADI-value
and Enterobacter species used methyl parahydroxybenzoate indicates the amount of substance added to foods in mg/kg
as a food source and convert the parahydroxybenzoate to body weight that one may take daily over a lifetime.
phenol [44, 45]. Brevundimonas species are also capable of The chronic toxicity of preservatives that are
using quaternary ammonium compounds as a carbon source, administered in the eye is a constant source of concern and
which not only has led to the failure of the preservation of is often reported; benzalkonium chloride and thiomersal
preparations but also to dangerous hospital infections when would eventually cause epithelial damage and
these substances were used as disinfectants. phenylmercuric compounds cause mercury deposition in
the lens. However, so far these preservatives have not been
banned for that reason. Recent investigations even show that
benzalkonium is not toxic for the cornea [47].
23.8.1 Hypersensitivity and Toxicity
Preservatives also have disadvantages: they can cause hyper-

23.8.2 Activity, Concentration and Applicability
sensitivity reactions, irritation and toxicity. Hypersensitivity
to preservatives is a particular issue when they are used in
Table 23.21 displays preservatives in pharmacy preparations
cutaneous preparations and eye drops. Toxicity of
with some characteristics, many of them having been taken
preservatives is especially important in oral preparations.
from [48].
Good preservatives have, by definition, a wide activity
23.8.1.1 Hypersensitivity spectrum. If one preservative covers the spectrum insuffi-
Hypersensitivity in cutaneous preparations is often caused ciently, combination with another, synergistic, preservative
by methyl parahydroxybenzoate. Sorbic acid or propylene or with a potentiating substance (for instance benzalkonium
glycol are to be preferred. Chlorhexidine digluconate, chloride with sodium edetate) improves the activity.
though giving few hypersensitivity, is not used very often Micro-organisms replicate only in the presence of water.
because it has quite a few incompatibilities [46]. Propylene The activity of preservatives depends therefore on the con-
glycol is proven safe up to a concentration of 15 % centration of the free and active form in the aqueous phase of
(150 mg/g) but occasionally causes some irritation. There- the preparation. ‘Free’ refers to the binding that some
fore, do not use it in cutaneous preparations that are applied preservatives can have with active substances, excipients
to non-intact skin. or packaging materials. Examples of the binding of
Hypersensitivity by eye drops is caused sometimes by preservatives are: the adsorption of phenylmercuric
thiomersal and benzalkonium chloride, although the adverse compounds to rubber stoppers, the adsorption of
reaction to benzalkonium chloride usually regards irritation. benzalkonium chloride to silicon rubber tubes and to cellu-
Phenylmercuric borate gives fewer hypersensitivity lose nitrate-membrane filters, the solubilisation of methyl
reactions but has been abandoned. Chlorhexidine, as said, parahydroxybenzoate by polysorbate 80 [49] and by sodium
is only suitable for a few preparations. lauryl sulfate [50] and the migration (distribution) towards
Hypersensitivity to preservatives is often the reason for the lipid phase of methyl parahydroxybenzoate in emulsions.
dispensing non-preserved eye drops, in single use For most of the preservatives the undissociated form is
containers. the active form because only this passes through the
Table 23.21 Survey of preservatives

Bacteriostatic/bactericidal
Group Substance concentrationa Applicable at pH range Hypersensitivity and toxicity
Quaternary Benzalkonium 0.04–0.1 mg/mL 4.5–8.0 Hypersensitivity and irritation in eye
ammonium drops
compounds Cetrimide 1 mg/mL Most effective at neutral or Hypersensitivity after repeated
slightly alkaline pH [5] application [5]
Mercury Phenylmercuric 0.01–0.04 mg/mL (slow) Independent from pH; at Ciliotoxic
compounds borate pH 8 slightly better than at
pH 6
Thiomersal 0.05–0.1 mg/mL Bactericide at acid pH, Ciliotoxic, sometimes
bacteriostatic or fungistatic hypersensitivity
at alkaline or neutral pH [6]
Hydroxybenzoic Methyl 1–1.5 mg/mL or mg/g, in Stability optimum pH 3–5; Allergic reactions
acid esters parahydroxybenzoate combination with propyl better activity in acid
hydroxybenzoate 0.5–0.6 mg/mL environment (pH < 8)
or mg/g
Propyl 0.3 mg/mL Antimicrobial activity at Allergic reactions
parahydroxybenzoate pH 4–8, decreasing with
increasing pH [5]
Sorbic acid and Sorbic acid 1–2.5 mg/mL or mg/g (as K-salt) Optimum pH ¼ 5 Irritating
benzoic acid Benzoic acid 1–2.6 mg/mL (as Na-salt) Hypersensitivity
Chlorhexidine Chlorhexidin 0.1 mg/mL pH 5–8; above pH 8 Hardly
precipitation occurs
Phenols Chlorocresol 0.75–2 mg/g Bactericidal activity within Hypersensitivity
broad range (pH < 8);
optimum pH 2–4
Cresol (o-, m- and p-) 2.5–3 mg/mL, in combination pH < 8, optimum pH 2–4 Less irritating than phenol [5]
with phenol 1.5–1.8 mg/mL
Phenol 2.5–3 mg/mL, in combination Largest antimicrobial Irritating
with cresol 0.6–0.65 mg/mL activity in acidic solutions
[5]
Alcohols, di- and Benzyl alcohol 9–15 mg/mL, incidentally up to pH 4.5–8.0 Hypersensitivity, limitations with
trioles 40 mg/mL prematures, neonates and children
PRODUCTION
up to 3 years because of toxicity
Ethanol 15–20 % No restriction Not relevant
Phenoxyethanol 5–10 mg/mL No restriction Not relevant
Glycerol 85 % >30 % No restriction Not relevant
Propylene glycol 10–15 % No restriction Irritation
Silver Silver ions Ag+: 0.5 mg/l No restriction No data
a
Whether a preservative is bacteriostatic or bactericidal is not predictable on forehand. It depends on the concentration of the preservative and the
kind of germs present in the product
bacterial membrane. This explains their pH dependency; The relationship between concentration and activity
many preservatives are acids and phenols that will only be differs greatly for the different preservatives and is rarely
active in their undissociated form, thus below their pKa. linear. The doubling of concentration does not necessarily
Thus the availability of preservatives for the higher pH lead to the doubling of activity. Increasing the concentration
region is very limited, especially for oral preparations. of phenylmercuric borate in eye drops from 0.002 % to
Those preservatives that are active at neutral to slightly 0.004 % for instance causes no better functioning [51]. In
alkaline pH, have a bad taste: propylene glycol, chlorhexi- contrast, halving the concentration parahydroxybenzoic acid
dine, quaternary ammonium compounds, phenylpropanol esters causes a roughly tenfold reduction of the activity.
[51]. In fact only the parahydroxybenzoic acid esters remain, The activity of preservatives is optimal against micro-
but they are susceptible to hydrolysis at increased pH. These organisms in a growth phase. This raises the question
characteristics also bring about that preservatives as a rule whether multidose preparations like eye drops should be
have limited water-solubility and are therefore likely to stay kept in the fridge after they have been opened up or not.
in the lipid phase, of which preservation is not really Micro-organisms introduced by the patient will be killed
necessary. faster from the preservative action at room temperature,
but will replicate slower in the fridge. Some experts consider Fig. 23.14 The formula of CO2Na
the first effect more important than the second one and so thiomersal
they advise that eye drops should preferably be kept at room Hg CH3
S
temperature.
The Chaps. 4–14 on the various pharmaceutical dosage
forms cover the use of preservatives in each of those groups
environment. Thiomersal however is still in use as a preser-
of preparations. Further background of preservation and
vative in eye drops, contact lens fluids, injection fluids and
preservatives can be found in Sect. 22.3 and in
vaccines [55]. The characteristics of the organic mercury
reference [52].
compounds phenylmercuric borate and thiomersal (see
Fig. 23.14) will be described. Because of their ciliotoxity
they are not used in nose drops and nebulisation fluids. The
23.8.3 Quaternary Ammonium Compounds
activity does not depend on the pH. The solutions are stable
when subjected to steam sterilisation. Organic mercury
Benzalkonium chloride and cetrimide (cetrimonium bro-
compounds can be adsorbed to different plastics and to
mide), are good water soluble preservatives that are resistant
some types of rubber (see also Sects. 24.2.4 and 24.4.2);
to steam sterilisation. The applied concentration lies
this has implications for the choice of the packaging
between 0.004 % and 0.01 % for benzalkonium chloride
material.
and approximately 0.1 % for cetrimide. They are slightly
Phenylmercuric borate is 0.08 % soluble in water. Mer-
more effective at higher pH due to the cationic interaction
cury is in this compound covalently bound to the phenyl
with the negatively charged cell wall of the micro-organism
group. It is incompatible with many anions, including
at higher pH [53]. The addition of disodium edetate
halides. However a 0.004 % solution is compatible with up
potentiates their antibacterial effect [54]. For the outer
to 0.7 % sodium chloride. The active concentration is
membrane of the micro-organisms is stabilised by cations
0.002 %, but a concentration up to 0.004 % may be used
like calcium and magnesium, by cross-linking the
to compensate losses by adsorption on the membrane filter,
polysaccharides in the cell membrane. Sodium edetate
etc. Eye drop bottles with chlorine and bromine butyl rubber
binds these cations and thus renders the outer membrane of
droppers cannot be used with phenylmercuric salts, because
the bacteria unstable. As a consequence benzalkonium chlo-
a precipitate will be formed. An alternative is packaging the
ride can penetrate deeper into the bacterial cell.
eye drops in a bottle with a polypropylene dropper (see Sect.
Benzalkonium chloride is a first-choice preservative in
24.4.2). Phenylmercuric borate causes few hypersensitivity
eye drops. For this application it is usually combined with
reactions, but with prolonged use, there might be a risk of
disodium edetate, because benzalkonium chloride alone
mercury deposition in the lens.
works poorly against non-fermentative gram-negative bac-
Thiomersal is approximately 0.02 % soluble in water.
teria. As a basis solution for eye drops the FNA uses the
The active concentration is 0.01 %. It is mainly used in
combination of benzalkonium chloride 100 mg/L and
eye drops, contact lens fluids and injection fluids. In solution
disodium edetate 1 g/L. Benzalkonium chloride in eye
the active molecule is ethylmercuric that is somewhat more
drops can irritate and can cause sensitisation. Chronic toxic-
toxic than phenylmercuric but less than ionogenic mercury.
ity is doubted (see Sect. 23.8.1.1).
Also the risk of hypersensitivity reactions is greater than
The safety of the use of benzalkonium chloride for
with phenylmercuric borate. With prolonged use in eye
the preservation of nose drops and nebulisation fluids is
drops or contact lens fluids damage of the cornea epithelium
not easy to be interpreted, see Sects. 8.5.1 and 6.6.3
may occur.
respectively.
Cetrimide is mainly used in cutaneous preparations, espe-
cially in creams in which it is used as active substance
(disinfectant) and emulsifier. 23.8.5 Hydroxybenzoic Acid Esters
Quaternary ammonium compounds are incompatible
with many anionic substances. Because quaternary ammo- The hydroxybenzoic acid esters are among the most widely
nium compounds are also surfactants, they also are used as used preservatives in pharmacy preparation. They are used
emulsifier (see Sect. 23.6.2). in oral liquids, enemas and cutaneous preparations. They are
not very active against gram-negative bacteria. The combi-
nation with disodium edetate is not commonly used although
23.8.4 Mercury Compounds it may overcome this drawback.
Their solubility in water is 0.1–0.2 %, which is just above
Phenylmercuric borate as a raw material is however not the applied concentration of 0.1–0.15 %. During preparation
available anymore because of toxicological problems to the the dissolution speed can be increased by heating. Fast
Table 23.22 Potassium Chloride Oral Solution 75 mg/mL [56] Fig. 23.15 The formula of O
methyl parahydroxybenzoate
Potassium chloride 7.5 g CH3
Methyl parahydroxybenzoate 0.1 g O
Peppermint oil 0.012 g
Water, purified 96.7 g HO
Total 104.3 g (¼100 mL)
micellar solutions and hydrophilic creams, it depends on

the composition of the aqueous phase [58]. A
microbiological challenge test is strongly recommended if
Table 23.23 Prednisolone Oral Solution 1 mg/mL (as disodium phos-
phate) [57] this use is considered.
Hydroxybenzoic acid esters can cause allergic
Prednisolone sodium phosphate 0.146 g
reactions [3].
Bananas essence (local standard) 0.1 g
Methyl parahydroxybenzoate (Fig. 23.15) or methyl-
paraben is the most common representative of the hydroxy-
Methyl parahydroxybenzoate 0.15 g benzoic acid esters.
Sodium dihydrogen phosphate dihydrate 0.21 g At a slightly acidic pH and room temperature methyl
Sorbitol, liquid (crystallising) 25.8 g parahydroxybenzoate solutions are fairly stable, but at
Water, purified 77.5 g pH 8 approximately 10 % hydrolyses in 6 months. An
Total 106.8 g (¼ 100 mL)
example of short shelf life due to decomposition of methyl
parahydroxybenzoate is the Prednisolone Oral Solution
(Table 23.23): the pH is rather high to prevent the hydrolysis
of prednisolone disodium phosphate, but as a result the shelf
dissolution can also be obtained by using concentrated life is determined by the preservative: only 12 months.
solutions in organic solvents such as propylene glycol, for Although the taste is better than those of many other
example: methyl parahydroxybenzoate 15 g with propylene preservatives, methyl parahydroxybenzoate causes unpleas-
glycol 91 g for 106 g (¼100 mL). Solubility may be ant sensations on the tongue in some patients, when used in
decreased by salts and storage temperature. This effect mouth washes. Solutions with a mildly acidic to neutral
should be carefully considered when designing a formula- pH, under favourable conditions and on validated lines, are
tion, see the examples in the box. stable to heating over boiling water for 30 min (see Sect.
PRODUCTION
30.7) and sometimes even against steam sterilisation 15 min
at 121 C.
Crystallisation risk of parahydroxybenzoates. Propyl parahydroxybenzoate is more lipophilic than
Salts: Because of the high phosphate content in oral methyl parahydroxybenzoate and therefore less soluble in
phosphate solutions, methyl parahydroxybenzoate has water (0.035–0.05 %), but the active concentration is also
to be used in a concentration of 0.1 %, otherwise it will lower: around 0.03 %. It is currently used with methyl
crystallise. Another example is a potassium chloride parahydroxybenzoate, mostly because of the synergistic
oral solution 75 mg/mL (Table 23.22). It consciously effect. Combinations methyl parahydroxybenzoate : propyl
contains a minimal amount of methyl parahydroxy- parahydroxybenzoate 7:1, 7:3 or 3:1 give a better preserva-
benzoate because its solubility is decreased by the relation than propyl parahydroxybenzoate alone. However, due
tively high concentration of potassium chloride. to the poorer water solubility of propyl parahydroxy-
Storage temperature: Prednisolone Oral Solution benzoate, those combinations will cause solubility problems
1 mg/mL (Table 23.23) cannot be kept below 15 C rather than methyl parahydroxybenzoate alone. No data are
because of crystallisation of the methyl known about its resistance to sterilisation.
parahydroxybenzoate.
Hydroxybenzoic acid esters show pH-dependent degra- 23.8.6 Sorbic Acid and Benzoic Acid
dation by hydrolysis. The stability optimum lies at pH 3–5;
beyond this range the hydrolysis rate increases to maxima at The ionisable preservatives sorbic acid (see Fig. 23.16) and
pH 1 and from pH 9. At high pH the phenolic OH-group also benzoic acid (see Fig. 23.17) are only active as the undisso-
becomes dissociated. ciated form, because this passes the bacterial membrane.
Due to the high fat-water partition coefficient, This explains their dependency on the pH for their effi-
hydroxybenzoic acid esters are not always suitable for cacy. Sorbic acid and benzoic acid are mainly present in
Fig. 23.16 The formula of CO2H concentration is 0.01 %. It is usually obtained as 20 %

sorbic acid H3C solution.
The optimal antibacterial activity lies in the pH range
5–8; above pH 8 chlorhexidine precipitates as its base.
Solutions of chlorhexidine in usual strengths are not
Fig. 23.17 The formula of CO2H completely resistant to autoclaving. Due to the toxic degra-
benzoic acid dation product 4-chloroaniline a limit test on this impurity
after autoclaving should be performed [5]. Chlorhexidine
only rarely elicits hypersensitivity reactions but has the
disadvantage that it is incompatible with many anions,
some of which will cause a precipitate only after many
undissociated form below their pKa (4.76 respectively and
days of storage. The combination with disodium edetate is
4.19) so they can only be used at pH values less than about
not common. Chlorhexidine digluconate is mainly used in
5. Reduction of the pH increases degradation thus pH 5 is the
cutaneous preparations and eyedrops.
optimum value from the viewpoints of both stability and
effectiveness.
Sorbic acid is mainly used in cutaneous preparations and
in oral liquid preparations. Because of the favourable 23.8.8 Phenols
oil-water partition coefficient it is suitable for formulating
hydrophilic creams, emulsions and micellar solutions for Phenols also only act as a preservative in their undissociated
oral use. For this reason it is preferred to methyl parahydrox- form (see also Sect. 23.8.6). That means that they can be
ybenzoate in these preparations. used at pH less than 8 with an optimum at pH 2–4 [59].
Sorbic acid is 0.15–0.2 % soluble in water, which is Of chlorocresol (see Fig. 23.18), p-chloro-m-cresol and
slightly above the active concentration of 0.1 %. By adding metacresol (m-cresol, see Fig. 23.19) only the last one is
it to boiling water dissolution is accelerated. Sorbic acid is mentioned as a preservative in parenteral preparations (see
volatile with water vapour; covering the vessel prevents loss Sect. 13.5.9). Chlorocresol is used as a disinfectant of clean
of sorbic acid during heating. By using potassium sorbate the rooms (see Table 31.5). The solubility of chlorocresol in
method of preparation can be made easier: potassium sorbate water is 0.4 %; the active concentration is 0.1 %. The solu-
is dissolved in water and the optimum pH is obtained by the bility of metacresol is approximately 2 %. Solutions of
addition of acid. chlorcresol or metacresol resist autoclaving.
Solutions of sorbic acid or benzoic acid are not resistant Phenol is up to 7 % soluble in water. The active concen-
to autoclaving. tration is 0.5 %. It is used as a preservative in parenteral
Sorbic acid is also oxidisable and sensitive to light. preparations and exceptionally in cutaneous preparations,
Containers should sufficiently protect the content from because of the unpleasant smell.
light. If semisolid preparations are packaged in a jar, they The parahydroxybenzoic acid esters can also be classi-
can be protected from oxygen by covering the preparation fied as phenols, but they are separately discussed in
with foil. Sect. 23.8.6.
Benzoic acid is soluble in water up to 0.3 %, while the
active concentration is 0.1–0.2 %. Benzoic acid also
sublimates at higher temperatures and is volatile with Fig. 23.18 The formula of OH
water vapour. It is only active in the undissociated form at chlorocresol
pH less than 5. Benzoic acid is second-choice preservative in
Cl
solutions. It works less well than sorbic acid against fungi
and yeasts. Benzoic acid in oral preparations and dosage CH3
forms is also undesirable for neonates and infants [3].
Fig. 23.19 The formula of OH

metacresol
23.8.7 Chlorhexidine
Chlorhexidine is used as a preservative in the form of the

very water-soluble chlorhexidine digluconate. The active CH3
Table 23.24 Some data of preservatives with an alcoholic structure

Preservative Active concentration (% g/g) Solubility in water (% g/g) Pharmaceutical dosage forms in which it is used
Benzyl alcohol 1 4 Intramuscular and subcutaneous dosage forms
Ethanol 15–20 Unlimited Oral liquids, enemas
Glycerol 85 % >30 Unlimited Oral liquids
Phenoxyethanol 1 2.5 Cutaneous preparations, vaginal irrigations
Propylene glycol 10–15 Unlimited Cutaneous preparations
should be protected against light because of discolouration

Fig. 23.20 The formula of
OH by reduction [60].
benzyl alcohol
23.9 Antioxidants
Fig. 23.21 The formula of H3C OH
chlorobutanol hemihydrate
, ½ H2O Antioxidants protect products with active substances that
H3C CCl3
are sensitive to oxidation by atmospheric oxygen. For a
description of the mechanism of action of antioxidants, see
Sect. 22.2.2.2.
23.8.9 Alcohols, Di- and Trioles The most used antioxidants are ascorbic acid (0.2–0.7 %)
and the sulfites: sodium metabisulfite (0.1 %) and sodium
Various alcohols, di-and trioles are used as a preservative. sulfite (0.2 %). A particular example of an antioxidant is
An overview can be found in Table 23.24. sodium thiosulfate, used exclusively for the protection of
Alcohols are active in the whole pH range. iodide against oxidation.
Benzyl alcohol (see Fig. 23.20) has weak local The percentage of antioxidant to be added, is related to
anaesthetic properties in addition to its preservative activity the whole preparation and not to the active substance.
and is sometimes used for that effect in preparations for Usually the antioxidant is dissolved prior to the dissolu-
intramuscular injection. However it should not be used in tion of the active ingredient. In this way it reduces in
injections intended for children < 6 months (see Sect. advance the amount of dissolved oxygen in the solvent.
13.5.9) nor in injections intended for prematures or neonates. This is especially relevant if a small amount of a highly
PRODUCTION
It also causes haemolysis in higher concentrations and active substance needs to be protected.
dosages [3]. Sodium metabisulfite (¼ sodium pyrosulfite) reacts with
Chlorobutanol (Chlorobutanol anhydrous and oxygen by formation of sulfate, causing the pH to decrease.
chlorobutanol hemihydrate Ph.Eur. see Fig. 23.21) is now It can also bind to some active substances such as predniso-
little used because of its poor solubility and strong perme- lone disodium phosphate and epinephrine tartrate. Sodium
ation through rubber and plastic. When heated in water it metabisulfite can cause an anaphylactic reaction at paren-
melts before it dissolves which decreases the dissolution rate teral administration; because of this risk take care with the
further. Furthermore, it decomposes at moderate tempera- use of this substance. Ascorbic acid generates a yellow
ture and during storage it is not sufficiently stable. oxidation product. This may discolour the preparation
although no degradation of the active substance has
occurred.
23.8.10 Silver A special group is formed by the radical scavengers
butylhydroxyanisole (see Fig. 23.22) and butylhydrox-
Oligodynamic preservation is a different subject. It is based ytoluene (see Fig. 23.23). They are used in non-aqueous
on the principle of preservation by low concentrations of environments. Concentrations usually start at 0.01–0.1 %
silver ions that are presumed to attack the SH-groups in of the complete formulation, if necessary increased to 1 %.
protein and DNA structures of micro-organisms. Their appli- Butyl hydroxytoluene is used in the lipid phase of a tretinoin
cability might be advantageous to circumvent risks of hyper- cream 0.05 % (Table 23.25).
sensitivity by preservatives in eye and nose drops. A silver In addition, these substances are sometimes present in
ion concentration of 0.5 mg/L is supposed to be sufficiently oils and fats (e.g. Wool fat). Its presence should always be
active as a preservative. Note that solutions with silver ions mentioned on the label.
Fig. 23.22 The formula of OH 2-

butylhydroxyanisole O O
N N
CH3 2 Na+ , x H2O
H3CO O Ca O
H3C CH3
O O O O
Fig. 23.24 The formula of sodium calcium edetate

Fig. 23.23 The formula of butyl H3C
hydroxytoluene
CH3
H3C increase, which will compensate for the acid reacting zinc
OH sulfate. Raising the pH of solutions containing zinc ions
generally generates a precipitate of zinc oxide (hydrate),
CH3 but this is prevented by the formation of citrate-zinc
H3C
H3C CH3 complexes.
Table 23.25 Tretinoin Cream 0.05 % [61] 23.11 Colouring Agents

Tretinoin 0.05 g
Alcohol denaturated 95 % V/V (local standard) 12 g Colouring agents are, together with taste and aromatic
Butylhydroxytoluene 0.04 g agents, used to make the medicine more acceptable for the
Cetomacrogol cream FNAa 88 g patient. Sometimes colouring agents used to prevent
Total 100 g mix-ups. This use, however, is contrary to the principle
a
that the label always should be read well. Colouring agents
Cetomacrogol emulsifying wax (BP) 15 g, sorbic acid 200 mg, decyl are also used to protect light-sensitive medicines or to pre-
oleate 20 g, sorbitol, liquid (crystallising) 4 g, water, purified 60,8 g.
total 100 g vent patients’ concerns about irrelevant decompositions. It
should, of course, not be used to mask a relevant decompo-
sition. Insoluble colourants are used for protecting the active
substance of tablets and capsules against the influence of
23.10 Complexing Agents light. Colourants are mainly divided by water soluble
colourants (dyes) and water-insoluble (pigments). An exten-
Complexing agents most used in pharmacy preparations are sive overview of all pharmaceutical colouring agents is
disodium edetate and sodium citrate. found in [5]. Table 23.26 is an overview of colourants
Disodium edetate reacts with metal ions resulting in the most used in pharmaceutical preparations.
formation of soluble 6-surrounding complexes as with For use in cutaneous preparations blends of iron oxides
calcium ions (see Fig. 23.24). are suitable. Table 23.27 gives an an example for blending to
In addition to quaternary ammonium compounds it get the desired colour.
potentiates the preservative action of these substances by Legislation on colouring agents for medicines follows
the binding of calcium from the cell membrane of the Food legislation [63] Azo dyes – especially tartrazine – are
micro-organisms, see Sect. 23.8.3. The complexation by suspected of adverse reactions. The latest evaluation by the
edetate of heavy metals is applied to prevent degradation European Food Safety Agency (EFSA) resulted in 2009 in a
that is catalysed by free heavy-metal ions. For this reason, continuation of the allowance [64]. Nevertheless the UK
the addition of disodium edetate is necessary in most Foods Standards Agency advices that avoiding of colourants
solutions of sympathicomimetics. Another example is the in the diet of hyperactive children may have a beneficial
addition to a sodium hydrogen carbonate infusion solution effect.
packaged in glass. By forming calcium complexes, edetate It is hard to find quality specifications for colourants.
prevents calcium carbonate precipitation when there is a risk Some of them (riboflavin, activated charcoal, titanium diox-
of calcium leaching from glass. ide) have a Ph. Eur. monograph. The specifications of all
Citrate ions may act as flocculating agent in liquid colourants with a E-number are mentioned in the
suspensions, see Sect. 18.4.2.2 and examples in Tables 5.6, EU-directive 95/45/EC [65], these are specifications for
5.8 and 5.15. Citrate ions form soluble complexes with zinc use in food, but they are well usable for pharmaceutical
ions. The addition of the alkaline reacting citrate to zinc purposes. Some colourants are specified in the monograph
sulfate eye-washes (see Sect. 10.6.1) causes the pH to Colouring Agents in [5].
Table 23.26 Overview of colourants

Water End concentration in the
Colouring agent and E number Synonym Type Colour solubility preparation Application
Allura red (E129) azo Red Soluble
Azorubine (E122) Carmoisine azo Red Soluble 0.01–0.03 % Solid and oral dosage
forms, liquids
Caramel (E150) Brown Soluble 0.05 % Solid and oral dosage
forms, liquids
Erythrosine (E127) Xanthen Red Soluble Solid and oral dosage
forms
Indigo carmine (E132) Indigotine Indigoid Blue Soluble Solid and oral dosage
forms
Iron oxides (E172) Yellow, red, Insoluble see Table 23.27 Solid and oral dosage
umber/black forms
Lacquersa Various colours Insoluble Solid and oral dosage
forms
Patent blue V(E131) Triarylmethane Blue Soluble 0.005 % Solid and oral dosage
forms, liquids
Patent blue V Green Soluble 0.005 + 0.01 % Liquids
(E131) + quinoline yellow
(104)
Ponceau 4R (E124) Cochineal azo Red Soluble
red
Quinoline yellow (E104) Chinophtalon Yellow Soluble 0.01 % Liquids
Riboflavin (E101) Vitamin Flavoprotein Yellow Soluble Solid and oral dosage
B2 forms
Sunset yellow (E110) azo Yellow Soluble
Tartrazine (E102) azo Yellow Soluble Solid and oral dosage
forms
Titanium dioxide (E171) Inorganic White Insoluble Solid and oral dosage
forms
Vegetable carbon (E153) Black Insoluble Solid and oral dosage
forms
PRODUCTION
Lacquers (or ‘lakes’) are soluble colouring agents that are made insoluble by precipitation onto aluminium dioxide
a
Table 23.27 Iron Oxide Concentrated Blend [62] The Ph. Eur. includes general monographs on herbal
Yellowish Orange-like Reddish products: herbal drugs, herbal drug preparations, extracts,
Iron oxide red 15 g 20 g 25 g herbal teas, essential oils. The Ph. Eur. contains (May 2013)
Iron oxide yellow 75 g 70 g 65 g 263 monographs on individual herbal drugs and herbal drug
Iron oxide black 10 g 10 g 10 g preparations. The science-based or evidence-based use of
Total 100 g 100 g 100 g herbal medicinal products for the treatment and prevention
of disease is called (rational) phytotherapy.
Definitions
For the European medicines legislation, herbal medic-
23.12 Herbal Raw Materials inal products, herbal substances and herbal
preparations are defined the European Directive
Herbal drugs or herbal substances serve as raw material for
2004/24/EC [61].
herbal medicinal products [66].a Definitions for herbal
Herbal medicinal product: Any medicinal product,
medicinal products as well as for herbal drugs (herbal
exclusively containing as active ingredients one or
substances) and herbal (drug) preparations are provided by
more herbal substances or one or more herbal
the European Community [66] and in the Ph. Eur. (see box).
preparations, or one or more such herbal substances in
combination with one or more such herbal preparations.
a
Contributed by Herman Woerdenbag, Groningen, The Netherlands. (continued)
Herbal medicinal products are also referred to in 23.13 Medical Gases

the international literature as herbal medicines, herbal
remedies, herbal products, phytomedicines, phyto- Medical gases that are administered to patients are
therapeutic agents or phytopharmaceuticals [67]. medicines and are defined in the Ph. Eur. The gas is in
Herbal substances: All mainly whole, fragmented cylinders or liquid tanks and is administered using a distri-
or cut plants, plant parts, algae, fungi, lichen in an bution system. This can be small-scale, for example a 10 L
unprocessed, usually dried, form, but sometimes oxygen cylinder to a wheelchair. Wider, more expansive
fresh. Certain exudates that have not been subjected distribution systems are found in hospitals, see Sect. 27.5.3.
to a specific treatment are also considered to be herbal The medical gas in hospitals is usually supplied from a
substances. Herbal substances are precisely defined by tanker as bulk, or smaller amounts in cylinders. Transport
the plant part used and the botanical name according to from the bulk storage, or from the cylinder takes place
the binomial system (genus, species, variety and through the pipe network towards the gas terminal units. In
author). a midsize hospital there may be several thousands of them.
The term ‘herbal substance’ in the European Com- In many hospitals, the preparation of Medicinal Air is
munity legislation is synonymous with the term performed locally, from outdoor air that is compressed,
‘herbal drug’ in the Ph. Eur. dehumidified and purified. For more information about the
Herbal preparations: Preparations obtained by responsibilities around quality assurance we refer to the
subjecting herbal substances to treatments such as literature [69].
extraction, distillation, expression, fractionation, puri-
fication, concentration or fermentation. These include
comminuted or powdered herbal substances, tinctures, References
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Containers
24
Jan Dillingh and Julian Smith
Contents 24.4.19 Dosage Delivery Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529

24.4.20 Child-Resistant Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
24.1 Orientation, Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 24.4.21 Containers for Arthritic Patients . . . . . . . . . . . . . . . . . . . . . . . . 532
24.1.1 Purpose of Packaging, Requirements . . . . . . . . . . . . . . . . . . . 502
24.1.2 Protection of the Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 24.5 Quality Control of Packaging Materials . . . . . . . . . . . . . 533
24.1.3 Transport, Handling and Information . . . . . . . . . . . . . . . . . . 503 24.5.1 Quality Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
24.5.2 Defining Quality Requirements . . . . . . . . . . . . . . . . . . . . . . . . . 533
24.2 Container Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503 24.5.3 Incoming Container Material Control . . . . . . . . . . . . . . . . . . 534
24.2.1 Glass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503 24.5.4 AQL-system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
24.2.2 Aluminium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
24.2.3 Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505 24.6 Overview Primary Containers . . . . . . . . . . . . . . . . . . . . . . . . 534
24.2.4 Rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
24.2.5 Paper and Cardboard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
24.2.6 Labels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
24.3 Closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
24.3.1 Closure Systems and Functions . . . . . . . . . . . . . . . . . . . . . . . . . 512 Abstract
24.3.2 Container Closure Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Packaging is an integral part of any medicinal product.
24.4 Packaging Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 Not only from a regulatory point of view, but also the
24.4.1 Bottles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 patients’. It is only the packaged medicinal product which
24.4.2 Containers for Eye Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 is stable and suitable for use. The stability of the product
24.4.3 Eye Lotion Bottles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
24.4.4 Enema Containers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520 follows from the successful combination of formulation,
24.4.5 Infusion Bottle and Injection Vials with Closure . . . . . . 521 packaging materials and method of production. The cor-
24.4.6 Containers for Bladder Irrigations . . . . . . . . . . . . . . . . . . . . . . 522 rect choice of container and closure system will impact
24.4.7 Jar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 every aspect of product life and usage. This is true for
24.4.8 Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
24.4.9 Eye Ointment Tube . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 industrial as well as pharmacy (re-) packaged products.
24.4.10 Suppository Strip . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 Packaging technology encompasses knowledge from
24.4.11 Blister Pack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 fields as material science, chemistry, engineering and
24.4.12 Powder Paper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 ergonomy. With appropriate development, the packaging
24.4.13 Bag . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
24.4.14 Single-Dose Containers (Miscellaneous) . . . . . . . . . . . . . . . 527 system and the many different functions it serves will go
24.4.15 Syringes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528 almost unnoticed. However, an unsuitable packaging system
24.4.16 Oral and Rectal Dosing Syringe . . . . . . . . . . . . . . . . . . . . . . . . 528 will result in the product’s failure to meet the patient’s needs.
24.4.17 Syringe for Parenteral Administration . . . . . . . . . . . . . . . . . . 528 This chapter aims to introduce the reader to the many
24.4.18 Stock Container . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
different aspects of pharmaceutical packaging technol-
Based upon the chapter Verpakkingen by Adrie de Jong and Yvonne ogy. It provides basic and applied knowledge, enabling
Bouwman-Boer in the 2009 edition of Recepteerkunde. the right choice of container system for almost every
J.H. Dillingh (*) medicinal product found in the pharmacy.
Dept. of Clinical Pharmacy and Pharmacology, Groningen University
Hospital, EB 70, NL-9700 RB Groningen, The Netherlands Keywords
Package Container Closure Design Glass Tube
J.C. Smith Dosage delivery devices Quality control
Viridian Pharma Ltd., Yew Tree House, Hendrew lane, LIandevaud,
Gwent NP18 2AB, United Kingdom

502 J.H Dillingh and J.C. Smith
24.1.2.1 Protection against Moisture

24.1 Orientation, Scope In case of dry preparations (powders, tablets, capsules) it is
important that moisture cannot permeate the container. A
24.1.1 Purpose of Packaging, Requirements hygroscopic product can absorb moisture from the atmo-
sphere and become damp. Moisture can enhance degrada-
Medicinal products are packed in containers to protect them tion, both chemically and physically. For example capsules
from the adverse effects of external physical, chemical and can get sticky and disintegrate.
microbiological influences. The container holds the medici-
nal product, making it possible to transport and use the 24.1.2.2 Protection against Oxygen
product. It also bears the information to identify the medi- Substances that are sensitive to oxidation should be
cine and the instructions on how to use it. protected from the ingress of oxygen into the container.
There are two kinds of containers: Plastic containers are more permeable to oxygen, when
• Primary containers, which are in direct contact with the compared to glass and aluminium ones. Different types of
medicinal product plastics are more or less permeable to oxygen.
• Secondary containers, which enclose the primary
container 24.1.2.3 Protection against Light
The closure system seals the container, completing the bar- Many container materials, for example coloured glass, effec-
rier between the container content and the outside world. tively shield radiation with a wavelength < 500 nm (ultra-
Labels belong to a special group of secondary packaging violet range) [1]. This light range will pass through
materials. A product’s packaging system is tailored to meet non-coloured glass and transparent plastics. Exposure to
the required level of protection and is comprised of the light may increase the degradation rate of the preparation.
complete set of packaging materials: primary container, White plastic that is not visually transparent, for example
closure system, secondary containers when necessary, and polypropylene, can allow light to pass through. This may
labelling. cause a faster degradation of product, for example sorbic
This chapter will cover the general requirements of acid in creams in polypropylene containers. Preparations
containers and closures for medicinal products, the raw that are susceptible to light should be stored in amber glass
materials from which containers and closures are being or brown plastic containers. In some cases these containers
made and the different shapes of containers that are being do not offer sufficient protection and the preparation must be
used. And finally the quality control of containers will be stored in the dark or wrapped with a material that does not
addressed. transmit light (for example aluminium foil).
The requirements for containers originate from the
functions: protection of the product, facilitate product use 24.1.2.4 Protection against Micro-organisms
and provider of information. In the design phase of the and Particulates
medicinal product the material, form and functions of the The container has to minimize the chance of (micro-
primary container are determined. Compatibility of the biological) contamination during the use of the medicinal
selected container with the medicinal product is product. The preferred container for creams is a tube instead
demonstrated by stability studies. of a jar.
24.1.2.5 Protection against Deformation/

24.1.2 Protection of the Product Fracture
Protection against deformation and fracture is a requirement
The characteristics of the medicinal product define the for solid pharmaceutical preparations such as tablets and
properties needed to protect the product. For example, the suppositories. A container for tablets for example protects
glass quality requirements for injections or eye drops are its contents from external mechanical forces.
different from those for an oral medicine.
The requirements could be different for a similar route of 24.1.2.6 No Interaction with the Container
administration. Medicinal products can interact with the container or with
Some products for example have to be protected from plastics from an administration system. Possible interactions
light. Protection from external moisture, oxygen, light, are absorption, adsorption or the release of additives from
micro-organisms, particles, fracture and deformation may the container. Migration of (active) substances from the
be necessary. The medicinal product should not lose mois- preparation into the container and migration from additives
ture or interact with the container in a way that would in the container (softeners, stabilizers) into the medicinal
adversely affect the quality of the product. product should not occur.
24 Containers 503
24.1.2.7 No Transmittance of Liquid, Vapour • Glass

or Gas • Metal (aluminium)
Gas, such as oxygen, or moisture should not permeate across • Plastic
container walls. This permeation should not occur from either • Rubber
the environment to the product or vice versa. Permeation of • Cardboard and paper
gas and moisture can affect the concentration of the product. These materials will be discussed in Sects. 24.2.1–24.2.5.
The chapter ‘Materials used for the manufacture of
containers’ in the Ph. Eur. describes the quality requirements
For example the content of nitroglycerin in nitroglyc- and the assay methods for some starting materials often used
erin tablets can decrease because of evaporation. To for pharmaceutical containers [7].
prevent this from taking place, the container is lined
with an additional layer of aluminium foil.
24.2.1 Glass
24.2.1.1 Contents and Characteristics

Glass is mostly formed out of silicon dioxide. The addition
24.1.3 Transport, Handling and Information of other oxides (for example sodium, calcium, potassium,
boron and aluminium oxide) decreases the very high melt-
The following characteristics and requirements of containers ing point of silicon dioxide (>1,700 C) [8]. The mixture
are important for the transport and handling of the medicine (glass) can thus be formed at lower temperatures. The
and the possibility of presenting information about the product: mixture solidifies without crystallising. The most outstand-
• Sizes and weight; a glass bottle is heavier than a plastic ing characteristic of glass is its transparency. As a result of
one; square bottles take less space in storage than round having only a partly ordered structure, glass does not scat-
ones; a container should be big enough for a label. ter light.
• Resistance to fracture; the container should not break The addition of boron- and aluminium oxides serves
during transport or use. primarily to improve the chemical resistance. To colour
• Resistance to temperature; the container of preparations glass, small amounts of sulfur and metal oxides (iron,
that are kept in the fridge or freezer should resist these chrome, cobalt) can be added.
low temperatures (it should not get too rigid or brittle); Glass consists of an irregular network of Si-O-bonds. The
the container of preparations which are sterilised by hot cations of the mentioned oxides are bound to these bonds.
PRODUCTION
air or steam should resist high temperatures and moisture. Glass is a (weak) ion exchanger and therefore not
• Child safety; some preparations should be dispensed with completely inert.
a child-resistant closure (see also Sect. 24.4.20). There are two basic types of glass: soda-lime-silica glass
• User friendliness for the patient; a container should be and neutral glass (also known as borosilicate glass). In
easy to handle by the patient. neutral glass a percentage of sodium oxide is replaced by
• Delivery of a reproducible dosage of the medicine (see boron oxide and aluminium oxide. Neutral glass is more
also Sect. 24.4.19). resistant to hydrolysis and temperature shock, but is more
• Product identification. Usually the label on the container expensive than soda-lime-silica glass. To increase its resis-
communicates the necessary information. Regulations tance to hydrolysis soda-lime-silica glass is surface-treated
concerning the labeling of drug products are extensive and with ammonium sulfate (wet granules are poured into hot
detailed. EU-guidelines [2–6] are accompanied by national bottles) or sulfur oxide. Hereby sodium ions are exchanged
legislation on the labeling of pharmacy preparations. for hydrogen ions. Another method is using a fluorine-
It is not always possible to develop a container that satisfies containing gas such as 1,1-difluoroethane to increase the
all the necessary requirements. Certain requirements can surface resistance [8].
counteract each other such as child-resistant closure versus Blown glass and tube glass can be distinguished from the
user friendliness and impermeability versus weight. Specific way they are manufactured.
requirements for different types of containers will be Blown glass is manufactured by pouring melted glass
described in separate paragraphs (see Sect. 24.4). into a mould and blowing the cavity from the inside.
Tube glass is made by pouring melted glass around a
tube [8].
24.2 Container Materials Tube glass is lighter than blown glass and has a very even
wall thickness. Tube glass is less sensitive to erosion than
The following substances are the most important starting blown glass. With blown glass more sophisticated structures
materials for pharmaceutical containers: can be created.
Advantages of glass as a container material are: of the silicate bridges will occur. Water molecules penetrate
• Few chemical and physical interactions such as absorp- into the glass. The network becomes looser, the glass swells
tion, adsorption and migration (gel forming) and the silicate ions and glass particles are
• Excellent protection against air, oxygen and moisture released into the solution. These glass particles often have
• Transparent material (inspecting the contents is possible) the shape of very thin shiny flakes or splinters which fall
• Protection against light is more or less possible apart in a fine precipitation when being shaken.
(by colouring the glass) The speed of erosion of glass is increased by many anions
• Resistant to high and low temperatures (suitable for [10–13]. At pH 7 this concerns phosphate, citrate and fluo-
steam and dry heat sterilisation and for deep freezing) ride, but not lactate, benzoate and acetate.
• Retaining its shape Neutral glass, which in principle is suitable for reuse, is
• Odourless and tasteless being eroded/impaired by borax containing solutions
• Easy to clean (pH around 9) [14]. This demonstrates that even neutral
• Environment-friendly (in case of reuse) glass will be impaired by solutions with pH >7. Therefore
Disadvantages of glass are: neutral glass bottles should be used only once for
• Risk of breaking autoclaving solutions with pH >7. Plastic containers are
• Rather heavy, although tube glass is relatively light probably more suitable for these solutions.
Calcium ions from glass can be incompatible with certain
24.2.1.2 Glass: Erosion substances from the solution such as phosphate (CaHPO4
Glass is hardly interacting with chemicals but it is not inert. will be formed) and carbonate. To prevent this interaction
It reacts with water, aqueous solutions and other solvents. with glass, for example sodium edetate is added to sodium
Even moisture in the air is able to erode the surface hydrogen carbonate injection solutions.
(‘weathering’). In aqueous solutions cations of the glass are
being exchanged by hydrogen ions. Because of this a surplus
With accelerated stability research (heating for 3 h at
of OH-ions is generated in the solution and the pH may
120 C and storage at 40 C) a solution for intraocular
rise. ‘Base release’ is a rather misleading term for this
irrigation with anions chloride, acetate and citrate even
process. The release of cations by the glass may be harmful:
affected neutral glass: the pH changed from 7.4 to
calcium may lead to precipitations and aluminium is toxic in
almost 8. This effect also happened when the irrigation
parenteral solutions.
was kept during a longer period at room temperature
It is hypothesized that the opposing process may also
[13]. If citrate was left out of the solution there were no
occur: exchange of Na+-ions from the solution against H+-
changes in the neutral glass during the storage time of
ions in the glass [9]. Until now this is only seen in sodium
2 years at 25 C. In plastic there was no pH change, not
chloride- and lithium chloride solutions.
even in the solution containing citrate.
In weak acid and acid solutions the exchange of cations
The pH changes ran more or less parallel to the
from the glass against H+-ions in the solution is restricted to
generation of particles in the solution.
the outermost surface. This release only slightly
In glass bottles of treated soda-lime-silica glass the
increases pH.
pH of the citrate containing irrigation rose from 7.5 to
9.3 within 12 weeks of storage at room temperature.
The small increase of pH in a weak acid environment An extensive generation of particles occurred
by ion exchange with the glass can be relevant to simultaneously.
the stability of certain weakly buffered preparations.
Atropine sulfate eye drops for example are hydrolysed
The release of aluminium from glass raises concern from
remarkably faster at pH 6 than at pH 4. If a small
the toxicological point of view. This is mainly relevant
increase of OH-ions is to be expected, which is
related to parenteral solutions and not so much as to orally
significant for the preparation, then the preparation
administered preparations. Aluminium is hardly absorbed in
should be buffered. When buffering is not possible
the gastrointestinal tract. Elimination of aluminium after
for other reasons (irritation), a better quality of glass
parenteral administration occurs mainly via the kidneys.
should be used.
Patients having a high risk of aluminium intoxication are:
– Neonates and prematures (high sensitivity for toxic
Besides an increase of pH in neutral and alkaline effects and low renal function)
solutions because of a surplus of OH-ions, also hydrolysis – Patients with impaired renal function
24 Containers 505
– Patients to whom large amounts of parenteral solutions

are administered, such as patients at intensive care units of soda-lime-silica glass. The final pH seems to
and patients who receive total parenteral nutrition [15] depend on the quality of the glass itself. The formation
The aluminium concentration of injection and infusion (and sometimes disappearance) of particles, visible by
solutions in glass containers should be checked at the end the naked eye, follows a course which is also depen-
of the shelf life. Neutral glass generally contains more alu- dent on the pH and on the composition of the solution
minium than sodium calcium glass. Solutions with calcium (in some solutions silicate dissolves for example).
gluconate, potassium phosphate, sodium acetate and those
with trace elements can contain a high concentration of
aluminium [10, 11, 16]. Solutions containing phosphate
extract aluminium from glass in such high amounts that
plastic containers are preferred [12].
24.2.2 Aluminium
Aluminium is being used as container material for tubes,

24.2.1.3 Glass: Hydrolytic Resistance
canisters with an inhalation solution and as part of blister
and Quality Control
packages. In blister packages the aluminium lidding foil has
The Ph. Eur. classifies glass by hydrolytic resistance: the
a heat seal layer that brings about the attachment to the
resistance against attack by hydrolysis [17]. Hydrolytic
plastic form foil or to the aluminium form foil. Furthermore,
resistance is determined by steam sterilisation of the glass
aluminium is still used as a primary container for
with water, followed by titration of the released OH-ions
suppositories and as a secondary container to give extra
with acid. Based on the amount of OH-ions the Ph. Eur.
protection to medicines against light.
classifies glass into three different classes:
Aluminium is also a part of closures:
I. Neutral glass or borosilicate glass with high hydrolytic
• A layer of pure aluminium is wrapped around a cork inlay
resistance due to the chemical composition of the glass
to obtain a damp tight container (for example a tablet
itself
container for nitroglycerine tablets).
II. Soda-lime-silica glass with a high hydrolytic resistance
• Infusion solution bottle closure (screw- and dust cap).
resulting from suitable treatment of the surface
• Crimp cap for bottle for infusion and injection solutions.
III. Soda-lime-silica glass with only moderate hydrolytic
Advantages of aluminium are:
resistance
• Impermeable to liquid, moisture, gas and air.
Glass is manufactured in a continuous process. The term
• Protection against light.
batch therefore has a different meaning than with the pro-
PRODUCTION
• Resistant to high and low temperatures.
duction of medicines. Glass does not have a composition that
• Odourless and tasteless.
can be fixed in a way that is comparable to specifications for
• Good impact resistance.
pharmaceutical starting materials. This disadvantage should
• Light-weight.
be met as much as possible through agreements with the
Disadvantages of aluminium are:
supplier and the design of a certifying system (see also
• Sensitive to corrosion.
Sect. 24.5).
• Incompatibilities; the chemical resistance of aluminium
An extra difficulty is posed by differences in the compo-
is only moderate with for instance acids, bases and
sition of the same glass type from different suppliers. Type I
halogenides; aluminium tubes are therefore often
glass from one supplier is therefore not identical to type I
protected by an inside and outside lacquer.
glass from another supplier. This has to be taken into
account when determining shelf life.
24.2.3 Plastics
The differences between bottles within one batch can
be observed by the course of the erosion of treated Plastics are mixtures of synthetic and natural polymers and
soda-lime-silica glass. The erosion in each bottle does additives. These polymers can be divided into two groups:
not start at the same moment [13, 18, 19]. A typical • Thermoplastics: plastics that soften on heating and set
course is that once the process has started, the pH rises again upon cooling
to a maximum (around 9.5) in a relatively short time • Thermosets: plastics that only soften during the produc-
(at the utmost several weeks) and stays constant there- tion process and irreversibly hardens by the action
after. The moment of the start of the pH-increase of heat
seems to depend on the irregularities in the treatment When a container made of a thermoset plastic is being
heated, the container will not soften, but will decompose.
(continued)
An example of a thermoset is phenol formaldehyde (Bake- authorisation of medicines an extensive declaration of the
lite). Thermosets are mostly applied as material for lids and composition of the primary plastic container is demanded
closures. and declarations of technical characteristics, suitability and
Most plastics that are used for containers of medicines toxicity have to be submitted.
belong to the type thermoplastics. The characteristics and use of the plastics will be
All plastics have advantages and disadvantages. Plastics discussed one by one.
can be assessed by the following characteristics:
• Mechanical characteristics (e.g. impact resistance, 24.2.3.1 Polyamide (PA)
flexibility) Polyamide is a polymer formed from condensation of
• Optical characteristics dicarbonic acids and diamines or from condensation of
• Chemical resistance amino acids and lactames. In publications, in English,
• Temperature resistance polyamids are called nylon. To distinguish them from one
• Permeability/barrier characteristics another a number is added that represents the number of
Tables 24.1, 24.2 and 24.3 give these characteristics of some C-atoms of the monomer or monomers. Nylon type 6.6
plastics. The data are based on literature and are meant as an (polyamide 6.6) is the most common commercial grade of
indication. The abbreviations will be explained in the nylon. It consists of hexamethylene diamine and
subsections. adipinic acid.
During the production process of a plastic, additives can The characteristics of polyamides depend very much on
be added to: the composition. They are generally wear-resistant and all
• Affect the production process, for example catalysts forms are hygroscopic. This absorption of water (plastifying
• Improve polymer stability, for example antioxidants effect) significantly changes the properties of polyamides.
• Alter the mechanical characteristics, for example The thermal resistance of most polyamides is high. They can
plasticisers be sterilised by steam or gamma radiation; polyamide 6.6
• Improve the visual appearance, for example colorants can even be sterilised by hot air.
Ph. Eur. specifies a number of additives allowed for plastics
for containers for pharmaceutical products [7]. Because of 24.2.3.2 Polycarbonate (PC)
the addition of additives, plastics from different suppliers do The most common polycarbonate is a polymer generated from
not have the same composition. Always request the compo- condensation of bis-phenol-A (¼ 2,2-diphenylolpropane).
sition of the plastic container being purchased, from the Polycarbonate has good thermal and mechanical
supplier, and only change the containers of one supplier for characteristics. It is a stiff material which is fraction- and
those from another after considering the differences in the impact-resistant and also resistant to strongly diverse
plastic. A raw material or a preparation cannot just be temperatures.
repacked from a certain plastic container to a container Polycarbonate is not resistant to alkali, strong acids and
from another plastic without reassessing the shelf life. For organic solvents (for example chloroform and acetone). The
gas permeability of polycarbonate is relatively high com-
pared to for example polyethylene, and comparable to
polystyrene.
Table 24.1 Temperature resistance of some plastics
Minimal Maximal 24.2.3.3 Polyethylene (PE)
temperature C temperature C
Polyethylene (¼ polyethene ¼ polythene) is a polymer that
Long
Long time Short time time consists of ethylene units. The different forms are deter-
HDPE 50 90/120 70/80 mined by the method of production:
LDPE 50 80/90 60/75 • Low density - polyethylene (LDPE)
PET 20 80 65 • High density – polyethylene (HDPE)
PP 0/30 140 100 LDPE is produced under high pressure (1,500 bar) and
COC 30 140 100 temperature (150–240 C), in the presence of catalysts.
PS 10 60/80 50/70 HDPE is produced under low pressure (0–2 bar) and tem-
SANa 20 95 85 perature (70 C), in the presence of catalysts. HDPE is a stiff
SBa 20 60/80 50/70 type of polyethylene whilst LDPE is more flexible. An
PVC (hard) 5 75/100 65/85 increase of the density gives a reduction of the flexibility
PVC + softener 0/20 55/65 50/55 and a not fully transparent product. However, other
a
See under polystyrene characteristics are improved by increasing the density.
24 Containers 507
Table 24.2 Chemical resistance of some plastics

HDPE LDPE PET PP COC PS SAN SB PVC Soft-PVC
Water cold + + + + + + + + + +
Water warm + ? + + +
Acids weak + + + + + + + + + +
Acids strong + + +
Acids oxidising +
Base weak + + + + + + + + +
Base strong + + + + + + + +
Sol.anorg.salt + + + + + + + + + +
Halogens
Aliphatic hca + + + + +
Choride hca
Unsat.chlor.hca
Aromatic hca
Alcohols + + + + + +
Esters +
Ketones +
Aldehydes ? ? + +
Ether +
Amines + ? ? + ? + + + +
Organic acids + + +
Mineral oils + + + + + +
Lipids, oils + + + +
moderately resistant
? no data
+ resistant
not resistant
a
hc is hydrocarbon
Table 24.3 Other characteristics of some plastics and glass
PRODUCTION
PVC PVC
HDPE LDPE PET PP COC PS SAN SB Hard Soft Glass
Impact resistance + + +
Flexible + +
Transparent + + + + + + +
Colouring + + + + + + + + + + +
Permeable to gas + + +
Biocompatible + + + +
Permeable to liquid + + +
Leaching of additives +
Resistant to 15 min at 121 C + + + * +
Streaming water vapour + + + +? * * +
+ yes/good
possible/moderate
* dependent on the composition (additives)
no/poor
For HDPE compared to LDPE: 24.2.3.4 Cyclic Olefin Copolymer (COC)

• The permeability to water vapour is lower Cyclic olefin copolymers are a new class of polymeric
• The permeability to gas is lower materials based on cyclic olefin monomers (as 8,9,10-
• The chemical resistance is higher trinorborn-2-ene) and ethene. These materials are also
• The light transmission is lower known as cyclic olefin polymers (COP) when only one
• The temperature resistance is higher single type of cyclic olefin monomer is applied. COC is
Both HDPE and LDPE are plastics that are widely used because very transparent, the optical properties are in many ways
of their low permeability to water vapour and their high chemi- similar to glass. COC is one of the few transparent polymeric
cal resistance. PE is very resistant to gamma radiation. materials able to withstand steam sterilisation. Permeability
to water vapour and gas is low. COC shows good chemical taste. Polystyrene is quite hard and brittle (little impact-
resistance to alcohols, acids and bases, but it is attacked by resistance). It is resistant to acids, alkali, alcohol and
non-polar solvents. inorganics. It is not resistant to boiling water and many
COC vials or syringes can be an alternative to glass organic solvents, such as chloroform and ether, or to fatty
containers. Strong points are good barrier properties, good oils. Therefore polystyrenes are not suitable for packaging
chemical resistance, high purity and low leachables of the dermatological products containing fats.
material, its clarity, and compatibility with sterilisation by The characteristics of polystyrene can be modified by:
gamma radiation, steam, or ethylene oxide. Being a stiff – Copolymerisation of styrene with butadiene (SB). This
polymer material, impact resistance can be low compared generates an impact-resistant polystyrene. This modifica-
to more flexible materials. tion however results in a loss of transparency and
necessitates the addition of stabilizers such as antioxidants.
24.2.3.5 Polyethylene Terephthalate (PET) – Copolymerisation of styrene with acrylonitrile (SAN).
Polyethylene terephthalate is a polyester. It is a linear ester This generates a transparent polystyrene that has a better
composed of ethylene glycol and terephthalic acid. PET has resistance to chemicals and higher temperatures.
excellent mechanical characteristics; it is for example pres- The permeability to oxygen and water vapour of polystyrene
sure- resistant. The chemical resistance is good compared to and modified polystyrene is relatively high.
other plastics. PET is not resistant to strong alkali and
limited resistant to strong acids and chlorinated 24.2.3.8 Polyurethane (PUR)
hydrocarbons (see Table 24.2). Polyurethane is a collective term for a group of polymers
that contain an urethane group (-NH-COO-). They are
24.2.3.6 Polypropylene (PP) generated from a reaction between polyesters and polyethers
Polypropylene (¼ polypropene) generates from polymerisa- with di- or poly-isocyanates.
tion of propene. With stereo specific catalysts three types of Dependent on the starting materials, polymers with
polypropylene can be produced: strongly diverse characteristics can be produced, varying
– Syndiotactic polypropylene; the methyl groups are alter- from thermoplasts to thermosets.
nately positioned with respect to the polymer chain. Polyurethane has a range of packaging functions and is
– Isotactic polypropylene; all methyl groups are placed on often used as filling material in tablet containers.
the same side of the polymer chain. Polyurethanes do not have a good resistance to acids and
– Atactic polypropylene; the methyl groups are randomly alkali.
placed with respect to the polymer chain.
The position of the methyl groups defines the extent of 24.2.3.9 Polyvinylchloride (PVC)
crystallinity and therefore the mechanical and chemical Polyvinylchloride is used as basic material for the produc-
behaviour. Isotactic polypropylene for example is stiffer, tion of infusion bags. It can also be found in blister packages.
harder and stronger than atactic polypropylene. The poly- Polyvinylchloride is generated from the monomer
propylene that is used for containers usually consists of a vinylchloride with the help of a catalyst. Pure PVC is a
high percentage of isotactic polypropylene. Atactic polypro- hard, transparent plastic.
pylene is not used pharmaceutically. Additives in PVC for infusion bags are: stabilisers and
Both chemical and physical characteristics of polypropyl- plasticisers. By adding a plasticiser a flexible, soft plastic is
ene resemble high density polyethylene, but polypropylene formed. The amount of plasticiser in PVC can rise to 60 %
is clearer, harder, has a lower density and a better thermal of the total weight. Plasticisers that are often used are di
resistance (polypropylene can be steam sterilised). Polypro- (2-ethylhexyl)phthalate (DEHP) and dioctylphthalate
pylene is less resistant to low temperatures than high density (DOP). DEHP is the only softener that the Ph. Eur. allows
polyethylene. The chemical resistance of polypropylene is to be used in PVC as material in containers for blood, blood
good (see Table 24.2). To protect polypropylene from oxi- products and aqueous solutions that are used for intravenous
dation, antioxidants are always added. Resistance to gamma infusion. In this case the amount of DEHP in PVC should not
sterilisation is relatively poor, but can be enhanced by be more than 40 % [7].
additives. DEHP is a lipophilic compound and can therefore
migrate from the PVC into medicines that contain lipophilic
24.2.3.7 Polystyrene (PS) or adsorbing substances. Exposure of the patient to softeners
Polystyrene is generated from the monomer styrene by should be minimized. Zinc or calcium salts are used as
polymerisation in the presence of a catalyst. It is a crystal- stabilizers. The use of stabilizers is also limited by the
clear plastic, easy to colour and completely free of odour and Ph. Eur. [7].
24 Containers 509
The interaction between PVC and liquid medicines has The choice of the rubber depends on the preparation and on
been studied extensively [20]. the functionality of the container:
Critical topics include the release of softener from the PVC • Adsorption from components of the preparation to the
as well as the sorption of medicines. Sorption of medicines surface of the rubber as well as migration into or through
occurs more to PVC than to glass and polyethylene [21]. the rubber should not happen.
PVC can be sterilised in a steam steriliser with pressure • The rubber should not release substances into the
compensation. preparation.
Hard PVC is used for blister packages. It is preheated in a • The material should be suitable for its use; rubber
blistering machine and then round or capsule-like cavities closures that are being used for multiple piercing by
are being formed in a moulding station. PVC is relatively needles have different requirements than the dropper of
permeable to water vapour and therefore not suitable to an eye drop bottle.
contain hygroscopic tablets or capsules. However, water Which rubber is selected for use in a particular pharma-
permeability is greatly reduced when the PVC-film is com- ceutical container not only depends on the compatibilities
bined with a thin layer of PVDC (polyvinylidene chloride). or the most suitable physical characteristics, but also
on the availability. In actual practice only industrial
producers of medicines are able to choose the most optimal
24.2.4 Rubber container.
Table 24.5 gives an overview of the characteristics of
Rubber is the starting material of elastic packaging materials some rubbers.
that are used in closures of containers. Natural rubber,
bromobutyl rubber, chlorobutyl rubber and silicone rubber 24.2.4.1 Vulcanisation Methods
can be distinguished [22–24]. There are three vulcanisation methods: with sulfur, with
Rubbers are generated by vulcanisation (crosslinking) of bifunctional reagents and with peroxides. Most importantly,
elastomers. Elastomers are macromolecular organic the vulcanisation method determines which contaminations
compounds that are formed from natural or synthetic will be present in the product. The vulcanisation density is
substances. In the production process additives are being the number of bonds between different chains per volume-
used as vulcanisers, catalysts, stabilizers, colourings, fillers unit.
and lubricants, see Table 24.4.
The different rubbers distinguish themselves by three
Vulcanisation with sulfur
PRODUCTION
factors:
Elementary sulfur or compounds that can be used as
• The basic elastomer
a source of sulfur form together with suitable additives
• The method of vulcanisation
at higher temperatures thio-ether-, disulfide- or
• The amount and type of additives
polysulfide-bridges in and between chains. This vulca-
Table 24.4 Composition of rubber nisation method is primarily suitable for those
elastomers that have unsaturated bonds. The rubber
Component Weight percentages
produced by this method has good mechanical
Polymer (elastomer) 40–95
characteristics. However, a disadvantageous chemical
Vulcanisers 1–4
characteristic of rubber vulcanised with sulfur is that
Catalyst 2–8
Filler 0–60
additives can leach into the product. An example is the
Colouring 0–10 release of thiol compounds, which are incompatible
Lubricant 0–4 with some mercury compounds.
Stabilizer 0–3
(continued)
Table 24.5 Characteristics of some rubbers

Characteristic Natural rubber (Halogen-) Butylrubber Silicone rubber Ethylene-Propylene rubber
Elasticity Very good Moderate Good Good
Deformation rest Very little Moderate/large Very little Little
Permeability (gas and water vapour) Very high Very little Very high Moderate/high
Reactivity (ageing) High Very little Very little Very little
Temperature resistance Very poor Very good Very good Very good
Release of substances Possible (Less) possible Less possible Possible
Fig. 24.1. The value of n is very high; the molecular weight

Vulcanisation with bifunctional reagents lies between 200.000 and 300.000.
The reagent, for example a diamine, forms covalent The chemical structure of the natural latex product
bonds with the polymer chains. Usually the use of determines the characteristics of the rubber produced from
catalysts is not necessary. This vulcanisation method that latex:
is mainly used for the production of halogen butyl • Natural rubber can, dependent on composition and origin,
rubbers and results in materials with good chemical release foreign substances (for example UV-absorbing) to
characteristics (few incompatibilities). a preparation.
Vulcanisation with peroxides • Due to high unsaturation of the basic elastomer, a high
The peroxide serves as a producer of radicals and is crosslink or vulcanisation density can be generated. This
not being built into the polymer. The result of this results in good mechanical characteristics, as a highly
vulcanisation is a chemically inert product. The use elastic product is generated.
of a catalyst is not necessary and with a right choice of • Due to the high number of unsaturated bonds that are still
the peroxide, combined with an after-treatment of the present in the end product after vulcanisation, the natural
material (extraction of the peroxide) a rubber that rubber is a chemically reactive compound. This reactivity
releases only very small amounts of substances is significantly reduces the chemical compatibility and
produced. This method is being used for the produc- useful shelf life of natural rubber.
tion of silicon-elastomer and of ethylene-propylene • Due to its structure, natural rubber has a high permeabil-
rubber. ity to gas and water vapour.
• Natural rubber is susceptible to the absorption of many
substances (for example preservatives such as
chlorobutanol and phenylmercuric borate).
24.2.4.2 Additives
Silicates, silicic acid, calcium carbonate or barium sulfate
24.2.4.4 Butyl Rubber, Bromobutyl Rubber
are used as fillers. Silicates and silicic acid make rubber
and Chlorobutyl Rubber
more sustainable. Colourings for rubber are for example
The basic elastomer of butyl rubber is the synthetized poly-
titanium dioxide and iron oxides. It is better to avoid organic
mer poly-isobutylene with approximately 3 mol% isoprene.
colourings due to the chance of migration of the colouring to
In case of the halogen butyl rubbers the isoprene is replaced
the rubber surface, followed by migration into the
by halogen isoprene. The structure of the basic elastomer is
preparation.
shown in Fig. 24.1. The basic elastomer of butyl rubber
contains relatively few unsaturated bonds compared to the
24.2.4.3 Natural Rubber basic elastomer of natural rubber. The reactivity of butyl
The oldest form of rubber is natural rubber. The basic elas- rubber is therefore less than that of natural rubber. To
tomer of natural rubber is taken from the latex of the rubber advance the vulcanization process, a higher concentration
tree (Hevea brasiliensis, Euphorbiacea family). Latex of reagents and/or a longer reaction time and a higher reac-
consists of carbohydrates, water, fatty acids, proteins and tion temperature are therefore necessary. This relatively high
stearines. The complex composition of latex varies signifi- amount of additives in butyl rubber can cause problems
cantly with origin, season, etc. This variation in composition when it comes into contact with the pharmaceutical
is the main disadvantage when using this material in phar- preparations. ‘Leaching’ may occur, where dispersed (not
maceutical products. chemically bound) additives migrate to the surface of the
Natural rubber consists of polyterpenes. The gross for- rubber, followed by extraction into the preparation.
mula of this basic elastomer in natural rubber is (C5H8)n. When producing the bromo- and chlorobutyl rubbers, the
The module is isoprene (the base of all terpenoides). It is a halogen basic elastomer is used. Like the non-halogen basic
polyunsaturated polymer with a structure as shown in elastomer, this contains relatively few unsaturated bonds.
a b c
H3C H CH3 CH3 CH3 CH3 CH3
C C CH2 C CH C CH CH2 CH2 C O Si O Si
H2C CH2 CH3 X CH3
n n CH3 n
CH CH2 m
Fig. 24.1 Structural formulas of (a): basic elastomer in latex; (b): basic elastomer of butyl rubber, in which x ¼ H for butyl rubber; x ¼ Cl for
chlorobutyl rubber; x ¼ Br for bromobutyl rubber; (c): basic elastomer of silicone rubber
24 Containers 511
The halogen atom activates the double bond and increases peroxide breakdown products. The odour disappears with
the reactivity of the basic elastomer. Therefore no extra time or after steam sterilisation.
measures to accelerate the vulcanization process have to be Silicone rubber is very resistant to ageing and oxidation.
taken, unlike the production of butylrubber. The halogen It shows a very high permeability to gas and water vapour,
butylrubbers therefore have largely replaced butylrubber. which significantly reduces the pharmaceutical usefulness.
The chemical structure of the halogen basic elastomer Silicone rubber is very resistant to a wide range of
determines the characteristics of the halogen rubber which chemicals. It is resistant to weak acids and alkali, salt
is synthesised from this basic elastomer: solutions and mono- or multivalent alcohols and phenols.
• Due to the fact that the basic elastomer is mainly unsatu- However, it is not resistant to strong acids and bases. In low
rated, only a small amount of crosslinking- or vulcanisa- molecular solvents (ketones, esters, aliphatic, aromatic and
tion density is generated. This leads to a product with chlorinated hydrocarbons) a reversible swelling of the elas-
relatively modest mechanical properties, when compared tomer occurs. Many preservatives and active substances are
to natural rubber. strongly adsorbed into silicone rubber.
• Due to low levels of unsaturated bonds in the final prod- The mechanical characteristics of silicone rubber are very
uct after vulcanisation, the halogen butyl rubber is chem- highly independent of temperature. The elastomer keeps its
ically unreactive; hence the product is inert and has a long original hardness and elasticity with temperatures lower than
shelf life. -50 C. Resistance to high temperatures is also very good
• During the production process of halogen butyl rubbers (to 250 C). Addition of metal oxides to silicone rubber can
relatively few additives are necessary and the chance that improve the temperature resistance even further.
additives are leached from the rubber into the pharmaceu-
tical preparation is less when compared to natural rubber 24.2.4.6 Ethylene Propylene Rubber
or butyl rubber. The basic elastomer ethylene propylene monomer (EPM) is
• Permeability to gasses and water vapour is much less for generated by copolymerisation of ethylene and propylene.
halogen butyl rubbers than for natural rubber. As the polymer chain does not have double bonds, vulcani-
Summarising: the mechanical characteristics of halogen sation takes place with the use of organic peroxides. The
butyl rubbers are not optimal (stronger deformation, less ethylene propylene rubber that is thus generated contains no
elastic than natural rubber), but the saturated structure double bonds. Therefore, the product is inert and has a long
leads to excellent chemical characteristics (see Table 24.5). shelf life.
Rubber stoppers to close injection- or infusion bottles and Ethylene propylene diene polymers (EPDM) are basic
–bags can be coated with a thin layer of a polymer that elastomers with double bonds in the side chain. They are
PRODUCTION
resembles Teflon (Teflon ¼ polytetrafluorethene, PTFE). generated by adding small amounts of diene monomers in
The result is a chemically inert stopper with significantly the copolymerisation of ethylene and propylene. Due to the
less “leaching” of substances from the rubber. presence of this unsaturated bond in the basic elastomer both
vulcanisation with peroxides and vulcanisation with sulfur
24.2.4.5 Silicone Rubber are possible. Vulcanisation with peroxides is usually chosen.
The basic elastomer for silicone rubber is a linear This generates a product that is relatively inert and well
polysiloxane, built from dimethyl siloxane units with a resistant to ageing.
small amount methylvinyl siloxane groups. The ends of the When synthesising ethylene propylene rubber usually a
chains are formed from trimethyl siloxane- or dimethylvinyl filler (for example aluminium silicate or calcium carbonate)
siloxane groups. The structure of the basic elastomer is and a plasticiser (for example an aromatic hydrocarbon) are
shown in Fig. 24.1. Peroxides are usually used for the added and a colouring if necessary.
crosslinking of silicone rubbers (for example dicumyl per- As with silicone rubber, ethylene propylene rubber can
oxide or 2,4-dichlorobenzoyl peroxide). give an aldehyde odour. Ethylene propylene rubber is highly
To improve tear resistance, the additive silicic acid can be resistant to water, alkali and dilute acids, and moderately to
added. Other additives are usually not necessary, so migra- poorly resistant to hydrocarbons, lipids and concentrated
tion of substances from the final product into the pharma- acids. It is resistant to the high temperatures of steam
ceutical preparation will usually be limited to residues of the sterilisation.
peroxide. By the right choice of the peroxide and adequate
after treatment of the final product this problem can be
reduced. The Ph. Eur. contains a test for the presence of 24.2.5 Paper and Cardboard
peroxide residues in the elastomer.
Silicone rubber, like other rubbers that are produced Paper is a single-layer material (7–250 g/m2); cardboard is a
following the peroxide method, can give an aldehyde multiple-layer material (250–600 g/m2). Both are made from
odour shortly after production. This is caused by traces of cellulose fibres that are compressed.
Paper is the primary packaging layer for the packaging of closure also allows access and use of the product. Where
single dose oral powders in powder paper (Sect. 24.4.12). tamper evidence is required the closure system must be able
However, it is more common for paper and cardboard to be to show that the container has been opened.
used as secondary or tertiary packaging layer. Paper is also In order to provide these functions, the forms and
the basic material of a special packaging material: the label methods used to provide an effective seal vary widely. The
(Sect. 24.2.6). closure systems used in pharmacy usually depend on a
Powder paper should not be contaminated, should not system were a relatively soft material is pressed onto a
shed fibres and within one batch there should not be much hard material. The softer, more resilient material will com-
difference in weight per surface area (¼ constant powder pensate for small imperfections on the hard surface, leading
paper weight). to an effective seal. The materials forming the closure are
For weighing of fatty or semisolid starting materials so pressed together by means of:
called greaseproof paper can be used. This type of paper is • Threaded screw cap. An example is the bottle screw cap
smoother and stronger compared to ‘normal’ powder paper. with a relatively soft liner material on the inside of the
Lipid penetrates slower into the paper, but interactions cap. A screw cap made of (softer) thermoplastic materials
(migration) are not excluded. often doesn’t need an additional liner material. The clos-
Cardboard is a popular material for the secondary con- ing torque force must be sufficient to provide a good seal.
tainer. It is relatively cheap, easy to design in suitable shapes • Material deformation. An example is the vial closure for
and easily printed with information. Cardboard is often used injectable drugs. The glass container is sealed by an
as tertiary container to protect the packaged products during elastomeric stopper, firmly locked in place by means of
transport. The objectives determine the requirements that are an aluminium overcap that is mechanically crimped over
set for the material. For example, to send a package to the the stopper and neck of the vial.
tropics, a cardboard box with an aluminium inside layer is • A snap-on closure where a raised ring is forced over a
appropriate to protect the contents against moisture. bead or lip. An example is the Sterillab snap cap eye drop
bottle (Sect. 24.4.2).
• A push-in closure where a tight-fitting stopper is pushed
24.2.6 Labels in place and stays closed by friction forces.
The other preferred form of closure system in pharmacy is
The label is an important part of the pharmaceutical product. heat-sealing. This usually achieves an effective and perma-
The most common label used within the European pharmacy nent seal, which can only be opened by destruction of part of
is the self-adhesive label. This consists of a laminate of two the packaging material. An example is the glass ampoule,
special types of paper: the carrier material and the label fused by heat. The fused glass forms a totally hermetic seal.
paper. The carrier material consists of paper on which a Another example is the blister packaging of tablets. A multi-
silicon layer is fixed. The label paper can be printed on the layered film of polymer material is preformed and filled with
printing side and on the carrier side it has an adhesive layer. tablets, and sealed by heat and pressure to a thin aluminium
The adhesive is usually of the permanent type, rendering the strip foil.
label non-removable once applied [25]. Label adhesives on A heat seal which can be peeled open is formed by
plastic containers such as infusion bags require additional materials which are not completely fused together. This
attention, see Sect. 24.4.13. can be achieved by the use of materials that are more or
Uniform labels of good constant quality are very impor- less incompatible [22, 24].
tant for pharmacy preparation. Quality control of incoming
labels, both printed or unprinted, should equal the
requirements for containers described in Sect. 24.5. 24.3.2 Container Closure Testing
The way in which information should be put on labels
(labelling) is dealt with in Sect. 37.3. The design and manufacture of quality packaging materials
is a science in itself. Container closure quality is essential
and needs to be demonstrated as an integral part of the
24.3 Closures design of the medicinal product. This task can be most
challenging when thousands of containers need to be reliably
24.3.1 Closure Systems and Functions filled and closed on pharmaceutical packaging lines.
Many different procedures have been developed to test
The container closure system seals the primary container container closure quality:
after filling, protecting the contents from interactions with 1. Dye ingress test: the closed container is submerged in a
the external environment. In the majority of cases, the dye solution. Leaks are more easily detected by the
24 Containers 513
application of external (air) pressure and the addition of a discussed. Delivery devices that are specific for a special
wetting agent to the dye. administration route will be discussed in the chapters on
2. Air leak detection: the closed container is submerged dosage routes and forms.
under water and a vacuum is applied. The addition of a
wetting agent helps in the detection of air leaks.
3. Liquid loss: the filled and closed container is inverted and
24.4.1 Bottles
checked for liquid leaks. Application of a vacuum helps
to identify a poor seal.
A bottle is a “container with a more or less pronounced neck
4. Water vapour permeability: a container is filled with
and usually a flat bottom” [26].
water, closed and stored in a warm and dry environment.
Bottles may be used to package liquid preparations for a
Weight loss by water evaporation is followed. Alterna-
variety of administration routes:
tively, a desiccant is placed inside the container and the
• Oral liquid preparations: oral solutions, suspensions and
closed container is stored in a high relative humidity
emulsions, drops for oral use
environment. Weight gain through moisture is followed.
• Rectal preparations: enemas
This last test is suitable to test tablet blister packaging and
• Dermal preparations: solutions, suspensions and
is the preferred method in USP <671 > Containers -
emulsions for cutaneous use, shampoos
Performance Testing.
• Parenteral preparations: injection solutions, infusion
5. Oxygen permeability: a solution of easily oxidisable drug
solutions
(ascorbic acid, or acetylcysteine) is filled in the container
• Preparations for the eye: eye drops, eye lotions
and the container is closed using nitrogen gas flushing to
• Solutions for irrigation of the bladder, the vagina, for
exclude any oxygen in the head space. At suitable time
wounds
points, containers are sampled and the ingress of oxygen
• Preparations for throat, nose and ear: mouth washes,
can be followed by quantification of drug loss.
gargles, ear drops, nose drops, nasal sprays
The above list is not comprehensive and usually perfor-
• Various: stock containers for base solutions for example
mance testing using selected tests will be sufficient. Many
Different administration routes lead to different require-
variations or combinations of these test methods can be
ments and different designs of bottles. These bottles will
made to tailor a particular packaging system. Testing is
also require different closures and different delivery devices.
performed as part of the product development phase and
This section describes the general characteristics of these
can be a part of container and closure quality testing on
bottles and the materials used to manufacture them. In
incoming materials, or even production process monitoring.
PRODUCTION
Sects. 24.4.2, 24.4.3, 24.4.4, 24.4.5 and 24.4.6 some specific
In small-scale production, it is recommended to request from
bottles are discussed. In Sect. 24.4.19 closures and delivery
the vendor any known data on container closure perfor-
devices are discussed.
mance testing as a container system quality attribute. For
any pharmaceutical application, it is wise to perform
in-house testing of the container closure to validate the 24.4.1.1 Requirements
outcome of the packaging process. All that is needed is a In addition to the general requirements for product protec-
balance and if possible some desiccant. tion (Sect. 24.1.1), handling and carrying information
(Sect. 24.1.2) there are several supplementary requirements
for bottles:
24.4 Packaging Forms • A similar filling opening for all volumes
• Standardized dimensions for the neck of the bottle to
In this section the different types of containers for pharma- enable the use of standard closures and dosage delivery
ceutical preparations will be discussed. Definitions, termi- devices (see Sect. 24.4.19)
nology, functional requirements and materials used for the • A grade mark on the bottle to indicate the fill volume
containers for pharmacy preparations will be dealt with. For glass bottles the Ph. Eur. describes general
Definitions and terminology are taken from the list of specifications. The suitability of the container for the prepa-
standard definitions of the European Directorate for the ration should always be assessed. Type I glass (see
Quality of Medicines (EDQM) [26]. Sect. 24.2.1) is considered to be suitable by the Ph. Eur.
Besides discussing packaging forms such as bottles, for all preparations. Type II glass is not suitable for aqueous
tubes, strips and bags some generally used dosage delivery parenteral products with pH >7. Type III glass is unsuitable
devices (Sect. 24.4.19), child-resistant containers for aqueous parenteral products. These specifications are
(Sect. 24.4.20), containers for arthritic patients based on the potential generation of particles in the solution
(Sect. 24.4.21) and stock containers (Sect. 24.4.18) are also (see Sect. 24.2.1). These guidelines will also apply to other
Table 24.6 Materials of bottles, jars and bags for different pharmacy preparations
Preparation Glass Plastic
I II III PE PP PVC PET
Oral
Liquid + + + + +
Solid + +
Rectal +
Dermala + + +
Parenteral
Liquid, aqueous + +b + + +
Powder; non aqueous +
Ocular
Eye drops + + + +
Eye lotions +
Irrigations
For the bladder + + +
For the vagina + + + +
Ear, nose, throat
Mouth wash, gargle + + + + +
Nose drops, ear drops + + +
Sterile base solution + +b
+ usual/possible
a
Shampoo preferably in plastic
b
Not for solutions with pH > 7
pharmaceutical products which are meant to be free from fitted while wearing gloves. Plastic bottles do not need a
particles (for example eye lotions). pouring ring.
24.4.1.2 Materials
24.4.2 Containers for Eye Drops
Materials generally used for bottles are:
• Glass, transparent or amber; required hydrolytic resis-
In this section the general requirements for eye drop
tance depends on usage
containers is discussed. Various multidose containers and
• Plastic; mainly PET (polyethylene terephthalate), PP
some single use containers are described.
(polypropylene) and sometimes PE (polyethylene)
The most significant advantages of plastic over glass are low
24.4.2.1 Requirements
weight and high fracture resistance. A major disadvantage is
The ideal eye drop container should:
the possible deformation when heated.
• Be easy to handle by the patient
Glass and plastic differ in permeability and interactions
• Deliver only one drop at the time
between the packaging material and contents. Glass is the
• Deliver a reproducible drop size
least permeable to air (oxygen) and liquid. The permeability
• Have a dropping tip that does not damage the eye
increases in the sequence: glass < HDPE < PP < PET.
• Be easy to fill
Glass, PP and PET generally present few interaction
• Have dimensions that are suitable for labelling
problems; HDPE can show adsorption. More material
• Make visual inspection of the contents possible
characteristics are described in Sect. 24.2.
• Allow steam sterilisation when closed (empty as well as
Table 24.6 provides an overview of the materials that are
filled)
being used for packaging different preparations in bottles.
• Be resistant to high (steam sterilisation) and low
The closure on glass bottles is usually made of
temperatures (fridge, freezer)
polypropylene.
• Not release substances into the preparation, not during
steam sterilisation and not during storage
24.4.1.3 Pouring Ring • Not adsorb substances from the preparation
Glass bottles may require a pouring ring (of polyethylene). • Not be permeable to gas or water vapour, not during
To avoid contamination of the bottle, the pouring ring is steam sterilisation and not during storage
24 Containers 515
• Protect the contents against light 24.4.2.3 Gemo Bottle

• Protect the preparation against microbial contamination The Gemo bottle® is named after Georg Moldow, the
during storage designer of the bottle. The bottle consists of several parts:
• Have a tamper-evident closure design a glass bottle (hydrolytic resistance type I), a polypropylene
• Be constructed so that microbial contamination during part with screw thread in which a rubber dropper is attached
usage is prevented and a polypropylene cap (Fig. 24.3). The dropper originally
• Be reliably reclosable in case of multidose containers, or consisted of silicone rubber. As silicone rubber is relatively
in case of single-dose packaging, the closure cannot be easy permeable to water vapour and as it shows strong
reclosed sorption of preservatives, it is replaced in the Gemo bottle
There is currently no eye drop container available for phar- “model Gemo” by halogen butyl rubber. In the ‘model
maceutical preparations that meets all these requirements. Sterillab’ the cap is also sealed with a strip on to the part
Table 24.7 shows which requirements are met by some with the screw thread.
containers. The cap of the model Sterillab has to be turned onto the
Most eye drop containers deliver drops that are too large shoulder of the bottle with the use of a tool. After closure it is
for the absorbing capacity of the eye [27]. The drop size no longer possible to unscrew the cap by hand. The model
varies from 25 to 75 microlitres. The drop size not only Sterillab snap cap has a bottle with a specially formed neck
depends on the type of dropper used, but also on the formula- for the snap cap push fit closure. The closure is pressed with
tion of the preparation. A smaller eye drop volume, from 5 to force onto the bottle using the lever of the closing device.
15 microlitres, provides a sufficient effect. Devices to admin- The container closure integrity of the snap cap bottle is
ister eye drops are discussed in Sect. 24.4.19. Physical factors superior to eye drop bottles with screw thread. The snap
that determine the drop size are also described in that section. cap bottle also stays hermetically closed during steam
sterilisation [30].
The Gemo bottle presents some drawbacks: condensation
24.4.2.2 Eye Drop Bottles for Multiple Use
under the screw cap and possible collapse of the rubber part
Eye drops are mostly dispensed in a multidose container.
as a consequence of steam sterilisation, generation of a
The Ph. Eur. describes that this container should contain a
precipitate and sorption from preparations that contain
maximum of 10 mL [28].
phenylmercuric borate.
Eye drop bottles for multiple use that are suitable for
The condensation as seen with the model Sterillab snap
pharmacy preparations are often composed of a glass bottle
cap disappears within several days and does not influence the
with a rubber or plastic dropper. There are differences in
quality of the product [30].
PRODUCTION
construction and the quality of these parts. In this section
Eye drop bottles with PP screw thread dropper caps lose
three types of Gemo bottles, the Eye drop bottle with a
their closure torque during steam sterilisation. This affects
polypropylene dropper and the Eye drop bottle with a
closure integrity, possibly to such an extent that the steam
Zentrop® dropper will be discussed.
The glass of eye drop bottles has hydrolytic resistance I
or III (see Sect. 24.2.1). Type I glass is preferable and is
most universally applicable. When closing threaded PP caps a closing torque force
Most eye drops that are available as a licensed product is applied. The torque force leads to some deformation
are packaged in a plastic bottle. These bottles have the of the PP thread and the resulting material stress
advantages of low weight and high fracture resistance. How- maintains the closure force. However, being a thermo-
ever, plastic bottles are not resistant to steam sterilisation plastic material the PP becomes soft and deformable
and therefore have to be filled under aseptic conditions. This during steam sterilisation. The internal material stress
is a problem for pharmacy preparation because of extra is relieved and after cooling the initial torque force is
facilities that are necessary for aseptic filling. In addition, lost. To maintain proper closure quality the torque
these bottles should be delivered sterile and free from dust. force has to be re-applied using the appropriate tool
Many pharmacies use a sterile plastic eye drop bottle that after cooling to room temperature. Relating to the risk
is described in the German NRF (see Fig. 24.2) [29]. This of microbiological contamination, any necessary
bottle consists of LDPE (low density polyethylene) to which sealing action after heat sterilisation would only be
no additives are added. The bottle is delivered clean and acceptable for eye drops containing preservatives and
sterile, ready for use. The NRF recommends the use of this with a relatively short shelf life.
bottle for povidone iodine eye drops.
516
Table 24.7 Data about several eye drop containers commercially available
Gemo bottle
Model Sterillab Bottle with Bottle with Zentrop PE dropper
Model Gemo Model Sterillab snap cap PP dropper dropper (Remy) Redipac bottle
Material bottle Glass (I) Glass (I) Glass (I) Glass (I) Glass (III) PP PE
Material dropper part Chlorine butyl rubber Chlorine butyl rubber Chlorine butyl rubber PP Chlorine butyl rubber N.a. PE
Material cap PP PP PP PP PP PP PP
Volume bottle (mL) 10 10 10 10 10 1 and 2 10
Neck bottle Screw thread Screw thread Snap fit Screw thread Screw thread N.a. Push-in
Steam sterilisation (closed) + + + +
No release substances
Bottle + + + + + +
Dropper + + + + + N.a. +
No sorption substances
Bottle + + + + + + +
Dropper + + +
Suitable for phenylmercuric borate + + +
Protection against light + + + + +
Protection against contamination (storage) + + + + + +
Suitable to freeze + + + ? + +
Contents can be well assessed + + + + +
Presence of tamper-evident closure + + + + +
Patient can not remove dropper + + + +
Dropper does not damage the eye + + + +
Easy to drop + + + + + +
+ good, moderate, not, or inferior, ? unknown, N.a. not applicable
J.H Dillingh and J.C. Smith
24 Containers 517
Fig. 24.2 10 mL PE dropper

bottle. On the left: before filling
and closing. Middle: after closing.
On the right: after opening, note
the tamper-evident ring
Fig. 24.3 Gemo bottles: model

‘Gemo’ (a), model ‘Sterillab’ (b)
a
and model Sterillab snap cap (c)
PRODUCTION
b
c
tamper-evident strip
glass bottle polypropylene rubber cap

part with screw dropper
thread
tamper-evident cap
strip
glass bottle A B
Fig. 24.5 Eye drop bottle with polypropylene upper part, front view
(a) and side-view (b)
• Upper part does not collapse as a consequence of steam

sterilisation.
• No precipitation in solutions containing phenylmercuric
Fig. 24.4 Bottle with PP upper part (left) and Gemo bottle model borate.
Sterillab snap cap (right), both with the cap taken off
• No sorption of phenylmercuric borate.
Disadvantages of this eye drop bottle are:
• For closing the bottles a special tool is needed.
sterilisation process becomes an “open” sterilisation process. • The hardness of the material of the upper part, combined
A bottle that can be sterilised hermetically closed is with its shape may damage the eye.
preferable [31]. With open sterilisation it is not possible to • The hardness of the material makes this eye drop bottle
predict what the net effect will be of evaporation of water less suitable for patients having impaired muscle power
from the bottle and condensation of water in the bottle. in their hands such as arthritic patients.
Open steam sterilisation usually leads to a reduction of • The polypropylene becomes weaker during steam
weight of the contents of the eye drop bottle. When open sterilisation. This loosens the screw closure and the
sterilisation cannot be avoided, it is recommended to weigh steam sterilisation tends to become an ‘open-sterilisation
the individual bottles before and after sterilisation as a process’.
check. • Removing the tamper-evident seal of the cap is rather
tough, and sometimes the seal strip breaks during
24.4.2.4 Eye Drop Bottle with Polypropylene removal.
Dropper
This eye drop bottle consists of a glass bottle (hydrolytic 24.4.2.5 Eye Drop Bottle with Zentrop®
resistance type I) and an upper part that consists completely Upper Part
of polypropylene. Due to the stiffness of polypropylene the The Zentrop upper part (Fig. 24.6) consists of a dropper
dropper does not have a round but a flattened shape so that fixed in a screw cap and equipped with a small cap on the
the patient needs less strength to create a drop. The polypro- tip of the dropper. There is no overall cap and no tamper-
pylene cap is sealed with a tamper-evident strip to the upper evident element. The dropper is made from rubber (usually
part (Figs. 24.4 and 24.5). After applying the upper part onto chlorobutyl rubber) or polyethylene. The threaded closure
the bottle using a special tool, it cannot be unscrewed with- and the cap are made from polypropylene.
out this tool, for example by the patient. For larger batches The glass quality of the bottle can be type I, II or III. For
an electrical closing device has been developed. example the Remy® bottles have a type III bottle and are
Advantages of this bottle are: therefore not generally suitable for eye drops.
• Most generally applicable from the point of view of Steam sterilisation should be done with unscrewed cap
incompatibilities. for Zentrop upper parts and precipitation and sorption can
• No visible condensation under the screw cap. occur in preparations that contain phenylmercuric borate.
24 Containers 519
cap
dropper
screw cap
glass bottle
Fig. 24.6 Eye drop bottle with Zentrop upper part
24.4.2.6 Single Use Eye Drop Containers

Containers for single use are necessary for eye drops without
preservative and desirable for eye drops that are only used in
small quantities (local anaesthetics, diagnostics).
A suitable container for pharmacy prepared single use Fig. 24.8 Minims
eye drops is the Redipac® (Fig. 24.7).
A Redipac is a drop container of polypropylene, available Redipacs are produced under GMP conditions. They are
in the volumes of 1 and 2 mL. Redipacs can be steam practically free from dust particles and have a good
sterilised. A Redipac looks like a small tube, flattened on microbiological quality after production. Redipacs are not
one side after closure. After removing the cap the container supplied sterile. When the preparation cannot be sterilised in
cannot be closed properly anymore so that Redipacs are only the Redipacs, the Redipacs should be sterilised empty before
suitable for single day use. The polypropylene material of use. When the Redipacs have become contaminated with
dust particles, for example during pre-process handling,
PRODUCTION
Redipacs is somewhat permeable to water vapour. It is
important to check the amount of water loss by evaporation they should be flushed several times with purified water
through shelf life research. Licensed single-dose eye drops and dried if they are not immediately filled.
are often packaged in small polypropylene containers called Redipacs are filled via the open side, which is closed by
Minims® (Fig. 24.8). heat sealing after filling. The closing device consists of a
The Minims have a more conical design. Another popular metal block with 10 or 8 holes and a closing mechanism. The
packaging material for single dose registered eye drops are filling and closing device for Redipacs is available in a hand
small blow-fill-seal containers from low density polyethylene. operated and a semi automatic type.
production filling and closing patient
Fig. 24.7 Redipac

24.4.3 Eye Lotion Bottles 24.4.4.1 Microenema Bottle

The microenema bottle (see Fig. 24.9) is meant for single-
The same requirements apply to eye lotion containers as for dose enemas with a volume of 3–10 mL. The bottle has a
eye drop containers (see Sect. 24.4.2), with the exception of bellows design and is made from low-density polyethylene.
the requirements to dropping. Eye lotions are usually dis- When compared to a syringe with a rectal cannula, a
pensed in special bottles that are: dust free, of good single-dose enema bottle has the advantage that the dosage
microbiological quality, a volume of 250 mL, equipped to be administered is fixed so that the patient cannot make a
with a hinged lid, made of transparent polypropylene and mistake. A disadvantage is that a small amount of the prod-
resistant to steam sterilisation. Steam sterilisation is only uct remains in the container, requiring an excess fill.
possible when the bottle is ‘open’ (the closure is turned Table 24.8 gives an example of the volumes to be filled for
back once). Therefore, the irrigation solution is exposed to chloral hydrate enemas for different dosages of chloral
an essentially ‘open’ sterilisation process. A disadvantage of hydrate.
the bottle for eye lotion is that it hardly protects from the Small enema bottles are challenging to label. When they
influence of light. When protection against light is required, have a long cap the label can be fixed onto the cap like a flag.
the bottle should be equipped with a secondary packaging. Sticking the label onto the cannula itself has the disadvan-
tage that glue and paper fragments can be left behind. The
bellows design of the small enema bottle has the advantage
that a round label can be fixed onto the flat bottom.
24.4.4 Enema Containers
When emptying the micro enema bottle some liquid
remains in the bottle. Independent of the fill volume this
Containers for liquid rectal preparations range in volume
loss is approximately 1.5 mL of aqueous solutions. When
from several millilitres to approximately 100 mL. The con-
filling the bottle an excess volume is therefore required.
tainer must be equipped with a rectal cannula to administer
When using a more viscous solution the loss in the single
the enema. Enemas can be packaged in enema bags (see
dose enema bottle will be greater.
Sect. 24.4.13.2). These have a longer cannula with which
During storage of aqueous enemas evaporation takes
the enema can be administered deeper into the rectum.
place. Due to this the concentration increases, but the
Another possibility is to package an enema in a syringe on
which a rectal cannula is placed (see Sect. 24.4.16).
As well as the general requirements to containers
(Sects. 24.1.1 and 24.1.2) the following requirements should
be met:
• No migration of product components into the container
• No migration of components of the container (for exam-
ple softeners, stabilizers) into the product
• No sorption of components of the product onto the con-
tainer material
• No permeability to gas or liquid
• Flexibility
• Volume remaining after administration should be repro-
ducible and preferably small
• No respiration (no material from the rectum should go
into the bottle)
• Protection against light Fig. 24.9 Microenema bottle 10 mL
Table 24.8 Filling volume, delivered volume and dose in enema bottle 10 mL, for Chloral hydrate enema 50 mg/mL and 150 mg/mL FNA (see
Table 11.15)
Chloral Hydrate Enema 150 mg/mL Chloral Hydrate Enema 50 mg/mL
Filling volume Delivered volume Dosage Filling volume Delivered volume Dosage
4,5 mL 3,3 mL 500 mg
6,5 mL 5 mL 750 mg 6,5 mL 5 mL 250 mg
8,5 mL 7 mL 1,050 mg 8,5 mL 7 mL 350 mg
11,5 mL 10 mL 1,500 mg 11,5 mL 10 mL 500 mg
24 Containers 521
container is ensured by suitable means. Closures ensure a

good seal, prevent the access of micro-organisms and other
contaminants and usually permit the withdrawal of a part or
the whole of the contents without removal of the closure. The
plastic materials or elastomers used to manufacture the
closures are sufficiently firm and elastic to allow the passage
of a needle with the least possible shedding of particles.
Standard dimensions of infusion bottles and injection
vials are described in ISO-norm 8536.
Glass as well as polypropylene infusion bottles are being
used. For the production of large batches, bottles are filled
and closed on automated ‘filling lanes’. Infusion bags of
polypropylene or polyvinylchloride are also being used
(see Sect. 24.4.13). For glass bottles the quality of the glass
is important, see also Sects. 24.2.1 and 24.4.1.
Fig. 24.10 Enema bottle 100 mL Infusion solutions are administered gradually. Therefore
infusion bottles should have a closure which makes this kind
administered dose does not change much. The water evapo- of administration possible but prohibits the ingress of micro-
ration can measure 5 % of the filled volume after 1 year and organisms and other contaminations at the same time. Rub-
10 % after 2 years at room temperature and should be ber is the most suitable material for this purpose. Infusion
properly addressed during stability studies. bottles are closed with a rubber stopper, fixed in place by
means of an aluminium crimp cap. This provides a more
secure closure than a rubber disk with a screw cap on top.
24.4.4.2 Enema Bottle 100 mL
The quality of rubber stoppers is important in relation to
The 100 mL enema bottle (Fig. 24.10) consists of a bottle
the release of substances or particles into the liquid, the ease
and a cannula of low density polyethylene (LDPE).
with which the rubber can be punctured and the flexibility
The nominal content is 100 mL, the maximal fill volume
around the puncture opening. The most often used material
130 mL. Graduation indicates 50 mL, 75 mL and 100 mL.
is bromine butyl rubber. For oily injections, closures made
The closure consists of 4 parts: a strong screw cap, a flexible
from an oil resistant elastomer (silicone rubber) must be
cannula, a rubber one-way check valve in the screw cap and
used. The Ph. Eur. describes requirements for rubber
PRODUCTION
a cap. The cannula is usually lubricated with vaseline. The
closures [33]. Rubber closures for containers for aqueous
length of the cannula is 52 mm and the top is rounded. Due to
parenteral preparations are classified in two classes: type-I-
the bellows design of the shoulder the bottle can bend which
closures and type-II-closures. Type-II-closures have addi-
makes administration easier. Water loss by evaporation is
tional mechanical characteristics, for example being suitable
relatively small in relation to the fill volume. After adminis-
for multiple piercing.
tration a small volume (<2 mL with a 100 mL enema)
The shelf life of rubber closures for infusion bottles is
remains in the bottle. The enema bottle provides little pro-
limited. Freezing of vials or infusion bottles with rubber
tection against the influence of light, so the bottle should be
stopper can result in damage to the stoppers and reduced
wrapped in aluminium foil or packaged in a secondary
closure quality. A comprehensive shelf life assessment must
container if necessary.
include the integrity of the rubber closure.
Glass and rubber can be the source of visible and subvisi-
ble particles in infusion liquids. Particle numbers are larger
24.4.5 Infusion Bottle and Injection Vials in glass bottles with rubber stoppers when compared to
with Closure infusion bags of polypropylene or polyvinylchloride. Most
particles appear in the production phase during the steam
Intravenous infusion solutions are filled in single-use sterilisation process. The rubber stopper can have the highest
containers. The Ph. Eur. requires that products for parenteral contribution to the particle contamination of the preparation.
administration are dispensed in glass containers or in other The silicone oil that is used in the production process of the
containers such as plastic containers and prefilled syringes rubber stoppers can be the most significant source of the
[32]. The material should be sufficiently transparent to make a particle contamination. To reduce this risk, the quality of the
visual assessment of the contents possible, except for implants silicone oil should be carefully controlled. The stopper
and in other justified and authorised cases. The tightness of the washing and rinsing process is very important and the
number and quality of the rinses should also be carefully A jar can be used as secondary container for single dose
controlled [34, 35]. A good rinsing process is necessary to oral powders in powder paper or sachets, and for
reduce particle contamination of the glass bottles as well as suppositories and pessaries in strips.
the rubber stoppers. The availability of high quality, In addition to the use as primary or secondary container
validated rinsing machines is of vital importance. for the patient, the jar can also be used as a pharmacy stock
Injection vials are mostly glass bottles closed with a container for semisolid and solid intermediate or base
rubber stopper and aluminium crimp cap. The information preparations.
about the infusion bottle in general also applies to the vials. The general requirements for containers apply to jars (see
Injection vials are usually produced from tube glass in con- Sect. 24.1). Usual materials are
trast to the larger infusion bottles from blown glass. • Glass, brown, hydrolytic resistance type III
• Plastic, polypropylene, amber coloured to provide light
protection
24.4.6 Containers for Bladder Irrigations The lid is usually a screw cap of polypropylene, with a
closing rim to provide for a good seal. A snap-on lid can
Bladder irrigation solutions are preferably packed in flexible be a problem for people with a limited function of the hand.
plastic bags, such as urotainers (See Sect. 24.4.13.1). These Glass jars sometimes have Bakelite lids. Bakelite lids
containers enable the product to be administered directly have the advantage that they are resistant to high
from the pack. Bladder irrigation solutions packed in glass temperatures although it may crack during heat sterilisation.
bottles often have to be transferred into another container for The disadvantage of Bakelite is that a liner is needed for a
administration. This process increases the risks of good closure. The liner can provide a growth place for
microbiological contamination during the transfer process. micro-organisms when the preparation contains water. A
Bladder irrigation containers should be tamper evident. To glass jar with a Bakelite lid is a suitable container for
enable this glass bottles are produced with single use “tear- sterilisation of eye ointments in dry heat, 2 h at 170–180 C.
off” crimp seals. Polypropylene bottles are produced with It is quite common for medicines to be sensitive to light.
closures that break away on opening demonstrating that the Therefore it is not recommended to dispense solid dosage
bottle has been opened. forms such as tablets and capsules in a jar that transmits light
(tablet container), despite the possible advantage that the
contents can be inspected for dispensing without taking off
the lid.
24.4.7 Jar In the stability assessment of products packed in plastic
jars attention has to be paid to the permeability to water
A jar is defined as “a container, without a pronounced neck, vapour. Water vapour can migrate to the inside as well as to
with a wide opening at the top and a more-or-less flat the outside. In plastic jars this can occur via permeation
bottom”. Jars are frequently reclosable and generally suit- through the container wall, but it can also occur via the
able for semisolid and solid pharmaceutical forms [26]. An closure. Permeation is dependent on for example the type
important difference between a bottle (Sect. 24.4.1) and a of packaging material and the storage conditions (tempera-
jar, is that the jar does not have a neck. The jar for tablets is ture, relative humidity). In case of aqueous preparations this
named separately as a tablet container. A jar with a sifter top can lead to a concentration change of the active substance. In
is used for powders for cutaneous application. case of solid dosage forms this can lead to an array of
The jar is the primary container for: negative quality changes.
• Solid preparations: tablets and capsules
• Semisolid (dermal) preparations that are too viscous or
too physically unstable to be dispensed in a tube 24.4.7.1 Special Jars
• Suppositories and pessaries that are not filled directly in The ‘Tupo’ and the ‘Dospo’ are polypropylene jars, with a
strips (their primary container); if necessary suppositories moveable piston base and in the lid a small diameter opening
can first be packaged separately in aluminium foil with cap. On the screw cap of the Tupo a cannula can be
• Powders for cutaneous application placed. These jars have the advantages of a tube (small
squeeze-out opening) as well as a jar (no deformation during
usage). The disadvantages compared to a tube are that they
Zinc Oxide Calcium Hydroxide Weak Paste (see transmit some light and that they are more difficult to handle.
Table 12.39) is a relatively unstable water-in-oil emul- Furthermore the patient can unscrew the lid. These jars are
sion that may disintegrate faster in a tube than in a jar, being used in combination with mixing devices Unguator®
because of the pressure in a tube. Therefore this oint- and Topitec® (see Sects. 28.6.8.4 and 28.6.8.3 respectively).
ment is preferably packaged in a jar. They are used as a receiver for the preparation of the product
and also serve as final container.
24 Containers 523
The jar with dose pump, tube with dose pump, pump tube (50 %) in cetomacrogol ointment (Table 12.8) damages the
or dose dispenser is a slim plastic jar (usually polypropylene inside lacquer.
with polyethylene piston), that releases the contents through Aluminium tubes are furnished with an outside lacquer
a pumping mechanism. No propellant is being used. The jar with print if necessary. This outside lacquer should resist the
with dose pump is easy to fill via the base and suitable for preparation as well as in small scale production and during
creams, ointments (not too viscous), gels, solutions for cuta- usage it is difficult to prevent any contact.
neous use and shampoos. The jar with dose pump is avail- Aluminium tubes are filled through the open end that is
able in volumes varying from 50 to 200 mL. This container then folded and closed with tube pliers or filled and closed
is not a tube because it is not made of a compressible with automatic machinery.
material. Plastic tubes have to be heat-sealed, but the reliability of
A sifter-top container (or a powder castor) is a jar that has closing can be problematic with small scale production.
a sifter top (this is a closure with small diameter openings to Plastic tubes also have the disadvantage that the material is
apply a powder onto the skin) and a lid. The sifter-top flexible and slightly permeable to light and air. During use,
container is made of plastic, usually polypropylene. The the plastic tube tends to regain its original shape after
sifter-top container can be filled via the top, after taking squeezing and draws in air at the same time. Therefore
the sifter-top applicator off or via a snap-on base. Sifter- substances that are sensitive to oxidation, such as sorbic
top containers are available in the volumes of 50 and acid, will degrade faster in plastic tubes than in aluminium
100 mL. ones. Drawing in air during use is also disadvantageous from
the microbiological point of view. Plastic tubes are more
environmentally friendly than aluminium ones, also because
24.4.8 Tube no secondary container is necessary.
A tube is a container for multiple doses of semisolid 24.4.8.2 Tube Cap

preparations. It consists of compressible material that is The screw cap of the tube is made from plastic, usually
squeezed to release the contents via an orifice [26]. A prepa- polypropylene and occasionally polyethylene. In addition
ration is better protected against micro-organisms in a tube to the general requirements for containers (see Sect. 24.1)
than in a jar. This is because when removing the product the cap should provide a reliable closure of the tube
from a tube a smaller surface can get contaminated by the (no leakage of the contents). When necessary, the cap should
user. If microbiological contamination has occurred the be able to withstand (heat-) sterilisation treatment.
circumstances in which further microbiological growth can For application of ointments and creams in the anus, a
PRODUCTION
occur are less favourable in a tube than in a jar [36]. This is rectal cannula (see Sect. 24.4.19.12) can be screwed onto the
mainly because there is less oxygen available in a tube than top of the tube, instead of the cap.
in a jar.
Next to the normal tube, there are some special designs: 24.4.8.3 Inside and Outside Lacquer Control
the membrane tube, the pump tube (see Sect. 24.4.7.1) and Pores in the inside lacquer of aluminium tubes allow the
the eye ointment tube (Sect. 24.4.9). preparation to react with the aluminium. The inside lacquer
therefore has to be tested for the presence of pores and
24.4.8.1 Material adherence onto the aluminium. Application of a copper
Tubes for packaging pharmacy preparations are made from sulfate solution demonstrates the presence of pores in the
aluminium or from plastic. Aluminium tubes are made from inside lacquer. The pores become visible due to a rust-
very pure aluminium. The shape is generated by a process coloured discoloration of the aluminium.
called impact extrusion. The formed aluminium is quite hard The resistance of the outside lacquer can be tested using
and brittle and needs an additional heat treatment called an aggressive preparation, for example a cream containing
annealing to make the aluminium capable of being shaped methyl nicotinate appeared to be quite aggressive towards
and folded. Because aluminium has poor chemical resistance the external lacquer.
(see Sect. 24.2.2), aluminium tubes are coated with an inter- Important criteria for tube quality control are detailed in
nal as well as an external coating. The internal coating is Table 24.9. Quality control of packaging is dealt with in
usually made of a mixture of two resins: an epoxy resin and a Sect. 24.5.
phenol-formaldehyde resin. The resin is sprayed into the
tubes and the resulting inside lacquer is dried quickly at 24.4.8.4 Tubes as Stock Container
high temperature. This inside lacquer is resistant to most Besides the function as container for creams, gels and
preparations. Some exceptions are sodium fluoride in an acid ointments for direct patient use, tubes can be used as a
gel and also dimethyl sulfoxide in a high concentration pharmacy stock container for intermediate products. A
Table 24.9 Tube quality control criteria Because of the risk of metal particle release membrane
Attribute Example tubes are not suitable to package eye ointments and eye
Delivery of the tubes Transport container is dry, clean and undamaged ointment base.
Tube material Dimensions
Strength
Tube neck Shape, dimensions 24.4.9 Eye Ointment Tube
Undamaged
Tube shoulder Shape, undamaged Eye ointments and eye gels are packaged in small, sterile
Screw thread Deformations tubes with a rounded cannula. A tube should contain no more
Plastic remnants than 5 g of eye ointment. The tube screw cap should provide
Metal remnants a reliable closure to prevent microbiological contamination
Inside lacquer Regular lacquer coating
[28]. Eye ointment tubes are also regularly used to dispense
Absence of pores
nose ointments and nose gels.
Outside lacquer Regular lacquer coating
Heat sterilisation is possible
Resistance to chemicals
24.4.9.1 Material
Print Colour quality
Eye ointment tubes are manufactured from aluminium or
Resistance to chemicals plastic, similar to the tubes used for dermatological products.
Missing text elements To retain sterility the drawing in of air should be prevented,
Shifted text therefore aluminium is preferred above plastic. The cannula
‘Double’ printing can be made of aluminium or polyethylene. A plastic can-
Global visual Contamination (inside, outside) nula reduces the risk of eye damage when compared to an
control Deformations aluminium cannula. The cap is usually made of plastic, for
Tube cap Presence example polypropylene.
Contamination
Heat sterilisation is possible 24.4.9.2 Sterilisation
Eye ointment tubes should be purchased sterile or should be
sterilised. An aluminium tube is generally not resistant to
special use is as a stock container for eye ointment base for
sterilisation by dry heat and limited resistant to steam
extemporaneous preparations. To use a tube in this way, it
sterilisation, because the outside lacquer may get sticky.
should be resistant to hot air sterilisation 140 C during 3 h
A polypropylene cap and/or cannula of low density-
(see Sect. 24.4.2). In this sterilisation process the tubes are
polyethylene are not resistant to sterilisation by dry heat;
filled to about 90 % of their capacity and placed on their
deformation takes place. The resistance to steam
cap to minimise leakage through the folded closure as much
sterilisation is very limited. Tubes with plastic parts how-
as possible. The tubes should not touch each other other-
ever can usually be sterilised by gamma radiation.
wise the outside lacquer will stick. The 15, 30, 50, 60 and
100 g tubes should only be filled with 12, 25, 45, 50 and
24.4.9.3 Metal Particles
90 g base. Although the standard Ph. Eur. sterilisation
In addition to the requirements for ‘normal’ dermatological
process using hot air is 2 h at 160 C, other combinations
tubes (see also Table 24.9) there are supplementary
of time and temperature are allowed if validated.
requirements for eye ointment tubes. The tube cannula
should be undamaged and metal or plastic particle
24.4.8.5 Membrane Tube contaminants should be absent. Eye ointments should be
A membrane tube is a tube of which the tube orifice is closed checked for the presence of metal particles. These often
by a membrane. This membrane has to be perforated by the originate from the location where the cannula is fixed in
user before using the tube. Therefore the membrane is still the tube shoulder. In case of an aluminium tube this is not
intact when a tube has not been used, providing a tamper- an issue because tube and cannula are made of one part of
evident design. aluminium. In case of tubes with a plastic cannula the inside
In aluminium tubes the membrane is formed by a thin coating is only applied after mounting the cannula, as a
layer of aluminium. In order to perforate the membrane: result of which these tubes rarely release metal particles in
• The aluminium membrane should not be too thick (ease the eye ointment. Finally metal particles can appear in the
of perforation) eye ointment through the opening and closing the cap of
• Metal particles should not be released during perforation tubes with an aluminium cannula. If necessary the methods
24 Containers 525
described in USP can be used to assess the presence (amount The PVC-polyethylene laminate combines the advantages of
and size) of metal particles [37]. both materials: the polyethylene layer is situated on the
suppository side of the laminate en thus prevents the release
of leachables. The laminate has a low permeability to water
24.4.10 Suppository Strip vapour and oxygen.
A strip is defined as a “multidose container consisting of two 24.4.10.2 Identification

layers, usually provided with perforations, suited for To identify suppositories in strips the following options can
containing single doses of solid or semisolid be considered:
preparations” [26]. • Printed suppository forms; the non-transparent side of the
Suppositories can be poured directly into the suppository suppository form is suitable for printing.
strips or into metal molds after which they are packaged • Taping up the suppository strip on the upper side with
separately. Pessaries (vaginal suppositories) are also pack- pre-printed tape; a disadvantage of the use of tape is that
aged in suppository strips. the patient has to cut the suppository forms with scissors
Important requirements for suppository strips are: to prevent the tape being removed from the whole strip.
• The suppository forms should be easy to open • Taping up the suppository strip on the upper side using
• Low permeability to water vapour paper labels with printed text; the advantage compared to
• Low permeability to oxygen the method described before is that paper is more easy to
• Protection against light tear as a result of which identification per suppository is
• No migration of (active) substances from the still possible.
suppositories into the primary packaging layer and no • Application of easy to tear, small printed labels at the
migration of components from the primary packaging bottom of the strip.
layer (for example plasticisers) into the suppository
• Possibility to assess the contents 24.4.10.3 Taping Up
• Ability to print on the surface Taping up a suppository strip at the upper side provides, as
Many users find it difficult to open suppository strips. well as the possibility of identification, the advantage that
Especially for patients with a limited hand function supposi- the suppository form is completely closed. This is advanta-
tory strips are a very difficult container to use (see geous for hygiene and when hygroscopic substances are
Sect. 24.4.21). The pharmacy can help those patients by being processed. Furthermore it minimises the chance of
taking the suppositories out of the forms and package them crumbling of the suppositories on the upper side and it
PRODUCTION
in a jar. prevents the loss of contents when they are inadvertently
Suppositories in strips are dispensed in a cardboard fold- exposed to high temperatures (for example in the doctor’s
ing box or in glass or plastic jar (see Sect. 24.4.7). bag).
24.4.10.1 Material 24.4.10.4 Pharmacy Suppository Strips

Some of the requirements contradict each other, so it is Suppository strips used for pharmacy preparations usually
difficult to meet all the requirements. To protect against contain 12 suppository forms per strip. They are available in
light non-transparent plastic is necessary. A printed text the volumes of 1.15 mL (for small children), 2.3 mL and
can be read better on a non-transparent plastic. Non- 2.8 mL. Although other plastics are possible, many supposi-
transparent plastic however hinders the possibility to assess tory strips are made of PVC-polyethylene laminate: the
the contents of the suppository forms. Pharmacy-filled sup- PVC-layer is situated on the outside of the forms and has a
pository strips therefore often have a layer of transparent thickness of 95 μm, the polyethylene layer is situated on the
plastic on one side and a layer of non-transparent plastic on suppository side of the forms and has a thickness of 75 μm.
the other side. The secondary container should thus protect The suppository forms are opened with the peel-off
against light if necessary. method: at one side of the suppository form there are two
Suppository strips for pharmacy preparations often con- ‘flaps’ that can be hold between thumb and forefinger. By
sist of a PVC-polyethylene laminate: PVC has the advantage tearing the flaps apart the form is opened on the sealed seam.
that it shows relatively little permeability to water vapour Quality control on incoming suppository strips should
and oxygen. It has the disadvantage that it always contains include checks on fill volume, ease of opening and
softeners that could migrate into the suppository. In the case contamination.
of polyethylene the permeability to water vapour is compa- As a secondary packaging for the suppository strips carton
rable to that of PVC, but the permeability to oxygen is folding boxes are available. The format 115 19 55 mm
greater. The used polyethylene does not release additives. is made for 1–2 strips of 6 suppositories; the format
115 37 55 mm is made for 3–4 strips of 6 suppositories. 24.4.13 Bag

On the reverse side of the specialised folding boxes there are
instructions on how to open the suppository forms. A bag is defined as: “container consisting of surfaces,
whether or not with a flat bottom, made of flexible material,
generally closed at the bottom and at the sides by sealing; at
the top possibly to be closed by fusion of the material,
24.4.11 Blister Pack
depending on the intended use. Equipped with special
attachments” [26].
A blister pack or strip is a container with a foil that is
Plastic bags can be used to package medicines. They are
shaped so that it can contain separate dosages [26]. An
primary containers for sterile irrigations, intravenous infu-
aluminium lidding foil closes the form foil. Blisters are
sion solutions, blood transfusion and enemas. For these uses
mostly used to package tablets or capsules. For blister
special attachments are necessary such as luer-lock catheter
packs a form foil of PVC or laminate of PVC/PVDC
connector sites or rubber puncture sites.
(polyvinylidene chloride) is used. The form foil is warmed
When labelling plastic bags the quality of the label glue
in a blister machine and a mold station makes round or
should be assessed. Some types of glue can react with the
capsule-like pockets with compressed air. PVC is perme-
bag plastic. Glue components may migrate into the bag and
able to water vapour and therefore not suitable for tablets
plastic components may migrate into the label and affect the
or capsules that are moisture sensitive. To package such
appearance of the label.
products the PVC form foil should include an outside layer
Plastic bags should be flexible and for most applications
of PVDC. PVDC permeates less water vapour. Dependent
sterilisable. PVC can be sterilised at 121 C. A disadvantage
on product sensitivity to moisture, different PVDC-
is that PVC is relatively permeable to water vapour. To resist
thicknesses can be chosen. When complete resistance to
product water loss the bags have to be enclosed in an
water vapour is necessary a form foil that consists of a
overwrap that is less permeable to water vapour, for example
formable aluminium laminate (consisting of polyamide,
a laminate material of nylon with polyethylene.
soft aluminium and PVC) has to be used.
Plastic bags provide little protection against light. The
Some patients have objections against blister packs
bag has to be overwrapped in aluminium foil or enclosed in
because they are difficult to open, they can be rather large
an opaque container in order to prevent light transmission.
and form a load on the environment [38].
Tubes connected to the bag, such as giving sets, may be
transparent to light, which may lead to degradation of the
medicines flowing through them. In order to prevent this
24.4.12 Powder Paper from occurring black coloured plastic tubes have been devel-
oped. Yellow and orange tubes will also provide limited
Single dose oral powders are dispensed in powder paper or protection against light.
sachets. For the packaging of single dose powders, paper
qualities of 40–120 g/m2 should be used. Powder paper must 24.4.13.1 Irrigation Bag
not be contaminated, should not shed fibers and there should Plastic irrigation bags are used to contain irrigation solutions
be minimal variance in weight per area (¼ constant powder for the bladder or solutions for continuous ambulant perito-
paper weight) within each batch. neal dialysis (CAPD). The Ph. Eur. requirements for
The constant paper weight distribution is important when containers for sterile irrigations [39] are the same as those
the weight distribution of single dose oral powders is deter- for parenteral solutions (see under Infusion bag), with the
mined on the powders/paper combination. When the paper addition that intravenous administration systems should not
weight is not constant the batch can be unjustly rejected fit onto the connection site. Small bags for bladder
based on an out of specification weight distribution. irrigations usually have a volume of 100 mL. They have a
The primary container powder paper is always enclosed tube with a catheter connection site. By carefully squeezing
by a secondary container. This can be: the bag, the irrigation for the bladder is administered. After
• A cardboard folding box an appropriate time span the irrigation solution is allowed to
• A jar (see Sect. 24.4.7) flow back in the bag and be disposed of. Bags for CAPD are
• A plastic bag, for example a Minigrip®-bag larger than those for irrigations for the bladder. CAPD-bags
(polyethylene) also have a tube with a catheter connection site.
The choice of the secondary container is dependent on the
extent of protection that the second package layer should 24.4.13.2 Enema Bag
offer. When extra protection against influence of moisture is In addition to being packaged in bottles, enemas can also be
needed, a glass jar can be used. packaged in enema bags. Enema bags can contain a volume
24 Containers 527
of 50–125 mL. Small scale filling can be achieved by the use usually colorless, except for preparations that contain
of a syringe. The bag can be rolled up during administration extremely light sensitive substances. For those preparations
so that a one-way valve needed for enema bottles is not there are ampoules of (amber) coloured glass. For parenteral
necessary. When the disorder is located more distal in the preparations the glass has to be of hydrolytic resistance
rectum an enema bag is preferable to an enema bottle type I (see Sect. 24.2.1).
because the long administration tube of the bag makes it Glass ampoules have the disadvantage that upon opening
possible to administer the enema solution to that part of the glass particles can fall into the solution. To minimize the
rectum. creation of glass splinters on breaking, ampoules with dif-
ferent break augmenting systems have been developed:
24.4.13.3 Infusion Bag – Ampoules with a ceramic break band: the break ring in
For infusion bags PVC and PP are used. PVC- as well as the neck of the ampoules are made with a ceramic paint,
PP-bags can be steam sterilised. Infusion bags have to meet which shrinks faster than glass during the cooling pro-
the requirements of the Ph. Eur. for containers for parenteral cess. The tension that arises thus eases breaking.
preparations [32]. The Ph. Eur. also describes a test for the – Ampoules with a score-ring: these ampoules have a notch
release of phthalates (plasticisers) from the PVC. This test that is applied around the ampoule. To further ease break-
has limitations and does not seem to predict every practical ing plastic ‘ampoule breaker’ caps are available.
situation; in practice the release may be much higher than is – OPC (one point cut): ampoules are cut at one point of the
predicted by this test [40]. break ring. On the place of the notch a coloured dot is
applied on the upper part of the neck of the ampoule.
24.4.13.4 Bag as Container for Oral Dry Dosage OPC-ampoules give the least chance of glass splinters if
Forms the correct breaking technique is used.
Automated dispensing systems (ADS) package tablets and Most plastic ampoules are from the blow-fill-seal types of
capsules into a mini bag printed with all necessary patient containers. These containers are formed, filled and closed in
information. The medicines inside these minibags are to be one production lane and are therefore not available as an
taken by the patient at a certain point in time. The minibag empty container for small scale filling. Some of these plastic
should be easy to open, for example by an elderly person containers are known as bottle-pack. These plastic
with impaired hand function. containers are designed for sterile liquid pharmaceutical
Single-dose oral powders in powder paper can be pack- preparations, which can be opened by tearing, screwing or
aged in a plastic bag with a clip. Single-dose oral powders perforating. The bottle-pack-assortment contains a wide
can also be packaged in small sealed pouches from a lami- range of containers from ampoules to bottles (1–1,000 mL).
PRODUCTION
nate foil material including an aluminium layer. These pri-
mary containers are called sachets. Next to the use as 24.4.14.2 Unit-Dose Cup
primary container, bags are also used as secondary This container (see Fig. 24.11) is meant to package single
container. doses of oral liquid preparations, for example methadone
mixture. The unit-dose cup consists of a polypropylene
24.4.14 Single-Dose Containers (Miscellaneous)
Many containers described in this chapter are meant for

packaging a single dose, for example an infusion bottle or
a bag containing a bladder irrigation. There are some pack-
aging types that are specially designed for packaging single
doses: ampoules, Minims, Redipacs and the ‘unit-dose cup’.
Minims and Redipacs have been discussed already in the eye
drop containers Sect. (22.4.2.6). Ampoule and unit-dose
cups will be discussed in this section.
24.4.14.1 Ampoule
An ampoule is a container that is closed by melting or fusing
and can only be opened by breaking [26]. Ampoules are used
as containers for small volume injection preparations; the
volume of an ampoule can vary from 1 mL to 20 mL. An
ampoule can be made of glass or plastic. Glass ampoules are Fig. 24.11 Unit-dose cup
container of 15 mL volume, with a pointed top that is broken Several systems for dosage syringes are commercially
off to open the cup. The cup is filled through the open available (Oral-dose, Rectal dose, Baxa® and Dose-pac®:
bottom; the bottom lid is pressed on after filling and cannot Fig. 24.12).
be opened thereafter. These systems consist of:
• A polypropylene screw cap with hinge lid and syringe
connecting orifice, fitting onto a bottle with a 28 mm
24.4.15 Syringes opening
• A polypropylene syringe with calibration; larger volume
Syringes consist of a piston and a barrel with a measuring syringes can be used
scale. They are usually made from plastic, the piston can • A cap
contain a rubber part. Plastic syringes with a one-piece plastic Using 1 mL dosage syringes it is possible to dose parts of
piston, without a piston rubber, are called two part syringes. millilitres. The dosage accuracy increases with increased
Three part syringes are equipped with a piston rubber part. A degree of filling (see Sect. 29.1.7). The Baxa-system also
syringe can be used as such, for example to administer oral offers a rectal cannula. An important difference between the
preparations. An administration device can be necessary: a systems is the type of syringe connecting orifice. This is
needle for the administration of parenteral preparations or a non-luer with the Baxa-system and luer with the Dose-pac.
rectal cannula for the administration of rectal preparations. Non-luer is preferable as non-luer syringes do not connect to
To connect the needle the syringe is usually provided with a needles or infusion tubing, reducing the risk of accidental
so-called luer nozzle (see Sect. 13.10.2). For other adminis- parenteral administration.
tration routes (oral, rectal) it is preferable not to have a luer Alternatively an adaptor can be used. This is a small plug
nozzle (‘non-luer’) to prevent accidental parenteral adminis- which is pushed into the neck of the bottle when the screw
tration of non-parenteral preparations [41]. For the measure- cap is placed.
ment uncertainty of syringes see Sect. 29.1.7. Before dispensing a prefilled syringe from the pharmacy
it should be provided with a secondary container. A suitable
container is a plastic box or a special plastic case of which
24.4.16 Oral and Rectal Dosing Syringe the length can be adapted to the length of the (pulled out)
dosage syringe.
A syringe can be used to accurately dose a few millilitres of a
liquid preparation. Specially designed bottle caps can be
employed as a dispensing aid, with the syringe nozzle fitting 24.4.17 Syringe for Parenteral Administration
the orifice in the bottle cap (see Fig. 24.12). The filled
syringe can be closed using a cap. Syringes for parenteral administration are delivered sterile
Sometimes, the pharmacy or an institution dispenses the and separately packaged. The maximum contents can vary
required dose in a pre-filled syringe closed with a cap. from 0,25 mL to 140 mL. The barrel and the piston rod
For rectal administration of enemas the syringe is usually consist of polypropylene, although other plastics
equipped with a rectal cannula. In this way a single strength and also glass can be used. The rubber piston consists of a
solution can be administered in varying volumes. synthetic rubber material. The nozzle of the syringe is luer or
Fig. 24.12 Dosage syringe with screw cap (a) and mounted on a bottle (b)
24 Containers 529
luer-lock. Dependent on the additives to the polymer system or provided separately. There are devices that are
materials syringes can be sterilised with ethylene oxide mounted on a bottle, a tube or a syringe. To enable flexibility
gas, gamma radiation or steam. of use – important with pharmacy preparations –both parts of
All plastic syringes contain silicone oil to ensure easy and the assembly should preferably be standardised. Many deliv-
smooth piston movement. The amount of silicone oil is ery devices are available for bottles, but there are fewer for
limited in the Ph. Eur. and production standards such as tubes and syringes. The delivery devices are discussed per
ISO 7886. route of administration. Devices for parenteral administra-
For parenteral use sterile syringes have to be filled asepti- tion are discussed in the chapter on parenteral preparations
cally (see Sect. 13.8.3) usually just before use. By filling the (Sect. 13.10).
syringe in the pharmacy under controlled circumstances of
aseptic handling (see Sect. 31.3) the (microbiological) shelf 24.4.19.1 Delivery Devices for Dermal
life can be extended. The filled syringe is closed with a sterile Preparations
cap. Various semi-automatic pump systems are available that To apply a preparation onto the skin the closure of a bottle or
can support the aseptic filling of sterile syringes. a jar can be provided with a:
The administration of infusion solutions employing a • Dabbing applicator
syringe pump is a common technique in hospitals. Because • Roll-on applicator
of the controllable infusion speed accurate, but flexible dos- • Brush
ing is possible. In most cases a 50 mL syringe is used on • Spatula
syringe pumps. • Liquid dispensing cap (for example flip top caps with
spray orifice)
• Sifter-top applicator
24.4.18 Stock Container A dabbing or roll-on applicator is in contact with the prepa-
ration and may release particles or leach substances.
For stock containers in pharmacies the same requirements A jar can be provided with a sifter-top; usually the jar and
apply as for primary containers for patients (see Sect. 24.1). the sifter top form one unit (‘sifter-top container’ [43]),
From the quality and logistic point of view it is preferable which is filled from the bottom (see also Sect. 24.4.7.1).
to fill a product directly in a patient container. Storage in a
stock container has the following disadvantages: 24.4.19.2 Delivery Devices for Oral Preparations
• After opening a maximum period of use should be taken A glass bottle needs a pouring ring when a liquid is to be
into account; this shelf life is restricted by the poured out of it. For oral preparations the delivery device is
PRODUCTION
microbiological, chemical and physical vulnerability of dependent on the amount that has to be taken per dose. For
the product. amounts of 5 mL and more a measuring spoon or cup is used.
• More time and material is used than if the preparation is For dosages less than 5 mL a measuring syringe is suitable
filled directly into a patient container. (see Sect. 24.4.16). Although dosing in parts of millilitres is
In some cases it is necessary to fill the preparation in a stock preferable to dosing in drops there is a series of droppers and
container, that is: pipettes available. If necessary the cap can be replaced by a
• With intermediate or base preparations, for example a child-resistant cap (see Sect. 24.4.20).
base solution, a base cream or an (eye) ointment base
• When the preparation will be dispensed in widely varying 24.4.19.3 Measuring Spoons and Cups
amounts A relatively large volume of an oral liquid can be
• To save storage space administered with a measuring spoon or cup (polypropyl-
When a preparation is kept in a stock container the size of ene). Dosing in kitchen spoons (teaspoon, spoon, tablespoon
the batch and the volume of the container should be related and dessertspoon) is relatively inaccurate and is preferably
to the usage period and to the number of uses. In general it is replaced by dosing in millilitres.
recommended to choose the volume of the ‘stock container’
in such a way that it only has to be opened about ten times 24.4.19.4 Dropper and Pipette
before it is empty. If a preparation is dosed in drops rather than millilitres, the
bottle has to be equipped with a pipette, or a dropper cap, or
a dropper insert, or a spout cap. The Ph. Eur. describes
24.4.19 Dosage Delivery Devices requirements with regards to the dose and the reproducibility
of the dose [42]:
For the administration of preparations the use of a delivery • The dropping speed does not exceed two drops per
device might be necessary. These can be part of the package second.
• The average of 10 doses of drops does not deviate more pipette, graduated pipettes for measuring millilitres are
than 15 % of the nominal dose. available: for example a pipette with a graduation of
• Out of 10 weighed doses no single dose deviates more 0.2–1.5 mL with a subdivision in 0,1 mL.
than 10 % of the average dose. Plastic pipettes are preferred to glass pipettes, because a
plastic pipette is unbreakable and weighs less.
The dropping pipette gives a more reproducible drop size
Drop Size
than the dropper insert.
The size of a drop is defined by:
• The type of drop bottle (the diameter of the outflow
opening) 24.4.19.6 Dropper Insert
• The method of dropping (passive outflow or A dropper insert is a dropping mechanism in the neck of the
squeezing in (a part of) the bottle) bottle (see Fig. 24.13). Many dropper inserts turn out not to
• The type of preparation (aqueous or oily) and the meet the requirements of the Ph. Eur.: the dropping speed is
formulation of the preparation (the surface tension too high or they don’t provide drops at all. The reproducibil-
of the liquid) ity of the drop weight is often poor. The drop size appears to
• The temperature of the liquid depend for example on the angle at which the bottle is held
• The angle at which the bottle is being held and on the amount of fluid in the bottle.
• The fill level of the bottle (this regards certain
droppers)
24.4.19.7 Spout Cap
The drop size is represented by the following formula:
A spout cap is a dropping mechanism on top of the neck of
m ¼ 2 π r τ=g ¼ π d τ=g ð24:1Þ the bottle. The most frequently used spout cap is the Zentrop
dropper. This consists of a chlorobutyl rubber dropper
in which m ¼ mass of the ideal liquid drop (kg), r ¼ mounted in a polypropylene screw cap and closed with a
the radius of the outflow opening (in m), d ¼ the small polypropylene cap. In case of incompatibility of the
diameter of the outflow opening (in m), τ ¼ the sur- liquid with the chlorobutyl rubber a Zentrop cap with a
face tension (N/m) and g ¼ the gravitational constant polypropylene dropper can be used.
(9,807 m/s2). This simplified formula should be The reproducibility of the drop size of the Zentrop drop-
expanded with a factor that corrects for the shape of per is poor. Both the amount of fluid in the bottle and the
the drop. The effect of the temperature on the size of angle under which the bottle is held seem to influence the
the drop is caused by the temperature dependence of drop size. However, to preserve the microbiological quality
the surface tension: the surface tension drops when the of the product a closure with a Zentrop upper part is prefera-
temperature rises. From this formula can be seen that ble to a closure with a pipette. For the use of the Zentrop
for different droppers, for caps with pipettes (with dropper as an eye drop device see Sect. 24.4.2.
different outflow openings) and for different liquid
pharmaceutical preparations (different surface ten-
sion) the drop weight of the pharmaceutical prepara-
tion in the drop bottle to be dispensed has to be
determined, so that with the help of this weight the
dose in drops can be calculated.
24.4.19.5 Screw Caps with Dropping

or Measuring Pipette
The bottle cap with a pipette consists of a glass or plastic
pipette mounted in a polypropylene screw cap. With the
dropper bulb air is squeezed out and liquid drawn in. The
liquid is administered drop by drop. The dropper bulb is
made from chlorobutyl-, bromobutyl rubber or from natural
rubber. The use of chlorobutyl- or bromobutyl rubber is
preferable to the use of natural rubber (see Sect. 24.2.4).
The cap and the dropping pipette are available in different
dimensions to suit the bottle. In addition to the dropping Fig. 24.13 Dropper insert on a 25 mL bottle
24 Containers 531
24.4.19.8 Supporting Devices

for the Administration of Eye Drops
and Eye Lotions
Due to the vulnerability of the eye some specific
requirements apply to the dropper system used for the
administration of eye drops. The combination bottle/dropper
is discussed in the paragraph on eye drop containers
(Sect. 24.4.2). The handling of an eye drop bottle can present
problems, for example for people with trembling hands. A
supporting device can help to drop successfully. The choice
of device depends on the type of dropping bottle the
patient uses.
For eye drop supporting devices the following
requirements apply:
• User friendliness
• Applicable to as many different bottle designs as possible
• Designed to direct the drop to fall into the conjunctival Fig. 24.14 Squeeze spray bottle (a) and nasal spray pump (b) for
sac and not in the middle of the eye spraying liquid into the nose
Some examples of eye drop supporting devices:
• Autodrop® and Eyot®: these suit most plastic eye drop Unpreserved nose drops should be packaged in single-use
bottles and are advised to people who have trembling or containers. The Redipac is suitable for this (see Sect. 24.4.2.6).
weak hands and who have difficulties in keeping the eye Non-viscous liquids can be sprayed into the nose as an
open while dropping. These devices also help to position alternative to drops. To aid this type of administration two
the bottle. types of containers are available: squeeze spray bottles and
• Autosqueeze®: this device also suits most plastic eye nasal spray pumps (see Fig. 24.14).
drop bottles and is meant for patients who have problems In case of the squeeze spray bottle (LDPE) the nasal spray
holding and squeezing the bottle. The patient can use it in fluid is sprayed by squeezing the bottle. The administered
combination with the Autodrop. dose depends on the squeezing force and the level of the
• Dripaid®: this device is meant for glass eye drop bottles liquid in the bottle. Because of inaccurate dosing, these
with polypropylene dropper. bottles are not suitable for the administration of highly active
PRODUCTION
• Some other devices exist which are specifically devel- medicinal products. When using the simple squeeze bottle
oped for a special type of eye drop bottle [44]. there is a chance the spray fluid gets contaminated with nasal
For the administration of eye lotions an eye irrigation cup is mucus. The patient has to keep the bottle squeezed in until it
used. This has to be cleaned after every use and stored in a is removed from the nose.
dry place. The nasal spray pump consists of a pump mechanism
with a spray nozzle mounted on a bottle. A dose is sprayed
24.4.19.9 Devices for the Administration of Nose by pressing the pump mechanism. During the first few pump
Drops and Nasal Sprays actions only air is delivered from the nozzle as the pump
Nose drops are dispensed in a bottle with a dropper cap or mechanism fills with liquid. The amount of liquid that is
dropping pipette. A dropping pipette is more practical sprayed per pump action is independent on the pump force or
because the correct dose can be measured in advance. The the liquid level. This results in accurate, reproducible dos-
pipette is preferably made of plastic instead of glass due to ing. The bottle needs to be in the upright position when the
the risk of breakage. The pipette should have a rounded tip to pump mechanism is released for a new dose to be drawn
minimize the risk of damage to the nasal mucosa. The use of from the bottle. The nasal spray pump is best used with the
a pipette is disadvantageous from a microbiological point of patient in the sitting position.
view. Without proper washing or wiping, mucus with micro- The nasal spray pump is less vulnerable to
organisms from the nose can be transferred into the nasal microbiological contamination of the spray fluid.
drops. Providing good instructions to the patient can reduce
this risk. The use of a spout cap to administer nose drops 24.4.19.10 Devices for the Administration of Ear
reduces the chance of contamination of the dropping fluid. Drops
The probability of microbiological contamination of the Non-sterile ear drops are dispensed in a bottle with a pipette
dropping fluid limits the in-use stability of (preserved) nose or dropper cap. Sterile ear drops are packaged like eye drops
drops to a maximum of 3 months (see Sect. 22.7). (see Sect. 24.4.2).
24.4.20 Child-Resistant Closure
The requirements for the ideal child-resistant container are:

• The container cannot be opened by children.
• The container is not too difficult to open by adults (espe-
cially elderly and handicapped people).
• The container is easy to close effectively.
• The closure continues to function appropriately, even
after frequent use.
There are international standards for child-resistant
containers, detailing the characteristics and tests they have
to withstand. In the European Union two standards are
applicable:
• ISO 8317 (2004) for reclosable child-resistant containers
for pharmaceutical products.
• EN 14375 (2003) for non-reclosable child-resistant
containers for pharmaceutical products.
The two standards describe the quality requirements for
child-resistant containers as well as their validation.
Fig. 24.15 Vaginal irrigator For a reclosable child-resistant container the screw-press-
principle is the most widely used. A combination of actions
24.4.19.11 Devices for the Administration (pressing and unscrewing a cap at the same time) is very
of Vaginal Preparations difficult for a child.
To administer vaginal creams a separate device, the vaginal Examples of non-reclosable child-resistant containers are
applicator, is available. This syringe-like device has a nozzle sachets and blister packages. These require a pincer-like
that fits onto tubes with a screw thread. The material of the movement with thumb and forefinger to open the package.
applicator cylinder is transparent polyethylene. The applica- This movement is difficult for a child to perform. However,
tor is intended for single use, but can be cleaned with hot it cannot be concluded that all sachets and blister packages
water. The applicator nozzle is mounted onto the opened are child-resistant. As it would necessitate a great deal of
tube, the applicator piston pushed onto the tube. The appli- work to validate all strips to the ISO-standard some general
cator is filled by squeezing the tube. When the applicator is (mechanical) properties are required to which the strip,
filled completely (a volume of about 7,5–8 mL) it contains sachet or blister package has to comply in order to be
approximately 5 g cream. child-resistant. Examples are the non-transparency of the
Irrigations for the vagina can be administered with an material and a sufficient tensile strength of the foil. ISO
irrigator. This consists of a plastic bottle with a long cannula 13127 (2012) describes mechanical tests which can be used
mounted on the top. This cannula has holes in the sides and to demonstrate the child resistance of some packaging fol-
with some designs the cannula is bent at an angle of 45 . The lowing minor modifications to existing child resistant
solution irrigates the vagina through the holes in the cannula containers.
when the bottle is squeezed (Fig. 24.15).
24.4.19.12 Devices to Administer Rectal

Preparations 24.4.21 Containers for Arthritic Patients
Administration of liquid rectal preparations requires a
squeezable bottle (see Sect. 24.4.4.1), a bag (Sect. 24.4.13.2) For patients with impaired hand function, opening of
or a syringe (see Sect. 24.4.16), with a rectal cannula (see containers can be a problem. The needs of this patient
Fig. 24.10). This cannula is preferably of flexible material group are not always suitably addressed [39, 45]. Pharmacy
to prevent damage to the rectal mucosa. This is less impor- preparations or repackaged products for arthritic patients
tant with short cannulas than with long ones. An enema bag should be dispensed in suitable containers. The container
has a long flexible tube cannula. This cannula should be should be:
lubricated or should be made of slippery material to ease • Easy to hold (not too small)
insertion. The cannula should have a rubber one-way check • Easy to open (no ‘precision handlings’ should be
valve when respiration is possible (with enema bottles, necessary)
not with enema bags). • Unbreakable
24 Containers 533
The most significant containers that arthritic patients have provide sufficient grip and the action needed to open the strip
difficulties with are those for tablets, capsules and is too precise. An alternative the pharmacy can offer is to
suppositories. remove the suppositories from the strip and repackage them
in a jar. When necessary the separate suppositories can be
24.4.21.1 Tablets and Capsules wrapped with some aluminium foil.
A blister package containing tablets or capsules is difficult to
open, or cannot be opened by an arthritic patient. The blister
packages that consist completely of aluminium give most 24.5 Quality Control of Packaging Materials
problems. Blisters with lidding foil that can be peeled off are
easier to open, except when the patient mistakes them for a 24.5.1 Quality Assessment
push-through lidding foil [39].
There are tablet presser devices available where a patient The quality control of containers is different to the quality
with limited hand strength can press the tablets out of a control of raw materials. Raw materials as powders or
blister package. Alternatively, the lidding foil can be cut solutions are homogeneous, so a small sample is representa-
open using a so-called Blisterpack Pen/Pill-pen. The phar- tive of the entire population. When the analysis of a raw
macist can also press the tablets or capsules out of the strip materials sample reveals a quality issue this problem gener-
for the patient and, provided that the storage conditions ally applies to the entire batch. Containers however are
allow it, pack them in a jar with a screw cap. discrete units and a sample container may not be representa-
Some easy to open screw caps for patients with reduced tive of the entire batch. For example a crack in a bottle
hand function have been designed (see Fig. 24.16). The sample does not mean that all the remaining bottles in the
bottle and cap are usually made from unbreakable polypro- batch will be cracked.
pylene. Special cap features are usually a larger size and ribs A sampling plan for attributes is a method to overcome
to provide a better grip. Some caps have projections that this problem. An example of such a plan is the Accepted
made it possible to open the bottle with, for example, a Quality Level system (AQL) (See Sect. 24.5.4. for a more
pencil. complete description of AQL and Sect. 20.4.5 for a statistic
background). In order for the AQL system to be successful
24.4.21.2 Tubes an extensive and statistically planned random sample has to
Tube caps should be large enough and should not have a be selected. The defects that are found are classified into
smooth or sharp surface. Filled or semi-filled aluminium levels, for example: critical, major, minor. Within each level
tubes are more difficult to squeeze by arthritic patients than the system defines an ‘acceptable quality level’. When a
PRODUCTION
plastic tubes. quality level is exceeded, then a batch should be rejected.
This method of testing requires time and expertise. Sampling
24.4.21.3 Suppositories has to be performed from a large number of containers from
Suppositories in strips pose an impossible barrier to patients the same batch. Within the pharmaceutical industry it is
with limited hand function. The container is too small to often necessary for such tests to be carried out by the con-
tainer manufacturer. For smaller enterprises such as
pharmacies quality control can be undertaken by the whole-
saler or an independent laboratory. Within a (hospital) phar-
macy the quality control is often limited to a visual
comparison to reference samples and a check of the presence
of the supplier’s statement that the containers comply with
the agreed specifications [46].
24.5.2 Defining Quality Requirements
In order to perform quality control the quality requirements

or parameters should be known. cGMP regulation demands
that the characteristics of containers important for product
quality are defined in specifications [5]. The Ph. Eur.
describes general requirements for some packaging types
and materials (glass, rubber and various plastics).
Fig. 24.16 Easy to open design of a tablet bottle Specifications for containers are more specific for individual
containers and include the shape, dimensions, printing and about their quality system. For complete testing an
the relation between different parts of the container (for AQL-system can be used.
example the closure of a rubber stopper on a bottle). Con-
tainer specifications can be requested from the supplier.
When specifications are not properly defined, they can be
24.5.4 AQL-system
an ongoing source of misunderstanding between supplier
and the purchasing pharmacy. It is essential that the quality
The AQL-system is a sampling and assessment system fre-
control department creates an archive of reference samples.
quently used to check containers. It is a type of attribute
Reference samples can be seen as a physical part of the
assessment, see Sect. 20.4.5 for statistical background. AQL
container specification. In addition to specifications the qual-
means Acceptable Quality Level. The AQL-value is the per-
ity control of containers demands an assessment protocol.
centage of rejected units accepted by a supplier or buyer to
This assessment protocol describes which tests have to be
approve the concerned batch. Tables are available which
done and how they have to be performed.
describe, for a certain batch size N and an agreed
AQL-value, how large the test sample n should be and how
many units of that sample are allowed to show a specific defect
24.5.3 Incoming Container Material Control
The AQL-system classifies defects in classes:
• Class 1 defects (critical defects): These are defects that
The quality control of incoming containers includes a receipt
have a negative effect on the contents of the container and
check and an attribute assessment. The receipt check
result in a possible danger to the user. For example, glass
consists of:
splinters in a bottle. A defect in this class makes the
• Checking the delivery note against the order information.
container unsuitable for use. Class 1 defects can be
This confirms whether the delivered materials correspond
subdivided into:
to those ordered.
– Class 1a defects: very dangerous defects
• Checking the condition of the transport container. This
– Class 1b defects: dangerous defects
confirms that the correct transport container was used,
• Class 2 defects (major defects): These defects can impair
that the outer transport container is dry, free from dirt,
the use of the container material and can lead to
undamaged and the label information is correct.
complaints by the user. For example: holes in the outside
The attribute assessment determines whether the container
lacquer of the tube.
materials meet the specifications. A risk assessment should
• Class 3 defects (minor defects): These defects reduce
be performed to determine what level of quality assessment
the quality of the product. For example: a small shift of
needs to be undertaken. This risk assessment should take
the print on the product. A defect in this class either has
into consideration the level of quality assessment performed
no effect or hardly influences the usefulness of the
by the manufacturer or supplier. For example, if the manu-
product.
facturer has a limited quality assessment system, then the
All types of container defects should be defined and
purchaser may be required to carry out an extensive number
allocated into one of these classes. For every defect class
of checks. An audit of the manufacturer is the best way to
an AQL-value is agreed between the purchaser and the
determine what level of assessment needs to be undertaken
supplier. Every parameter within each defect class should
by the purchaser. An audit may be part of certification or
be described and the maximum number of non-complying
accreditation of the manufacturer or the supplier. Audit
units for this parameter defined; this is called the single error
findings can provide a list of so-called ‘reliable suppliers’
(SE). Also, the limit for the total amount of defects of all
(see also Sect. 21.5.1). The level of quality control
parameters in one defect class can be defined; this is called
undertaken by a container manufacturer can be obtained
the accumulated error (AE). The AE is the sum of SE in that
from one of these audit reports. When using an established
defect class.
approved supplier, a purchaser could reduce the amount of
testing that needs to be undertaken. For example the level of
testing could be reduced to an identity test and assessment of
the supplier’s certificate of conformity. A limited identity 24.6 Overview Primary Containers
test could include; dimensions, colour and text. Additional
tests for parenteral product containers could include: To conclude this chapter, Table 24.10 provides an over-
• Type of hydrolytic resistance in case of glass view of pharmaceutical dosage forms and primary
• Presence of microbiological contaminations containers. As for pharmaceutical dosage forms the classi-
Containers will require more extensive testing when pur- fication of the EDQM [26] is provided for containers wher-
chased from suppliers who provide insufficient information ever possible.
24 Containers 535
Table 24.10 Overview of dosage forms and primary containers

Dosage form Bottle Jar Tube Strip Bag Other details
Application liquid + Brush, spatula
Irrigation for the bladder + +
Capsule + +
Cream + + Possibly rectal cannula, vaginal applicator
Oral liquid + Cup, measuring spoon, dosage syringe
Drops for oral use + Dropper or pipette cap, dropper insert
Emulsion for cutaneous use + + Possibly brush or spatula
Gel + +
Gargle + Cup
Injection fluid + Vial, ampoule
Intravenous infusion fluid + +
Enema + +
Irrigation for the mouth + Cup
Nose drops + Dropper or pipette cap
Nose ointment +
Eye drops + Dropper cap, Redipac®
Eye gel +
Eye lotion + Eye irrigation cup
Eye ointment +
Ear drops
Nonsterile + Dropper or pipette cap, dropper bottle
Sterile +
Solution for cutaneous use + Possibly brush or spatula
Pessaries + +
Paste + Spatula
Powders
Single dose + Sachet, laminate or paper
Non divided +
Shampoo +
PRODUCTION
Powders for cutaneous application + Sifter-top container
Tablets + + +
Irrigation for the vagina + Irrigator
Solution for inhalation vapour +
Ointment + + Possibly spatula
Suppositories + +
5. EU-cGMP Guidelines (EudraLex Vol.4). http://ec.europa.eu/

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Human Resources
25
Jan de Smidt and Hans van Rooij
Contents Abstract
This chapter deals with functions, competences, educa-
25.1 Human Resources in Pharmaceutical Healthcare . . . 537
tion, awareness of and management by pharmaceutical
25.2 Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538 professionals and their professional decisions.
25.2.1 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
25.2.2 Product Care, Production and Quality Management . . . . 538 Pharmacists and QP’s in industry carry the responsibility
25.2.3 Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539 for the production of medicinal products considering their
25.2.4 Scheme of Responsibilities, Product Flow education and ethical attitude. Clear and formal relations
and Communication Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539 between the responsible pharmacist or QP, the manage-
25.3 Competences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539 ment of the organisation and relevant employees have to
25.3.1 Functions of Pharmacists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539 be laid down in functional descriptions and in an
25.3.2 Pharmacist in Patient Care and Product Care . . . . . . . . . . . 540
25.3.3 Technicians and Assistants in Healthcare . . . . . . . . . . . . . . . 540
organisation chart giving full regard to the respective
25.3.4 Qualified Person . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 law and regulations of the individual countries, which
are to be harmonised with European Directives and
25.4 Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
25.4.1 Basic Academic Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 Regulations. Certification such as ISO 9001/EN 15224
25.4.2 Preparation in Pharmacies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544 may require continuing education of professionals.
25.4.3 Pharmaceutical Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545 Professional organisations of pharmacists and national
25.4.4 Qualified Person . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
authorities require on-going training (Continuous Person-
25.4.5 Academic Professionals from Other Disciplines . . . . . . . . 547
25.4.6 Assistants and Technicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547 nel Development) for all personnel involved in any aspect
of the profession and in the topics covered in this book.
25.5 Awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
25.5.1 Structure and Responsibilities Within the Organisation 547
25.5.2 Training and Continuous Education . . . . . . . . . . . . . . . . . . . . . 548 Keywords
25.5.3 Assessment of Employees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548 Pharmacist Technician Qualified person
25.5.4 Supervising Preparation of Medicines by Others . . . . . . . 548 Competences Awareness Responsibilities Training
25.5.5 Patient Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
Decisions
25.6 Decisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550
25.1 Human Resources in Pharmaceutical
Healthcare
The basis of human resources in medicines production,

product and patient care may be, following ISO-9001/EN
15224 [1], defined as:
J.H. de Smidt (*) • Professional, trained individuals are necessary to prepare
Royal Dutch Pharmacists Association KNMP, Alexanderstraat 11, medicines, to purchase and keep them and to advice
2514 JL Den Haag, The Netherlands patients about their practical use.
• Those individuals perform work affecting conformity to
H.H. van Rooij product/health service requirements, so they shall be
Independent consultant and Qualified Person, OZ Voorburgwal 109 N,
1012 EM Amsterdam, The Netherlands – Competent on the basis of appropriate education,
e-mail: [email protected] training, skills and experience

538 J.H. de Smidt and H.H. van Rooij
– Aware of how their activities contribute to the employees, also of persons trained outside the pharmaceuti-
achievement of the quality characteristics and quality cal field. Finally professional decisions and responding to
objectives demands from the patient population are discussed.
Competences of the pharmacists will be described, focus-
sing on their functions in production and product care. The
pharmacist is, in most of European countries, the profes- 25.2 Processes
sional who is responsible for the production, availability,
storage and procurement of medicines. Part of the role lies 25.2.1 Development
in advising and pharmaceutical patient care. The pharmacist
must be aware that he is responsible for solving unexpected Traditionally, the pharmacist combined preparation, control
situations that might have severe consequences despite and dispensing. He was held responsible as a person when a
existing and functioning quality systems. In order to prevent patient was harmed. In addition, when a pharmacist
such situations generally, the pharmacist needs a broad view. suspected an error in a prescription of a physician he
Trained support personnel (technicians, assistants) are initiated a relevant action. Also when a patient reported an
used to support and supplement the activities of the pharma- adverse event, the pharmacist informed authorities and
cist. They can be specialised in the production of medicines. industrial parties, the Marketing Authorisation Holder.
The pharmacist must be aware that other persons play a The fields of manufacture, control and distribution have
major role in the administration of medicines to patients. been loaded with GMP and GDP related regulations and
The pharmacist may be asked, or feel morally or legally, recommendations in order to minimise errors. These
obliged to give care and training to the reconstitution of regulations require a Qualified Person (QP), or Responsible
medicines (see Fig. 1.2) on a ward by nurses, at nursing Person or Authorised Person to be involved before the product
homes or home for the elderly or to home care workers or is admitted to the market. Adverse event monitoring and
family of the patient. reporting have been subject to pharmacovigilance regulations,
When the Qualified Person (QP) is mentioned, a legally supervised by a Qualified Person for Pharmacovigilance
required professional unique for the pharmaceutical industry (QPPV). These developments in industry have in their turn
in Europe will be meant. The person is not only involved in increased attention and requirements to similar functions in
manufacturing by releasing batches, but, if the QP is a preparation in community and hospital pharmacies.
pharmacist, he may in practice in some countries act as a
health care professional as well in providing information for
other health care professionals (HCP’s) on product availabil- 25.2.2 Product Care, Production and Quality
ity and pharmacovigilance issues. Finally the QP handles Management
quality related complaints from HCP’s and patients (product
care) including recall of products. When the Qualified Per- When considering dispensing at small scale such as in a
son for Pharmacovigilance (QPPV) is mentioned, a person is community pharmacy and small hospitals, the pharmacist
meant who deals with reporting adverse events, lack of will, personally, not produce every medicinal product. He
efficacy and safety of products. has to rely on industry and other (hospital) pharmacies but
When the Responsible Person (RP) is mentioned, will need product knowledge to fulfil his position in the
European Guidelines on GDP (see Sect. 36.2.4) are referred supply chain.
to. Those guidelines focus on procurement, storage, distri- Small scale preparation will already bring about different
bution and shipment. functions, delegation of tasks and the creation of a pharma-
This chapter starts by presenting responsibilities for the ceutical quality system.
pharmaceutical processes embedded in an organisation Large scale production operations in the hospital environ-
starting at receiving a prescription and ordering, and ending ment require more personnel involved in production, dis-
at dispensing and instructing the patient, sometimes ending pensing and quality control of medicinal products. For the
with a (medical) complaint. These processes are in essence preparation process the pharmacist has to delegate parts or
similar for industry and hospital pharmacies, and processes almost all activities to other trained professionals.
in community pharmacy will fit in this template as well. The Assistants, technicians of various educational levels,
section on Competences discerns varying pharmaceutical cleaning personnel and operators may be involved.
functions in the production of medicines and product care. Logistics and clinical pharmacy are day to day practice in
The section Education zooms in from the general pharmacy community and in hospital pharmacies. Logistics in industry
education onto production and product care. The section is a discipline that has been emphasised, due to current GDP
on Awareness includes how to increase awareness of Guidelines [2] and Quality Management.
25 Human Resources 539
Quality Management, common both to industry and 25.2.4 Scheme of Responsibilities, Product Flow
pharmacies is dealt with in Chap. 35. and Communication Lines
The chart (Fig. 25.1) is a generalisation and presents an

25.2.3 Pharmacovigilance overview of processes involving the main actors,
Marketing Authorisation Holder/Responsible Pharmacist,
Pharmacovigilance is about the detection, assessment, QP/Responsible Pharmacist, Patient and QPPV. Verifying
understanding and prevention of adverse effects or any correct prescription and ordering processes have been kept
other medicine-related problem (see Sect. 35.4.2). The Mar- out of the chart.
keting Authorisation Holder of a product has to have at his
disposal a qualified person who is responsible for the
pharmacovigilance of that product, the Qualified Person for 25.3 Competences
Pharmacovigilance (QPPV) [3].
Annex 16 of Volume 4 of the Good Manufacturing Prac- 25.3.1 Functions of Pharmacists
tice Guidelines proposes that the ultimate responsibility for
the performance of an authorised medicinal product over its Professionals dealing with medicines are engaged in the
lifetime; its safety, quality and efficacy lies with the Market- following processes: logistics, dispensing, production and
ing Authorisation Holder (MAH) [4]. control of medicines.
In (hospital) pharmacies the responsible pharmacist is in • Logistics is about good distribution practice which
charge of pharmacovigilance of the products prepared in the includes procurement, receipt and correct storage at all
pharmacy.
Marketing Authorisation Holder (Industry) Qualified Person for

COMPLAINTS
Responsible Pharmacist #1 (Hospital) Pharmacovigilance QPPV
QP (Industry)
MANUFACTURING/PREPARATION CUSTOMER or
QUALITY OPERATIONS Responsible Pharmacist
PRODUCTION
OPERATIONS PATIENT
#2(Hospital)
VALIDATION
QUALITY SYSTEMS
RELEASE
5. Quality Risk Management 1. Management review
OPERATIONS
6. Trend analysis 2. CAPA
7. Stability monitoring 3. Change control

PROCURE
8. Cold Chain 4. Deviation Management
9. Lab QC
TECHNICAL
SERVICES
WAREHOUSE
Responsibility Product flow Communication
Fig. 25.1 General chart for process responsibility, product flow and communication
stages within the chain and final delivery to pharmacies for further specialisation, e.g. training courses on a wide
and the end user (patients) (see Chap. 36). variety of subjects.
• The dispensing of medicines is based on prescription During the last decades new insights in the competences
checking (see Sect. 2.2), picking the right medicine, of health care professionals have evolved, centring on the
appropriately preparing it for patient use and instructing communication with patients. Basic education may be piv-
patients about their practical use. otal in pharmacy, however insight and oversight of
• The production of medicines is the prime focus of this Healthcare institutions and the way pharmaceutical
chapter. companies organise their processes are necessary as well.
• Control of the quality of medicines is focused on the The Canadian CanMEDS system [5] has inspired many
chemical and (bio)-pharmaceutical properties and some basic and specialised medical and pharmaceutical courses
are directly related to clinical effects of medicines in throughout the world. This system is based on the roles and
patients. competences that a health care professional has to play in
• If medicines are produced on a larger scale, i.e. for more practice and by consequence provides information for an
than one individual patient, more professionals will be educational program. The diagram of Can MEDS has been
involved. adapted for pharmacists and is given in Fig. 25.2.
Production will be separated from quality control, in a The different sections of Fig. 25.2 symbolise the different
hospital pharmacy just as it is in pharmaceutical industry. core competence areas of the pharmacist: pharmaceutical
In all areas pharmacists can be employed as well as other expertise as a pharmaceutical professional, communication
professionals, assistants, technicians and workers. In specific with patients, cooperation with other health professionals,
departments of the hospital pharmacy such as the production management as an executive, commitment to society (health
department, the sterile production department, the analytical advocacy) in advising patients, scholarship in an attitude
lab, and the microbiological lab employees of other towards medicines related problems.
disciplines may also be employed. Many academic schools use the CanMEDS framework. It
is also very useful as a basis for specialised training and for
continuing education. A typical example for the training of
pharmacists, based on the CanMEDS-system can be found in
25.3.2 Pharmacist in Patient Care
the training of industrial pharmacists in Belgium (see Sect.
and Product Care
25.4.4).
Certification of health institutions such as hospitals and
Product care and patient care are the essential functions of
pharmacies for instance via ISO 9001/EN 15224 may
the pharmacist at the end of the supply chain where the
include observations on education of HCP’s, stipulating
pharmacist meets the patient. Product care is associated
additional programs.
with procuring (availability), storage and dispensing, includ-
ing instruction of the patient of medicinal products as well as
with preparation if necessary. Patient care may include
counselling on the choice of medication regimens, a key 25.3.3 Technicians and Assistants in Healthcare
part of basic academic pharmaceutical education. It may
also be associated with properties of medicinal products The competences of assistants and technicians are derived
such as efficacy and safety; or lack of safety and lack of from the corresponding competences of the pharmacist. In
efficacy. Healthcare professionals and patients are then the this view they perform parts of the roles of the pharmacist. If
first to complain about the services delivered by the properly organised, they can be responsible for carrying out
pharmacy. the part of the work that has been delegated to them
The basic education of the pharmacist is directed to these according to the local procedures. The responsibility
responsibilities and to changes and developments in the remains with the pharmacist. The CanMEDS diagram can
pharmaceutical field. The education of the pharmacist has be used to develop a suitable educational program for these
to be on an academic level to equip him with independent professionals as well.
thinking and to guarantee a good discussion with An international study about the role of pharmacy
e.g. physicians, other healthcare professionals (HCP’s) and assistants and their education [6] reveals many differences
commercially orientated managers. In addition it may be and many similarities throughout Europe. About the actual
expected that scholarship from a scientific discipline is a preparation of medicines a variety of functions was found. It
reasonable guarantee to cope with progress in current scien- happens to be mainly a function of the assistant (e.g. in the
tific and technical knowledge of the pharmaceutical profes- Netherlands) or the assistant is not involved in preparation at
sional. Further, basic training has to be at an adequate level all (in e.g. Slovenia). In some countries (e.g. in Germany)
Fig. 25.2 CanMEDS diagram CORE COMPETENCES OF THE COMMUNITY PHARMACIST

adapted for pharmacy (Copyright
# 2005 The Royal College of
Physicians and Surgeons of COMMUNICATION
Canada. http://rcpsc.medical.org/
canmeds. Reproduced and
adapted with permission) SCHOLARSHIP PROFESSIONALISM
PHARMACY DRIVEN
OPERATIONS
MANAGEMENT COMMITMENT TO
SOCIETY
COOPERATION
the assistants are trained to carry out chemical analysis on PIC/S GPP ([8], see also Sect. 25.5.5) acknowledges a
raw materials and pharmacy made preparations. similar function for preparation in pharmacies: Responsible
Technicians and assistants are working in hospital Person or Releasing Officer:
pharmacies as well. In general the same educational program 6.5 Release
can lead to competences in both community and hospital 1. The Responsible Person is ultimately responsible for the
pharmacy. quality of the medicinal products prepared and released. The
actual release can be delegated to another appropriately compe-
tent person (i.e. Releasing Officer).
2. Product release should include verification that the medic-
PRODUCTION
25.3.4 Qualified Person inal products comply with the valid specifications and that they
have been prepared in accordance with valid procedures and
with the principles of Good Practices for preparation described
25.3.4.1 Functions in this Guide.
A Qualified Person (QP) has a key position in the pharma-
ceutical industry and it is that person who releases the The title, Responsible Person, is also used in the
batches for the market. The QP deals with quality related guidelines on Good Distribution Practices of the European
complaints and is leading in recall operations. Commission [2]
European Directive 2001/83/EC [7], as amended, states An extensive regulation of the Qualified Person has
that the QP in the pharmaceutical industry has the responsi- evolved in recent years because of the important implications
bility for ensuring that a particular batch has been resulting from his duty. The role may be considered within the
manufactured in accordance with its marketing pharmaceutical company formally as that of a watchdog (as it
authorisation, EU Good Manufacturing Practice (GMP) is legally), by assuring that released products meet the
and equivalent regulations. Other tasks are: specifications from the Marketing Authorisation.
• Starting materials compliance and supply chain security
• Manufacturing and testing performance History and Position of the QP
• Manufacturing and testing process validation Until about 1900 pharmacists prepared all medicinal
• Changes and investigations completion products in their own pharmacy,. mostly with help of
Duties of the QP are described in more detail in Volume 4 self-trained assistants. With the upcoming pharmaceu-
Good manufacturing practice (GMP) Guidelines, respec- tical industry more complex organisations came to life
tively Annex 16 to GMP (see Table 25.1). and more pharmacists were needed apart from the
The formal function of a QP exists in Europe and is legal pharmacist/owner. The introduction of managers and
for manufacturers of licensed medicines and investigational
medicinal products. (continued)
Table 25.1 Duties of the Qualified Person

Duties Reference to GMP
Release Chapter 1.4 (xv) and 1.9 (vii)
Producing a quality review
Specific place in hierarchy; relation to heads of production, quality control, Chapter 1.4 (iv,v) Chapter 1.5
quality assurance, quality unit
Description of duties: Chapter 2.6
Ensure compliance with Marketing Authorisation (MA)
Permanently at disposal of the Manufacturing Authorisation holder
Handling unplanned deviations Annex 16 (draft) 5
Contract manufacture Annex 16 (draft) 2.3.3.
Chain quality Annex 16 (draft) 3.5.5
Handling complaints Chapter 8.1
Product recalls Chapter 8.9
of incidents, deviations, problems with personnel hygiene

administrative as well as specific technical personnel and problems with equipment is valuable for a QP, but
led to management structures as shown in Fig. 25.1. sometimes there has to be reliance, for those issues, on the
Most of the scientific positions within the pharmaceu- head of production. In France the daily physical presence of
tical industry are typically suited for pharmacists. In a QP within a manufacturing plant for radiopharmaceuticals
case of lack of interest of pharmacists to work in a is required before manufacture starts.
pharmaceutical company a shortage of scientific per- The functions of an industrial QP resemble very much the
sonnel may have been filled up with chemists, functionality of a quality manager as described in ICH Q10
biologists and doctors. Their specific knowledge and PQS guidance (see Sect. 35.5.9) or ISO-9001 (see Sect.
scientific abilities cannot be missed in the pharmaceu- 35.7.2). It is not surprising that a person fulfilling the QP
tical industry any more. The QP needs typical pharma- function is increasingly seen as the quality manager, despite
ceutical knowledge and abilities. If he is not a comments that his independent individual opinion may be at
pharmacist, additional courses, based on the pharma- stake. The 7 Pillars model (see Sect. 35.7.5) sees the QP as
ceutical education, are available to meet the the owner of the “Release System” as indicated by law [4]
regulations of the EC. If the QP is a pharmacist by and as an expert to be consulted about all other elements of
education, he can additionally represent the company the Quality Management System.
towards colleague-pharmacists, doctors and patients as All these considerations being true, the very first
a healthcare professional. priorities of a QP position is his autonomy in decision
making and in having direct access to senior management.
Some countries in Europe, such as the Netherlands have 25.3.4.3 Qualified Person for Pharmacovigilance
installed a system of administrative penalties for the com- (QPPV)
pany in relation to non-compliances as well as the possibility The Marketing Authorisation Holder of a product has to
of bringing the company into court when a criminal offence have at his disposal a qualified person who is responsible
is suspected. A QP could be involved as well. Jail as a for pharmacovigilance of that product [7]. The MAH is
penalty is common in other countries, such as Ireland. supported by expertise from Regulatory Affairs officers
who are responsible for taking care of dossier documenta-
25.3.4.2 QP and Quality Systems tion, including Quality, Toxicology and Clinical Sciences,
The principle of Quality Management has evolved, which and updates.
has assisted the work of the QP. The European approach in The QPPV should have documented qualifications and
nominating an individual to be an independent arbiter of experience within pharmacovigilance. If the individual is not
quality is also applied to Good Distribution Practices in medically trained, e.g. a biologist, then the QPPV must have
which a Responsible Person (RP) is introduced in legislation easy access to a medically qualified person. The tasks of the
for Pharmaceutical Wholesalers [2]. QPPV are extensively described in pharmacovigilance
As explained in Sects. 34.9 and 35.1 the release of guidelines [3].
pharmaceutical preparations cannot only be based on the Dealing with medical information and complaints of
assay of the content or on studying the preparation docu- HCP’s and patients is another duty that relates to a potential
mentation, but has to be based above all on knowledge of non-compliance with the marketing authorisation: off label
and trust of Pharmaceutical Quality Systems. The reporting use, medical related complaints.
Each adverse reaction must be investigated and an expla-

nation must be provided whether product quality may be the 25.4 Education
root cause. Furthermore, it is a GMP requirement that the QP
(and delegated QPs) is informed of adverse effects indepen- 25.4.1 Basic Academic Education
dent of whether these are related to product quality issues.
Every pharmacist must be acquainted to the production of
medicinal products and product care. So the basic education
25.3.4.4 QP/QPPV- Like Functions in Pharmacy of pharmacists must include chemical, physical,
A legal QP and QPPV is required if investigational medici- microbiological and biopharmaceutical disciplines. Knowledge
nal products are being prepared for use in clinical trials (see of herbal products and their production must also be a part of
Sect. 35.5.10). Apart from those legally defined functions for the basic pharmaceutical education, as well as pharmacology
the QP/QPPV are not frequently encountered in hospital and toxicology. Directive 2005/36/EC as amended, provides
pharmacies in routine processes but decision making and criteria that are applied when a pharmacist from outside the EU
being held responsible have been assigned to other can be recognised [9]. This list allows pharmacists to travel and
individuals of which the pharmacist is an example. For work in the EU countries. It is a minimum list and only appli-
example the presence of a QPPV-like function in the hospi- cable for the training of a basic pharmacist. For specialised
tal pharmacy organisation is required when medicines are pharmacists more training is available and in many countries is
imported from outside the EU and are supplied to other a requirement. The list has not been based on CanMEDS
pharmacies. systematics and is without focus or hints as to the intensity or
duration of the training of the subjects of study.
Digifab® Case Different types of workers will be employed in pharma-
After intoxication with digoxin a physician may need ceutical industry with differing levels of education. Many
digoxin antibodies (Digifab®). Digoxin antibodies courses are offered to employees both as in-company and
bind to digoxin reducing the digoxin level in heart courses by outside companies in the educational market.
tissue and in blood. This may be a live saving treat- Pharmaceutical manufacturing is a widely used term for
ment. No licensed product is available in the these occupations. Pharmaceutical productions operator is
Netherlands and currently not elsewhere in Europe. more specific for employees with certain well-defined and
However, there is a product on the US market, established jobs in industry. The duration of these courses
Digifab®. differ from 20 h to 2 years, depending on the position of the
In the Netherlands only a few cases per year occur, worker and the responsibilities.
PRODUCTION
which does not warrant a stock position in every Dutch As it is assumed that within 5 years knowledge and skills
hospital. Therefore the Central Hospital Pharmacy in are lost if not applied in practice, initial training at
The Hague imports the Digifab® from the USA and universities should not contain many subjects that are not
serves as a central stock keeper for all Dutch hospitals. useful in expected occupations. If a substantial proportion of
An imported medicine is legally considered a pharmacists are not involved in production of medicines
non-licensed medicine in the importer country. The only the principles of production should be in the training
Inspectorate agrees with the above construction on programs. However, this level should allow students to fol-
conditions: low specialised pharmaceutical training without delay. This
• The request has to be justified and authorised by the equilibrium has to be maintained by the educational
treating physician and handed over to the compe- institutes.
tent authority. Article 44, 3 from the recognition of qualifications for the
• The Inspectorate requires the hospital pharmacy to pharmacist [9]:
declare that it performs pharmacovigilance. There- Training for pharmacists shall provide an assurance that
fore the Central Hospital Pharmacy supplies the person concerned has acquired the following knowledge
Digifab® together with a request to the physician and skills:
to report whether or not side effects were observed. (a) Adequate knowledge of medicines and the substances
Every year a review of all cases is submitted to used in the manufacture of medicines
Inspectorate. (b) Adequate knowledge of pharmaceutical technology and
• All tasks and responsibilities have to be described the physical, chemical, biological and microbiological
in a SOP and Technical Agreement authorised by testing of medicinal products
the relevant involved pharmacists from the (c) Adequate knowledge of the metabolism and the effects
distributing pharmacy and the client pharmacies. of medicinal products and of the action of toxic
substances, and of the use of medicinal products
(d) Adequate knowledge to evaluate scientific data

concerning medicines in order to be able to supply [11]. The Faculty of Pharmacy and Pharmaceutical
appropriate information on the basis of this knowledge Sciences of the Monash University support this Shar-
(e) Adequate knowledge of the legal and other requirements ing and Building Educational Resources platform. It
associated with the pursuit of pharmacy can be used to develop and share educational programs
The work which a pharmacist is allowed to perform on the and educational materials. Especially for large rural
basis of this education is formulated by the European areas such as Australia it offers a good opportunity for
Commission as follows: developing and keeping up of professional
Article 45, 2: competences. Even materials for (virtual) practical
The Member States shall ensure that the holders of evi- training can be found in the SABER-community.
dence of formal qualifications in pharmacy at university
level or a level deemed to be equivalent, which satisfies the
provisions of Articles 44, are able to gain access to and
pursue at least the following activities, subject to the require-
ment, where appropriate, of supplementary professional
25.4.2 Preparation in Pharmacies
experience:
(a) Preparation of the pharmaceutical form of medicinal
If a product is prepared for a single patient in a community
products
pharmacy by the pharmacist himself, the quality risks are
(b) Manufacture and testing of medicinal products
considered to be low. The academic education, the ethical
(c) Testing of medicinal products in a laboratory
requirements, his legal position and the supervision by Phar-
(d) Storage, preservation and distribution of medicinal
maceutical Inspection, are all intended to guarantee an ade-
products at the wholesale stage
quate product for the individual patient. Eventually the
(e) Preparation, testing, storage and supply of medicinal
patient himself can complain to the pharmacists who made
products in pharmacies open to the public
the product about the quality thereof insofar the patient has
(f) Preparation, testing, storage and dispensing of medicinal
enough insight in that. Section 25.6 as well as Sect. 35.6.13
products in hospitals
deal with processing patient complaints.
(g) Provision of information and advice on medicinal
The proper education of the pharmacist in the community
products
setting has to include theory and principles of quality control
As a result of the Declaration of Bologna, the academic
in order to allow the pharmacist to work in a responsible
education of pharmacists in Europe has to be unified. In
way. In some countries specialised courses for community
order to stimulate this trajectory a so-called Pharmine proj-
pharmacists are available or even required. In these courses
ect has been started [10]. It offers help to the different
there should be time for the specific problems of the produc-
European countries to be active in renewal of the pharma-
tion of medicines in the setting of a community pharmacy.
ceutical education. Apart from adaptation to European
Nevertheless, proper documentation of all actions during
standards, new subject areas are to be developed based on
the preparation should be available, as explained in detail in
the evolving pharmaceutical practice in both community and
Sects. 33.5 and 34.5. If assistants or other personnel are
hospital pharmacies. In many countries pharmacists seek
involved in the preparation of products for more patients,
new roles in patient counselling, doctor counselling, medi-
there is urgency for extensive documentation. The responsi-
cation reviews, development and maintenance of
ble pharmacist has to release the products. It is the responsi-
pharmacotherapeutic formularies, advising of special groups
ble pharmacist who is held to account if the product does not
of patients. Next to these new occupational goals for practi-
have the desired quality.
cal pharmacists, new diseases and new groups of patients
The pharmacist is responsible for ensuring that the
will allow the pharmaceutical industry to develop new types
professionals or workers to whom practical work is
of medicines and new production scales. All types of
delegated are indeed capable of performing those tasks. In
pharmacists will have to be prepared to handle these
some countries specialised educational programs are avail-
challenges. Continuous renewal of the educational programs
able on a national specified level. So, vocational education
is therefore a must for all educational institutions.
allows pharmaceutical assistants or technicians to work as
trusted professionals in any pharmacy. They can have a high
As a useful initiative for education and discussion the level of independence and of responsibility for carrying out
SABER community has to be mentioned here the tasks that are given to them. The pharmacist always
retains the overall responsibility.
(continued)
The basic academic training as a pharmacist must allow K3 Be familiar with unusual hospital pharmacy preparation
the students to follow the specialised courses without delay. techniques and their necessary equipment, including the
In most of the European countries a specialised course is requirements these must meet
available for the hospital pharmacist. K4 Be familiar with work hygiene and radiation hygiene
If preparation of medicines for many patients or even (level 4b) and apply them when preparing medicines
semi-industrial production is done in the hospital pharmacy, K5 Be familiar with the administration of drugs and the
a prolonged study of the relevant disciplines is a necessity. standards administration must meet and the devices
Especially for the preparation of sterile products, used (parenteral and feeding tube administration)
antineoplastics, and radiopharmaceuticals additional exper- C1 Be able to assess preparation requests on pharma-
tise has to be required. cotherapeutic ratio and efficiency
To become an all-round hospital pharmacist a specialised C2 Be able to identify and assess relevant chemical and
educational period of 4 years is not uncommon. Part of this physical qualities of raw materials, additives, packaging
education period is used for educating the “student” pharma- materials and containers
cist for preparation skills. C3 Be able to draw up drug-preparation protocols and prod-
A course example for hospital pharmacists, which is uct files that meet the technical, biopharmaceutical and
intended for the preparation of medicines, is derived from other relevant quality standards
a project in the Netherlands [12]. The first part (A, B, C etc.) C4 Be able to design, set up and validate (including shelf-life
of this list gives the competences that the hospital pharma- tests) non-sterile, aseptic and sterile preparation pro-
cist needs for proper functioning. The second part (K1, K2 cesses and implement them
etc) consists of knowledge goals, the third part contains C5 Be able to prepare medicines for individual patients and
skills (C1, C2 etc.) and the fourth part (A1, A2 etc.) gives stock production at such a level that the relevant quality
the attitudes of the well trained hospital pharmacist: standards and legislation are met
V. Preparation C6 Be able to assess whether specifications set for prepara-
Preparation includes contributing to pharmacotherapy, tions have been met, and consequently release medicines
drawing up protocols, preparing drugs (including radiophar- C7 Be able to instruct physicians and nursing staff as to
maceuticals), assessing the quality of preparations and preparing prior to administration and to administration
supporting the administration of medicines. itself
After training the hospital pharmacist is competent to: C8 Be able to formulate and communicate clearly
(A) Assess the pharmacotherapeutic relevance of individual The hospital pharmacists should
preparations or stock A1 Be prepared to work accurately and carefully
PRODUCTION
(B) Draw up batch preparation protocols for individual A2 Be able to handle insecurity, make considerations and
preparations and stock production and draw up and take decisions
maintain product files for stock production
(C) Prepare non-sterile, aseptic and sterile medicines for
individual patients as well as for stock
(D) Design and validate preparation processes for non-sterile, 25.4.3 Pharmaceutical Industry
aseptic and sterile preparations and implement them
(E) Assess the quality of individual preparations and stock A graduate with a degree in pharmacy will be suitably
production on the basis of set specifications and deter- qualified to apply for jobs in pharmaceutical industry such
mine whether preparations may be released for use as marketing and sales, pharmacoeconomics, IT, research
(F) Determine which specifications products, necessary for and development (R&D), production, quality control, qual-
production (raw materials, additives, packaging ity management, regulatory affairs, pharmacovigilance and
materials, equipment and premises), must meet and if in clinical research. In general, the basic academic education
they actually meet these specifications given by the Faculties of Pharmacy equips an individual for
(G) Support and give instructions on preparation and admin- the above-mentioned area of interests and for specialised
istration of medicines jobs in industry at least as a junior manager.
In order to have the above mentioned competences, the All pharmaceutical companies have in-house training and
hospital pharmacist must: educational programs on top of the already acquired knowl-
K1 Be familiar with the requirements that batch preparation edge. Specialised courses additional to the basic academic
protocols and product files must meet education are available Europe wide and are attended by
K2 Be familiar with technical and biopharmaceutical personnel from pharmaceutical companies in order to cope
requirements that dosage forms must meet with current scientific insights and progress.
Such training of key personnel may be checked by Ma IP 2.2 Is able to design procedures for laboratory
Inspectorates and find its legal basis in European Legislation based research and implement and control them
as well, by referring to progress in scientific and technical Ma IP 2.3 Is able to perform fundamental and applied
knowledge (Directive 2001/83 EC e.g. article 23) [7]. A scientific research
period of on the job training of 2 years is sometimes Ma IP 2.4 Is able to integrate specialised knowledge of
required in individual countries. The training program of different disciplines in a creative way
Master’s Degree Industrial Pharmacy in Belgium [13] may 3. Intellectual competences
be used as guidance for education of industrial pharmacists: Ma IP 3.1 Is able to think analytically and synthetically as
The industrial pharmacist has the following competences: well as problem solving orientated
1. Knowledge of the production of medicines: Ma IP 3.2 Is able to analyse complex problems
Ma IP 1.1 Understands the processes of the production of Ma IP 3.3 Is able to think and operate research directed
medicines on industrial scale and is able to work Ma IP 3.4 Possesses an attitude of scientific curiosity and
accordingly of lifelong learning
Ma IP 1.2 Has an integrated vision on the different disci- Ma IP 3.5 Is able to reflect on his functioning in a
plines that are involved in the development of a medic- complex context: “if you are not part of the solution
inal product you are part of the problem”.
Ma IP 1.3 Is able to design an adequate delivery form for 4. Competences in communication and working together
a drug substance Ma IF P.1 Is able to report about own research
Ma IP 1.4 Has knowledge about the production and uses Ma IP 4.2 Is able to communicate and work together in a
of biotechnological medicinal products multidisciplinary professional environment
Knowledge of the analysis and quality control of medicinal 5. Societal competences and societal commitment
products Ma IP 5.1 Is able to function professionally in an ethical
Ma IP 1.5 Is able to apply relevant techniques for the and deontological way
analysis of medicinal products
Ma IP 1.6 Is able to implement and supervise the pro-
cesses of quality control of medicines 25.4.4 Qualified Person
Ma IP 1.7 Has insight in the principles and practice of
analytical validation processes The education for a qualification as QP is given in article
Knowledge of quality management and knowledge of the 49 of Directive 2001/83/EC, [7] as amended. As a basis for
juridical and economical aspects of the pharmaceutical the education of the QP a course of at least 4 years in one of
industry. the following scientific disciplines is mentioned: pharmacy,
Ma IP 1.8 Is able to manage quality systems (QA, GMP, medicine, veterinary medicine, chemistry, pharmaceutical
ISO) chemistry and technology or biology. The course shall
Ma IP 1.9 Understands systems of quality management include theoretical and practical study bearing upon at least
and quality care the following basic subjects:
Ma IP 1.10 Knows the laws and regulations concerning 1. Applied physics
pharmaceutical industry 2. General and inorganic chemistry
Ma IP 1.11 Is able to give help to marketing and sales 3. Organic chemistry
Ma IP 1.12 Is able to apply the principles of company 4. Analytical chemistry
economics 5. Pharmaceutical chemistry, including analysis of medic-
Ma IP 1.13 Is able to manage the principles and the inal products
practice of the registration of medicines 6. General and applied biochemistry (medical)
Knowledge about clinical research and experimental 7. Physiology
clinical-pharmacological research. 8. Microbiology
Ma IP 1.14 Is able to give help for clinical research 9. Pharmacology
Ma IF 1.15 Is able to participate in experimental clinical- 10. Pharmaceutical technology
pharmacological research. 11. Toxicology
2. Scientific competences 12. Pharmacognosy
Ma IP 2.1. Is able to educate himself in the pharmaceuti- A pharmacist with QP experience is the most preferred
cal areas with help of ICT, printed material and edu- for the QP function. Because of limited availability of
cational meetings specialised industrial pharmacists, national authorities
allow graduates from other scientific disciplines, as men- accepted diploma. Additional training is mostly available as
tioned above in the Directive. well as forms of continuing education and assessment, as
Several courses at graduate level are available lasting 3–4 explained in Sects. 25.5.2 and 25.5.3.
years and 2 years of practical training, indicated by the
European Commission. Apart from the above mentioned
subjects the knowledge of pharmaceutical law, the role and
25.5 Awareness
professional duties of the QP, and knowledge of quality
management systems are objects of study.
Each person in an organisation should be made aware of the
The Responsible Person as defined by GDP Guidelines
organisation structure that governs pharmaceutical
has to have a similar level of knowledge and/or experience in
operations. In addition, individual awareness or anticipation
Quality Management systems.
on quality related topics is essential during day to day
A difference between authorised and delegated qualified
operations, in industry, hospital and community pharmacy.
persons is described by GMP. Each company has to have one
Each professional should have a leaning towards risk analy-
authorised Qualified Person, but they can delegate their work
sis and risk minimisation in order not be annoyed when
to one or more delegated Qualified Persons. Only the
problems pop-up. This section identifies some well-known
authorised Qualified Person has the overall responsibility
issues from daily practice. The QP above all has to have full
for the release of a product. The Danish authorities for
awareness of hazards, risks and harm.
instance explain clearly the difference:
When an authorised QP delegates the release to a delegated QP,
the authorised QP must countersign for all releases that the
delegated QPs have made on behalf of the authorised QP. The 25.5.1 Structure and Responsibilities Within
authorised QP must randomly review the releases carried out by the Organisation
the delegated QPs.
The EU Directive requirements for QP’s is more or less Each organisation whether it is hospital or industry needs its
equivalent to a degree in pharmacy. A document of the own chart that shows preferred communication lines and the
Danish authorities presents a possible exception to that. It framework of the company. The chart provides transparency
says: “However, the requirement that a QP must have who is in business development, purchasing materials, com-
received training in all of the above-mentioned basic mercial activities or who is in quality. Such a chart clarifies
subjects can be waived.” A similar waiver exists in responsibilities when the company is part of a corporate
Germany. organisation with headquarters elsewhere or part of a
PRODUCTION
country-wide non-profit healthcare organisation with
delegated responsibilities. European subsidiaries of global
25.4.5 Academic Professionals from Other corporate organisations are considered to be the entities for
Disciplines bringing the products to the market in Europe from a legal
perspective.
Different types of workers will be employed in pharmaceu- Line functions and staff functions within the organisation
tical industry with differing levels of education. Many have to be clearly identified. Line is associated with process
courses are offered to employees both as in-company and flow. Line functions have direct responsibility and have the
courses by outside companies in the educational market. authority and power for realising the mission of the com-
Pharmaceutical manufacturing is a widely spread term for pany. Knowledge of reporting lines is useful. ‘Staff’ supplies
these occupations. Pharmaceutical productions operator is information, materials and advices to the ‘line’. Staff
more specified for employees with certain well defined and functions are e.g. counselling on human resources, on
established jobs in industry. The duration of these courses procedures, on analytical methods and on systems, on man-
differ from 20 h to 2 years, dependent on the position of the aging a science based service department handling medical
worker and his responsibility. information, complaints and recall. A QP or hospital phar-
macist may have both line and staffs function(s).
The responsible pharmacist has to be sure that the
25.4.6 Assistants and Technicians professionals who perform (parts of the) pharmaceutical
functions are suitably educated and have the required knowl-
As explained in Sect. 25.3.3, the level of competences and edge and skills.
responsibility of assistants and technicians differ greatly in Organisational charts, a proper and meaningful job
European countries. A vocational training of 2–4 years com- description, a system of allowed delegation of tasks, a sys-
bined with elaborate work placement can lead to a nationally tem for personal development and a system for continuous
education are all meaningful tools of the pharmacist and the common practice in industry and in hospital pharmacies with
employer for delegation of pharmaceutical tasks. aseptic operations (see Sect. 31.6.3). The human factor is
In a well organised production unit on a daily basis, the considered to be the most hazardous part in the production
pharmacist will be involved only when this is necessary and process.
will timely be asked for help but must be in a position to Assessment and where necessary additional training has
intervene. This supposes a high level of motivation of all to be followed by an additional qualification test before the
professionals who work at the preparation of the specific employee is considered fit for production. Feedback
product. Communication is essential and in process controls improves awareness of employee and his departmental man-
cannot be missed, especially when large batches are being ager as well.
produced. Some countries, such as France and Belgium
require that the pharmacist is present on the day and time
of operations, to be documented in a daily listing
25.5.4 Supervising Preparation of Medicines
Senior management, the boss in smaller organisations,
by Others
has the ultimate responsibility to ensure effective Pharma-
ceutical Quality Systems (Chap. 35) are in place, adequately
Doctors and veterinarians are generally not allowed to pre-
resourced and to assure that roles, responsibilities, and
pare medicines from raw materials (see Fig. 1.2). If it cannot
authorities are defined, communicated and implemented
be avoided, professional education and supervision by a
throughout the organisation.
pharmacist is a must. A better solution may be referral to
Each boss likes however empowered individuals, as they
or asking for support in a nearby or centrally located
are better suited for solving problems. Staff meetings and
specialised pharmacy.
review of management are therefore often and frequently
If medicinal products have to be reconstituted in the
required.
setting of a nursing or LTC home or in a hospital ward
doctors, nurses and other caretakers can be involved in
handling of medicines. The pharmacist should take care to
25.5.2 Training and Continuous Education
educate and if possible to supervise the doctors and nurses.
In some cases medicines have to be reconstituted at the
Once employed, the professional has to maintain his own
bed of the patient at home. Family members or nurses will
level of professionalism. Management in pharmaceutical
perform the reconstitution of the product. The responsible
industry will see that the professional has the adequate
pharmacist, either from a community pharmacy or hospital
level and maintains that level. The senior management or
should instruct personnel that are involved on the spot or
directors of the hospital will be charged with maintaining the
supervise them in order to avoid any harm for the patient. If
quality level of the professionals and employees. In commu-
the quality cannot be guaranteed, a different solution for the
nity pharmacy no authority is available to observe the qual-
patient has to be found.
ity of the professional, unless the organisation of
pharmacists or government sets rules for continuous occu-
pation and continuous education and monitors it, which is
the practice in some Member States e.g. UK. 25.5.5 Patient Complaints
The value of continuous education on the skills of a
professional is not guaranteed. A controlling system of skills Quality complaints and medical comments by patients have
and attitude can better ensure the quality of the work of the to be dealt with by the organisation in a conscientious way as
professionals. Different types of tests can give insight in the it is in the interest of the company or hospital. A quality
performing level of the workers. system for evaluation, archiving and reporting of complaints
should be in place (see Sect. 35.6.13). It can give unexpected
information about the quality of a pharmaceutical product,
25.5.3 Assessment of Employees including how difficult it is to understand package inserts.
As a part of quality systems, standard procedures can be QP and Patient Complaints

implemented for functional assessment of employees. Job Quality defects are reported often by the patient to a
description of employees and their training records are effi- physician, to the pharmacist and to industry. Such
cient documents for that purpose. Procedures for the training complaints come to the attention of the QP and the
of a new professional, the continuous education and the Qualified Person responsible for Pharmacovigilance
yearly examination of qualification can all be part of the
quality system of the preparation unit. Such qualification is (continued)
pharmacist such as in situ preparation for only one patient,

(QPPV). The latter is involved when it comes to which is costly and disturbs the planned processing.
adverse events possibly related to insufficient pharma- Regulations for industrial supply of such products are
ceutical quality. referred to as “patient named basis” or “compassionate
For example wrong delivery of product or filthy use” (see Sect. 3.5) and delivery of these products requires
boxes of product by the logistic department is a a broad oversight of efficacy and safety risks.
major QP concern as it requires corrective actions The responsible pharmacist or QP may decide not to
and taking the lead in that process or the defect may deliver the product because of lack of timely available qual-
even result in a recall. ity control, although that may cause delay in the treatment of
Due to limitations in sampling, quality defects may the patient. This scenario is not pleasant for the patient or for
pass final quality control. Not every tablet in a batch the medical institution or the hospital because it causes
can be checked by QC for full compliance. For exam- irritation and even a bad reputation. It is however not advis-
ple when a batch of tablets is being packed into able to deliver insufficiently controlled medication to
blisters, it could well be possible that line clearance patients, which would be against the philosophy of quality
of the packing line has missed the presence of systems. In case of individual preparations it is not against
remnants of another product. the law to deliver without analysis. The responsible pharma-
The patient is therefore, surprisingly, much more cist has to make a risk assessment on the basis of his clinical
competent for an optimal control of quality, as one can insight and product knowledge.
be sure that each unit of the batch is inspected for Another challenge appears, when a professional pharma-
apparent quality defects by the intended patient popu- ceutical decision has to be made when a patient or physician
lation before taking their medication. The patient has insists on the preparation of a medicinal product that should
an analogous position to the QC laboratory and has not be made available e.g. because of lack of scientific
better control on the quality of the batch in relation to evidence on efficacy or lack of safety. This scenario is not
important user (patient) related aspects. uncommon in a community pharmacy. The responsible
pharmacist has to decide whether or not the prescription
will be prepared and dispensed to the patient.
The position of the QP/QPPV may therefore be consid- If not, this patient will probably not visit him again
ered as the closest contact with the patient such as the because of his decision. If yes, the pharmacist prepares
community or hospital pharmacist nowadays is supposed to and sells a product that does not meet the medication and
be. Responsibility consists of proper and pro-active handling therapy standards of local Health Care Professional
PRODUCTION
of complaints, including medical complaints and timely Communities. Those standards are in general considered
reporting of complaints to management. as absolute truth worthy and claimed to be valid for the
Some professional magazines, such as the Pharmaceutisch entire patient population. However, an individual patient
Weekblad of the Netherlands, publish reports about quality may belong to a specific sub-population not categorised yet
problems that were detected by patients. This can be useful and may benefit from such a product. Again, risk assess-
information for the individual pharmacist and for the manu- ment including clinical need (see Sect. 2.2) is expected
facturer as well. from the pharmaceutical professional but keeping in mind
that the physician has the final decision to prescribe
medicines to patients.
25.6 Decisions The discussion between HCP’s, patients and authorities
on availability of products will probably continue to chal-
As said (Sect. 25.1) the pharmacist has to be competent to take lenge the pharmaceutical and regulatory field. Current
professional decisions and respond to demands from the non-availability of products is a major concern in the Health
patient population. Decision making requires experience but Care population. Authorities therefore have implemented an
also knowledge and awareness about tasks, responsibility and orphan medicinal product regulation for products with a
legislation. The demands may take the shape of dilemmas. small market potential and potential efficacy within a small
Reliable production of medicines takes time. So an urgent patient population (see Sect. 3.6.1). Older products will
request to a production department to prepare or provide a reappear as registered product in the European market such
necessary medicinal product not yet licensed causes as para-aminosalicylic acid in 2013 in the treatment of
dilemmas for the responsible pharmacist or the QP. The multidrug resistance of tuberculosis, If however the market
time needed for all of the quality controls does not allow for those orphan medicinal products continues to be small or
the product to be prepared and released very quickly for the alternatively huge investments are found necessary in less
acute use. Different options are open for the responsible frequently used production lines, the non-availability will
reappear or continue to exist. Profitability will not disappear 5. The CanMEDS Framework. Royal College of Physicians and
from industry, products will. surgeons of Canada. http://royalcollege.ca
6. Boer S de, Onderzoeksrapport Het beroep apothekersassistent in
Europa 2013 (in Dutch, but with websurvey in English). To be
obtained at secretariate of Optima Farma, secretariaat@op-
References timafarma.nl
7. Directive 2001/83/EC on the Community Code relating to medici-
1. European Committee for Standardization. EN 15224:2012: nal products for human use, Accessed 14 Oct 2013
E. Health care services – quality management systems – 8. Pharmaceutical Inspection Convention, Pharmaceutical Inspection
Requirements based on EN ISO 9001:2008 Co-operation Scheme. 6.5 Release. PIC/S guide to good practices
2. European Commission. Guidelines of 5 November 2013 on Good for the preparation of medicinal products in healthcare
Distribution Practice of medicinal products for human use 2013/c establishments. PE 010-1: 2008. http://www.picscheme.org
343/01. http://ec.europa.eu/health/documents/eudralex/vol-4/ 9. Directive 2005/36/EC of the European Parliament and of the Coun-
index_en.htm (Other documents related to GMP) cil of 7 Sept 2005 on the recognition of professional qualifications
3. European Commission (2011) The rules governing medicinal 10. Atkinson J, Rombaut B (2010) The Pharmine paradigm- Matching
products in the European Union.EudraLex Volume 9B – the supply of pharmacy education and training to demands;
Pharmacovigilance for Medicinal Products for Human and Veteri- European Industrial Pharmacy 6/6;4–7
nary Use. http://ec.europa.eu/health/documents/eudralex/vol-9/ 11. Faculty of Pharmacy and Pharmaceutical Sciences of the Monash
index_en.htm University. SABER project. http://saber.monash.edu/pharmatopia
4. European Commission. EudraLex—Volume 4. Good 12. ELOZ III program hospital pharmacist The Netherlands, to be
Manufacturing Practice (GMP) Guidelines. Annex 16. Certification obtained at the secretariate of NVZA, http://www.nvza.nl
by a Qualified Person and Batch Release. http://ec.europa.eu/ 13. Master in de industriële farmacie (KULeuven-U/Gent-VUB-UA).
health/files/eudralex/vol-4/pdfs-m/v4_an16_200408_en.pdf http://www.pharm.kuleuven.be
Occupational Safety and Health
26
Yvonne Bouwman-Boer, Shi Wai Ng, and Sylvie Crauste-Manciet
Contents 26.6 Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

26.6.1 Occupational Safety and Health Directives . . . . . . . . . . . . 569
26.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 26.6.2 European Regulation REACH . . . . . . . . . . . . . . . . . . . . . . . . . . 570
26.2 Definitions and Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 26.6.3 GHS and CLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
26.2.1 Categorisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 26.6.4 Carcinogens or Mutagens Directive . . . . . . . . . . . . . . . . . . . . 571
26.2.2 Containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 26.6.5 Pregnancy Workers Directive . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
26.3 Hazard of Pharmaceutical Substances . . . . . . . . . . . . . . . 553 26.7 Risk Mitigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

26.3.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 26.7.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
26.3.2 Hazard Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 26.7.2 Exposure Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
26.3.3 Carcinogenic, Mutagenic and Reprotoxic (CMR) 26.7.3 Risk Matrix Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
and Sensitisation Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554 26.8 Hazardous Substances in Hospital Pharmacy
26.3.4 Information Sources on Hazards . . . . . . . . . . . . . . . . . . . . . . . . 557 Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
26.3.5 Categorisation of Hazards of Substances . . . . . . . . . . . . . . . 559
26.3.6 Categorisation of Hazards of Products . . . . . . . . . . . . . . . . . 561 26.9 Calamities with Hazardous Substances . . . . . . . . . . . . . . 578
26.9.1 Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
26.4 Exposure Routes and Protection . . . . . . . . . . . . . . . . . . . . . 561
26.4.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 26.10 Needlestick and Sharp Injuries . . . . . . . . . . . . . . . . . . . . . . . 579
26.4.2 Eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
26.4.3 Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 26.11 Fire and Explosion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
26.4.4 Ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 26.11.1 Work Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
26.4.5 Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 26.11.2 Fire Prevention and Handling Measures . . . . . . . . . . . . . . . 581
26.5 Exposure Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581

26.5.1 Necessity of Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
26.5.2 Advanced REACH Tool (ART) . . . . . . . . . . . . . . . . . . . . . . . . 564
26.5.3 Exposure at Pharmacy Preparation . . . . . . . . . . . . . . . . . . . . . 566
26.5.4 Surface Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 Abstract
Hazardous substances according to the European legisla-
tion are those substances with at least one ‘H(azard)-state-
ment’. While preparing medicines or manipulating them,
Based upon the chapter ‘Arbeidsomstandigheden’ by Mirjam Crul and exposure to hazardous substances as such or as medicinal
Yvonne Bouwman-Boer in the 2009 edition of Recepteerkunde. products can occur, which may cause a health risk. The
Y. Bouwman-Boer types of toxicity (acute, chronic, carcinogenicity, teratoge-
Royal Dutch Pharmacists Association KNMP, Laboratory of Dutch nicity, sensitisation, etcetera) together with the extent and
Pharmacists, The Hague, The Netherlands route of exposure, determine the health risk. This chapter
S.W. Ng (*) focuses on exposure via inhalation and skin contact.
Royal Dutch Pharmacists’ Association KNMP, Den Haag, Categorisation of toxicity according to a REACH com-
The Netherlands
patible approach as well according to NIOSH is dealt with.
For categorisation of exposure the Advanced REACH
S. Crauste-Manciet
Tool as well as a specific model for pharmacy preparation
Laboratoire de Pharmacie galénique, Bordeaux University,
U689 Inserm, Bordeaux, France is discussed. Exposure via surface contamination is well
researched for antineoplastic medicines with wipe tests.
CHU de Bordeaux, Groupe Hospitalier Sud, Bordeaux, France
e-mail: [email protected]; sylvie.crauste- Employers have the primary legal responsibility for
[email protected] the occupational safety and health of their workers and

should assess and diminish health risk to a level that is resulting risk does not take the form of a concrete level or
accepted by society. value. Still the pharmacist wants to know if the health risk is
Workers have a legal duty to protect their own safety acceptable or not.
and health and that of their co-workers within the phar- This chapter describes proper handling of hazardous
macy or organisation. The European regulations on occu- substances in the workplace and exposure to these hazardous
pational safety and health are discussed. The strategies substances. It provides some risk assessment methods for
for preventing or minimising risks are discussed, includ- different types of preparation and handling of hazardous
ing the use of collective (containment, ventilation) and substances and medicines. However, other risks that are
personal protective equipment such as gloves and not covered by this chapter should be considered as well,
respirators. Occupational Exposure Levels (OELs), risk in particular work stress and ergonomics which may give
acceptance and communication about best practice are rise to musculoskeletal disorders.
part of such strategies. In addition, this chapter focuses on, calamities, needle-
Fire, explosion, calamities and sharp injuries are dealt stick and sharps injuries, fire and explosion
with separately.
There are many examples of medicines that can be
Keywords
hazardous when prepared. Common situations that
Hazard Toxicity Exposure level Health risk
may present significant risks to the operator include:
REACH NIOSH Legislation Hazardous substances
– Some antibiotics, such as penicillins, that with
CMR Wipe test OEL Calamity Sharps Fire
inhalation or skin contact may cause serious aller-
gic reactions. Proper precautions should be taken
by individuals allergic to the penicillin class of
26.1 Orientation substances to minimise or eliminate exposure
when in a facility where penicillin class of products
Although the intent of preparation of medicines is to are handled.
benefit patients, the substances used may present occupa- – Aseptic handling of antineoplastic medicines, such
tional hazards to the operators preparing these medicines. as injections prepared with cyclophosphamide.
Pharmacists, nurses, doctors and others who prepare, han- – Preparation of capsules, creams, suppositories or
dle and administer these medicines may be exposed to eye drops with steroids such as progesterone, tes-
significant health risks during their work. The greatest tosterone, estradiol, and estriol.
risk is for the operators, but people in adjacent work
areas (e.g. clerical workers, support staff, maintenance
personnel, and visitors) may also be at risk from exposure
by inhalation of aerosols or by contact with contaminated
surfaces and floors. Pharmacists may be expected to be the 26.2 Definitions and Principles
professionals who should know most about this topic, but
consultation of an occupational health specialist is neces- This section defines and describes the main concepts of
sary as well. occupational safety and health that are used in this chapter:
Employers should determine if their workers are at risk of (health) risk, hazard, exposure, (health) risk assessment,
exposure to hazards associated with preparation, reconstitu- categorisation and containment.
tion, repackaging, etcetera. Specific measures should be Risk is defined as: the likelihood that the potential for
implemented to reduce direct skin contact, reduce exposure harm will be attained under the conditions of use and/or
via inhalation and minimise the possibility of chemicals exposure, and the possible extent of the harm [1]. In other
being brought home on workers’ clothing. As with all poten- words, risk is the probability that exposure to a hazard will
tially hazardous exposures, protective measures should lead to a negative consequence.
include: engineering controls (e.g. barriers and Hazard is the intrinsic property or ability of something
containments, laboratory hoods, glove boxes, and worker (e.g. work materials, work methods and equipment) with the
isolation), administrative controls, personal protective potential to cause harm [1].
equipment (e.g. respirators, gloves and lab coats) and Exposure is the state of being in contact with something,
training. either directly or indirectly. For example through
For contact with hazardous substances in the pharmacy contaminated surfaces or clothes. A hazardous substance
categorisation models are developed for both hazard may cause harm if the worker is exposed to it. Exposure to
(Sect. 26.3.5) as well as exposure (Sect. 26.5.3) because a substance means that the substance is in close contact with
there is little quantitative data known. This means that the the body that may lead to interaction or even harm. Exposure
26 Occupational Safety and Health 553
has two qualities: its route and its level. Only a significant several uncertainties will affect the ‘accounting’ of the risk,
level of exposure, which can be extremely low such as with the risk is not an exact characteristic, level or value, although
sensitisation, via a relevant route may lead to harm. qualifications as: ‘high’, ‘medium’ and ‘low’ can be given.
Health risk – or potential harm – depends on hazard
severity and level of exposure, and thus depends on the
substance’s characteristics and the nature of the work. The 26.2.2 Containment
relationship between risk, hazard and exposure is expressed
in: Containment is an engineering control measure, the second
Risk ¼ hazard exposure risk mitigation principle (see Sect. 26.7.1). It may be defined
as a process or device to contain product, dust or
If there will be no exposure to a substance, no matter how contaminants in one zone, preventing it from escaping to
hazardous it may be, there is no risk of harm. Substances another zone [2] or, to put it differently, the prevention of the
which pose only a small hazard but to which there is frequent escape of a substance.
or excessive exposure may pose as much risk as substances
which have a high degree of hazard but to which only limited
exposure occurs. 26.3 Hazard of Pharmaceutical Substances
The terms hazard and risk are often used interchangeably,
however these are two very distinct terms. Basically, a 26.3.1 Definition
hazard is anything that can cause harm or adverse effects.
A hazard poses no risk if there is no exposure to that hazard. This section discusses the hazard that may be created by
Health risk assessment is the process of examining and substances used to produce medicines, with emphasis on
evaluating the risk to the health and safety of workers while workers in health care. These workers are mainly
at work arising from the circumstances of the occurrence of a pharmacists, operators, nurses and doctors.
hazard at the workplace [1]. A risk assessment is a careful Every substance can present a hazard in general. In prin-
examination of what, at the workplace, could cause harm to ciple, being ‘hazardous’ is a consequence of one or more
people, so that the employer can decide whether he has taken intrinsic hazard properties of a substance. In accordance
enough precautions or should do more to prevent harm. with the Classification, Labelling and Packaging (CLP) Reg-
Workers and others have a right to be protected from harm ulation [3], see also Sect. 26.6.3, hazardous substance are
caused by a failure to take reasonable control measures. those substances that fulfil the criteria of at least one hazard
PRODUCTION
Accidents and ill health can ruin lives and affect the business class. The hazard classes comprise physical hazards, health
too if for example output is lost, machinery is damaged, hazards or environmental hazards (see Sect. 26.3.2).
insurance costs increase or the employer even have to go However, the use of the term ‘hazardous substances’ with
to court. regard to pharmacy preparation and reconstitution, is often
As a rule risk levels are treated for setting priorities: to restricted to carcinogenic, mutagenic and reprotoxic
decide about the risks that have to be mitigated in the first substances. Radiopharmaceuticals and gene therapeutics
place. may be counted under this term as well. The National Insti-
If a manufacturer will be reproached or even sued by any tute of Occupational Safety and Health of the US (NIOSH)
competent body, it will be based on a societal decision about however also counts substances with a high chronic toxic
the level of risks that is not (any more) accepted by a group potential to ‘hazardous substances’, see further Sect. 26.3.3.
or nation: ‘society’. So the term hazardous substances may have different
notions. In this chapter the CLP definition is followed mean-
ing that all substances are considered potentially hazardous.
26.2.1 Categorisation Carcinogenic, reprotoxic and mutagenic substances are
either noted as such or as a group as CMR. Occupational
The risk of each work situation with exposure to substances safety and health care investigates all processes and all
is unique: it depends on the hazards of the substances, on the substances, to prevent health damage of workers.
exposure of the worker to these substances and on the physi-
cal condition and constitution of the worker. However, it is
practically impossible to investigate the risk for any individ- 26.3.2 Hazard Types
ual in any situation. Therefore categorisation is applied to
exposure as well as to hazards of substances and even Hazards of substances can be acute, for example if a strong
individuals. With categorised hazards and exposures, also acid is spilled on the skin, or chronic, if long term exposure
the risks (¼ hazard exposure) are categorised. Because results in health damage, such as sensitisation or cancer.
The Globally Harmonised classification and labelling European countries and are based on CLP regulations, see
System (GHS, see Sect. 26.6.3), discerns three major hazard further Sect. 26.6.3.
groups:
• Physical hazards: hazards that are directly safety-
According to the Regulation (EC) No 1272/2008 [3],
threatening, for example, substances and mixtures that
the substance morphine hydrochloride is for example
are (in)flammable or explosive (such as ether and
provided with the following hazard en precautionary
ethanol).
statements [6]:
• Health hazards: Firstly direct hazards (acute toxicity),
such as from substances that are irritating (trichloroacetic H302 Harmful if swallowed
acid, sodium hydroxide), intoxicating (ether) or H336 May cause drowsiness or dizziness
suffocating. Secondly hazards that arise in the longer P261 Avoid breathing dust/fume/gas/mist/vapours/
term (chronic toxicity), such as damage to the respiratory spray
system, the nervous system or reproductive organs in the P264 Wash hands and other exposed areas thoroughly
after handling
long term. Also skin and airway allergies and cancer
P301 + P312 IF SWALLOWED: call a POISON CENTER or
belong to this type of hazards.
doctor/physician if you feel unwell
Within chronic health hazards a further distinction is P304 + P340 IF INHALED: remove victim to fresh air and
made into: keep at rest in a position comfortable for
– Carcinogenic: may induce cancer or increase its breathing
incidence P312 Call a POISON CENTER/doctor/physician if
– Mutagenic: may induce heritable genetic defects or you feel unwell
P330 Rinse mouth
increase their incidence
P403 + P233 Store in a well-ventilated place. Keep container
– Reprotoxic: may produce or increase the incidence of tightly closed
non-heritable adverse effects in the offspring and/or P501 Dispose of contents/container to: Hazardous
causes either a decrease in fertility or problems with waste. Comply with applicable regulations
foetal development
– Respiratory sensitising/inhalant allergenic: causes In addition, the signal word ‘Warning’ and a picto-
allergy via inhalation gram with a white background, a red frame and an
• Environmental hazards: for example substances and exclamation mark identify morphine hydrochloride.
mixtures that are directly or in the long term a hazard to Each packaging must be labelled with the
aquatic life or that are poorly degradable. This group also relevant hazard pictograms, signal word and H- and
include hazards to the ozone layer. Environmental P-statements. More detailed hazard and precautionary
hazards are further dealt with in Chap. 38. information can be found in the material safety data
sheets (MSDS) of the substance.
26.3.2.1 Hazard and Precautionary Statements

in GHS
The GHS defines Hazard and Precautionary statements
(in brief H- and P-statements), which represent standard 26.3.3 Carcinogenic, Mutagenic and Reprotoxic
phrases used to respectively describe the hazards of hazard- (CMR) and Sensitisation Hazards
ous substances and mixtures and the recommended measures
to be taken when using/disposing of hazardous substances The carcinogenic, mutagenic and reprotoxic hazards are
and mixtures. The GHS couples any H-statement to a together called CMR hazards. Substances that are carcino-
P-statement. These statements will assist in ensuring that genic, mutagenic or reprotoxic (CMR substances) are of
all users of the products, worldwide, will know and under- very high concern due to the long term and serious effects
stand proper precautionary measures when interacting with that they may exert on human health. Within the regulation
the chemicals. on Registration, Evaluation, Authorisation and Restriction
H- and P-statements are one of the key elements for the of Chemicals, Regulation (REACH) (see Sect. 26.6.2) CMR
labelling of containers under the GHS. Some H-statements substances are classified and listed in Annex VI of the EU
are depicted as EUH-statements (these are a classification GHS Regulation [4]). Substances appear on this list if they
from previous legislation). These apply, legally, only to are registered under REACH or notified under the CLP
regulation (see Sect. 26.6.3) or both. The classification in

Annex VI is legally binding for Europe. National authorities Table 26.1 Correspondence between H-statements and
European CMR classification
may have extended this list with substances they consider
being relevant [7]. Category 1A Effects on or
The National Institute for Occupational Safety and Health or 1B Category 2 via lactation
(NIOSH) of the United States describes in the section ‘Deter- Carcinogens H350: May H351: Suspected
cause cancer of causing cancer
mining whether a drug is hazardous’ how human and animal
Mutagens H340: May H341: Suspected
data on carcinogenicity, reprotoxicity and genotoxicity are cause genetic of causing genetic
interpreted for their list of hazardous substances [8]. defects defects
Reprotoxics H360: May H361: Suspected H362: May
26.3.3.1 Classification of Carcinogens damage of damaging cause harm
fertility fertility or to the
According to CLP, CMR substances are classified into three or the unborn or unborn child breast-fed
categories based on the strength of evidence showing that child children
they present one of the CMR types of hazards to human
health. Apart from the European CMR classification, there
are other classifications, in particular the classification sys-
tem established by the International Agency for Research on
26.3.3.2 Carcinogenicity and (Non-)Genotoxicity
Cancer (IARC). This classification includes agents, groups of
Apart from differentiation on the basis of the level of evi-
agents, mixtures and carcinogenic exposure circumstances. It
dence, as done by categories 1A, 1B and 2, another distinc-
includes four groups of classifications, based on different
tion within the category carcinogenic substances can be
levels of scientific evidence of carcinogenicity for humans.
made: whether they are genotoxic or non-genotoxic.
Genotoxic carcinogens interact directly with DNA,
European CMR classification [5]: causing damage to DNA which may lead or contribute to
– Category 1A: Classification is largely based on cancer development. Non-genotoxic carcinogenic
human evidence. substances have no direct interaction with DNA but are
– Category 1B: Classification is largely based on capable of influencing by one of many secondary
animal evidence. mechanisms the proliferation process of the tumour,
– Category 2: Classification is based on the evidence thereby leading or contribute to cancer. The action of
obtained from human and/or animal studies, but non-genotoxic substances is subjected to a threshold;
PRODUCTION
which is not sufficiently convincing to place the below a certain concentration there will be no effect
substance in Category 1A or 1B. (No Observed Effect Level, NOEL). By definition for
Carcinogenic classification from IARC [9]: genotoxic carcinogens no safe threshold without a theoreti-
– Group 1: “Carcinogenic to humans” There is cal cancer risk can be derived.
enough evidence to conclude that it can cause can- This difference between genotoxic and non-genotoxic
cer in humans. carcinogens brings about a principally different approach
– Group 2A: “Probably carcinogenic to humans” to protection. If exposure to non-genotoxic substances does
There is strong evidence that it can cause cancer not exceed the threshold value, humans are considered to be
in humans, but at present it is not conclusive. safe from getting cancer from those substances, just as is the
– Group 2B: “Possibly carcinogenic to humans” approach regarding other toxic substances having a thresh-
There is some evidence that it can cause cancer in old value. Exposure to even one molecule of a genotoxic
humans but at present it is far from conclusive. substance however may lead to cancer, although the chance
– Group 3: “Unclassifiable as to carcinogenicity in that it occurs is limited. A decision about that limited level of
humans” There is no evidence at present that it risk is made by society. This leads to an acceptable level of
causes cancer in humans. exposure, rather than a threshold, to keep a distinction
– Group 4: “Probably not carcinogenic to humans” between both approaches. With a genotoxic carcinogen,
There is strong evidence that it does not cause linear extrapolation is used for estimating the risks
cancer in humans. associated with a given level of exposure [10].
The corresponding H-statements (see Sect. 26.3.2) for For pharmacy practice this distinction between genotoxic
CMR substances, according to the European CMR and non-genotoxic carcinogenic substances is at the moment
classification, are depicted in Table 26.1. of little practical value, because only very few carcinogenic
active substances have been defined as non-genotoxic.
(continued)
damage to DNA in different ways, but only when there has

Among the most widespread non-genotoxic been damage to DNA in sperm and ova, are they mutagenic.
carcinogens are a group of compounds collectively Mutagenicity is thus a form of genotoxicity (Fig. 26.1).
referred to as peroxisome proliferators. Peroxisome
proliferators are a diverse class of chemicals, includ- 26.3.3.4 Classification of Monoclonal Antibodies
ing the lipid and cholesterol lowering fibrate drugs (mAbs)
(clofibrate, fenofibrate, and gemfibrozil), plasticisers A decade ago all antineoplastic agents (ATC class L01) were
(phthalate esters), solvents (e.g., trichloroethylene), considered to be carcinogenic. That is no longer the case,
and naturally occurring chemicals (e.g., phenyl ace- especially if monoclonal antibodies (mAbs) are considered.
tate) or hormones (e.g., dehydroepiandrosterone NIOSH re-evaluated the inclusion of monoclonal
sulfate) [11]. antibodies as hazardous substances because of their specific
Chloroform is another example of a non-genotoxic targeted mechanisms of action and their high molecular
carcinogen. In most European countries chloroform weight that prevent skin penetration and accidental inhala-
has a 8 h limit value (see Sect. 26.7.2) of 10 mg/m3 tion. The 2014 NIOSH list of hazardous substances [8]
[12]. contains now only mAbs conjugated with antineoplastic
active substances.
A German working group evaluated whether mAbs are to
As a summary Table 26.2 lists the characteristics of
be classified as carcinogens, mutagens or reprotoxic at der-
genotoxic and non-genotoxic carcinogenic substances.
mal, oral or inhalative exposure. Sensitising properties were
It is to be noted that the decision on a threshold and a
evaluated as well. They assigned H-statements to mAbs
non-threshold mode of action may not always be easy to
based on a systematic literature review, European
make, especially when, although a biological threshold may
public assessment reports (EPARs) and data provided by
be postulated, the data do not allow identification of it. If not
national and international occupational safety and health
clear, the assumption of a non-threshold mode of action
organisations. Expert opinions were also obtained.
would be the prudent choice.
Recommendations for the protection of workers handling
Establishing exposure limits with genotoxic and
mAbs were agreed with experts in the fields of chemistry,
non-genotoxic substances, is dealt with in Sect. 26.7.2.
pharmacy and occupational safety as well as representatives
of the pharmaceutical industry. They happened to classify
26.3.3.3 Reprotoxicity some mAbs as reprotoxic however not as carcinogenic
Next to the classification based on the evidence, also for [14, 15].
reprotoxic substances two types of toxicity can be discerned: Swiss hospital pharmacists [16] do not consider monoclo-
1. Mutagenic: causes damage to genetic material in sperm nal antibodies as hazardous for healthcare practitioners and
and ova; only gloves are recommended for their manipulating at
2. Teratogenic: causes damage to the unborn child. wards.
The concepts of genotoxicity and mutagenicity are some-
times used interchangeably, but do not have the same con- 26.3.3.5 Respiratory Sensitisation
tent. All mutagens are genotoxic, however not all genotoxic Exposure to inhalant allergens can lead to respiratory
substances are mutagenic. Genotoxic substances can cause allergies. This generally begins with sensitisation (¼ to
Table 26.2 Characteristics genotoxic and non-genotoxic substances (From Klaunig et al. [13] with permission)
Genotoxic carcinogens Non-genotoxic carcinogens
Mutagenic Non-mutagenic
Direct DNA reactivity Non-directly DNA reactive
Tumorigenicity is dose response
Threshold?? Exhibits threshold
Can be complete carcinogens
Irreversible Reversible
Usually not strain or species specific Usually exhibits strain, species and tissue specificity
Functions at initiation and progression stages of cancer process Functions at the tumour promotion stage of the cancer process
Examples: nitrosamines, polycyclic aromatic hydrocarbons, Examples: chlorinated substances, organochlorine pesticides, hormones,
aromatic amines barbiturates
Fig. 26.1 The relation between carcinogenic reprotoxic

mutagenicity and genotoxicity
non -
genotoxic mutagenic
genotoxic teratogenic
become sensitive to the relevant substance). Eventually,

however, an allergy develops that is harmful to health, Reliability of SDSs
even when exposure is minimal. The clinical description of The compilation of a good SDS requires extensive
this process is to be found in [10]. For the endpoints knowledge in different fields, as the SDS itself covers
sensitisation and irritation it is supposed that a substance a wide range of aspects concerning the substance or
exerts its effect by a threshold mode of action, but the mixture properties, occupational health and safety,
available data do not allow a reliable identifcation of the transport safety and environmental protection.
threshold [10]. A situation similar to that of genotoxic REACH indicates that the SDS should be compiled
carcinogens occurs. This will lead to a similar risk-based by a competent person, but no specific definition of
approach to setting exposure levels (see Sect. 26.7.2). competent in this context is given in the
Regulation [20].
The SDS is commonly first compiled by the manu-
facturer but the requirements of REACH in relation to
26.3.4 Information Sources on Hazards
the provision of SDSs apply at each stage of the supply
chain. Any supplier of a substance or mixture must
Information on hazards of substances may originate from
provide a SDS for it. Each supplier remains responsi-
several sources. The first recommended source is the Safety
PRODUCTION
ble for the accuracy of the information in the SDS they
Data Sheet (SDS) of substances and mixtures, under the
provide even though they may not have prepared the
REACH regulation. The second source may be human toxi-
safety data sheet.
cological and pharmacologic data.
Some of the SDSs found on the Internet may be of
questionable quality or may not be the most current
26.3.4.1 Safety Data Sheets version. The manufacturer is often the best source of
The SDS contains information on the identity of the sub- the current and accurate SDS. Employers may rely on
stance or the mixture, potential health effects, toxicological the information received from their suppliers. If
properties, physical hazards, safe use, handling and storage, receiving one that is obviously inadequate, an appro-
emergency procedures, and disposal requirements specific to priately completed one should be requested.
the chemical (see Fig. 26.2). Intermediate products are to be A number of studies and investigations have
considered as mixtures of substances. raised concern that some SDSs may be incomplete or
For some products, such as licensed medicines, safety contain erroneous or out-of-date information. The
data sheets do not have to be provided [18] but sometimes U.S. Occupational Safety and Health Administration
suppliers provide them anyhow. So if pharmacists or nurses (OSHA) has confirmed there are inaccurate SDSs
have to manipulate oral dosage forms they usually cannot in circulation, but a comprehensive study on this
refer to a SDS but sometimes they can. The Summary of topic that provides more than anecdotal evidence
Product Characteristics (SmPCs) usually doesn’t provide about a limited number of SDSs has not been
information for these situations. In the United States performed [21].
so-called manufacturers’ safe handling guidance (MSHG) The authors consider the SDSs for the Ph. Eur.
are available for some medicines, including antineoplastics reference substances [22] as a reliable source of
[19] and in section 16 of the Label information leaflet a safe- SDSs for pharmaceutical substances.
handling warning may be given.
PARACETAMOL CRS
Safety Data Sheet
Safety Data Sheet in accordance with Regulation (EC) No. 1907/2006, as amended.
Date of issue: 22/08/2013 Revision date: 07/03/2014 Supersedes: 22/08/2013 Version: 10.0
SECTION 1: Identification of the substance/mixture and of the company/undertaking

1.1. Product identifier
Product form : Substance
Trade name : PARACETAMOL CRS
EC no : 203-157-5
CAS No : 103-90-2
Product code : P0300000
Other means of identification : RTECS No : AE4200000 (paracetamol)
1.2. Relevant identified uses of the substance or mixture and uses advised against
1.2.1. Relevant identified uses
Main use category : The product is intended for research, analysis and scientific education.
Use of the substance/mixture : For professional use only
Function or use category : Laboratory chemicals
1.2.2. Uses advised against

No additional information available
1.3. Details of the supplier of the safety data sheet
European Directorate for the Quality of Medicines & Healthcare
EDQM, Council of Europe
67081 Strasbourg - France
T +33(0)388412035 - F +33(0)388412771
www.edqm.eu
1.4. Emergency telephone number

Emergency number : +44(0)1235239670
SECTION 2: Hazards identification

2.1. Classification of the substance or mixture
Classification according to Regulation (EC) No. 1272/2008 [CLP]
Acute Tox. 4 (Oral) H302

STOT RE 2 H373
Aquatic Chronic 3 H412
Full text of H-phrases: see section 16
Classification according to Directive 67/548/EEC or 1999/45/EC

Not classified
Adverse physico-chemical, human health and environmental effects

No additional information available
2.2. Label elements
Labelling according to Regulation (EC) No. 1272/2008 [CLP]
Hazard pictograms (CLP) :
GHS07 GHS08
Signal word (CLP) : Warning
Hazard statements (CLP) : H302 - Harmful if swallowed
H373 - May cause damage to organs through prolonged or repeated exposure
H412 - Harmful to aquatic life with long lasting effects
Precautionary statements (CLP) : P260 - Do not breathe dust/fume/gas/mist/vapours/spray
P264 - Wash hands and other exposed areas thoroughly after handling
P270 - Do no eat, drink or smoke when using this product
P273 - Avoid release to the environment
P301+P312 - IF SWALLOWED: Call a POISON CENTER/doctor/…/if you feel unwell
14/03/2014 EN (English) 1/6
Fig. 26.2 First page of a EDQM safety data sheet of paracetamol [17]
26.3.4.2 Human Toxicological approach: 4 or 5 categories of increasing hazards with cate-

and Pharmacologic Data gory 1 representing the lowest grade with the (relatively)
For occupational safety and health information for the prep- lesser hazards and the highest category (which is 4 or
aration of pharmaceutical products a second valuable source 5 depending on the model) containing the most serious
about hazards is the information on pharmacologic and hazards. Only Tielemans [26] and Vincent [27] make use
toxicological effects on humans of active substances and of the GHS hazard statements. All of them make use of
excipients. This information can be used with some human toxicological and pharmacologic information.
restrictions: H-statements (in fact the original R-phrases) have been
• For occupational safety and health, the inhalation and divided over the different categories guided by the COSHH
dermal routes are most interesting; most therapeutic (Control of Substances Hazardous to Health) essentials
information is however about oral and parenteral scheme [28], mainly led by the height of exposure giving
administration. toxic effects, the presence of a threshold value, the severity
• Any adverse effect is accepted (or not) by a patient in of the effect and reversibility of the effect.
relation to his illness; for workers the same effect usually Table 26.3 reflects the general approach that all three
weighs more heavily because it is related to a long-lasting sources follow. About category 1 Tielemans [26] says: If
work situation. there is no exposure limit value, no H-statements to attach,
no dosage details are known and it is plausible that the
26.3.5 Categorisation of Hazards of Substances substance causes no harm; the substance is classified into
hazard class 1. Whereas Ader [24] considers category 4 as
Categorisation of hazards of substances (also called ‘control the ‘default category’, to be understood as: if there are any
banding’) instead of considering every substance separately doubts about harmlessness, consider it to belong to cate-
serves practical work procedures. Two approaches are met: gory 4.
• Categorisation of all substances based on grouping The relation between hazard statements and classes of the
H-statements and making use of human toxicologic and system of Tielemans [26] are given in Table 26.4, with the
pharmacologic data notion that the translation of the R-statements into the H-
• Categorisation of the most toxic substances by a proce- statements, is the authors’ view.
dure with public consultation (NIOSH)
This categorisation system relates to occupational
26.3.5.1 Categorisation Based on the GHS exposure limits (OELs) as well. An OEL being a
and Human Toxicology limit level of exposure (so the product of hazard
PRODUCTION
and Pharmacology exposure, see Sect. 26.2), it needs some explanation as
Based on the ideas of Naumann [23]: categories of hazards to how it is used in the categorisation of just hazards.
of pharmaceutical substances have been distinguished by Although the reason for categorisation is to determine
3 (groups of) investigators: Ader et al. [24, 25], Tielemans
et al. [26] and Vincent et al. [27]. They all use a comparable (continued)
Table 26.3 Categories of hazards, generalised approach based on [24–27]

Category 1 Category 2 Category 3 Category 4 Category 5
Harm characterisation Very low Low Intermediate High Extremely high
Type of toxicity (example) Reversible Reversible Irreversible effects Irreversible effects
(for connection with Low acute Systemic toxicity Carcinogenicity, Genotoxic carcinogenicity,
H-phrases see Table 26.4) or chronic mutagenicity, reprotoxicity mutagenicity, reprotoxicity
toxicity
Pharmacological effect, Very low Low (effect Moderate (toxicity Significant potency Highly potent
potency > 100 mg/day at at 0.1–10 mg/day) (effect ~ 0.01–1 mg/kg or pharmacological effect
10–100 mg/ 0.1–1 mg/day clinical dose) (~10 micrograms/kg
day) or < 0.1 mg/day)
Example of adverse effect Irritant to Weak (skin or Sensitisers Severe sensitisers
the skin or respiratory)
eyes sensitisers
Approximate OEL [24] >0.5 mg/m3 10 micrograms/m3 30 ng/m3 to <30 ng/m3
3 3
to 0.5 mg/m 10 micrograms/m
Approximate OEL [26] >5 mg/m3 1–5 mg/m3 10–1,000 1–10 micrograms/m3 <1 micrograms/m3
micrograms/m3
Table 26.4 Categorisation based on hazard statements, OEL and therapeutic dose [26]
Category (hazard class)
560
Criterium 1 2 3 4 5
Therapeutic dose (mg/day) >100 10–100 0.1–10 0.1 <0.1
Occupational Exposure Limit value >5,000 1,000–5,000 10–1,000 1–10 1
(micrograms/m3)
Acute toxicity H304 H302 H301 H300 H370 (R39/26, R39/26/27, R39/26/27/28,
H336 H312 H311 H310 R39/26/28, R39/27, R39/27/28, R39/28)
H332 H331 H330
H371 H370 (R39/23, R39/23/24, R39/23/24/25, R39/23/
25, R39/24, R39/24/25, R39/25)
Irritation (skin, respiratory tract H315 H314
and/or eyes) H319 H318
EUH066 H335
Sensibilisation (skin and or H317
respiratory tract) H334
Chronic toxicity H373 H372
Mutagenicity H340
H341
Carcinogenicity H351 H350
H350i
Reproduction toxicity H360F
H360D
H361f
H361d
Flammability H224 (flash point < 23 C and H224 (boiling H220
boiling point 35 C) point 35 C)
H225 (flash point < 23 C and H225 (boiling H221
boiling point > point > 35 C)
35 C)
H226 (flash point 23 C) H250 H224
EUH018 H242
EUH029
Explosivity EUH001 H200
EUH006 H201
EUH019 H202
EUH044 H203
H204 H205
H240
H241
Oxidising properties H242
H270
H271
Y. Bouwman-Boer et al.
Reactivity with water EUH014

While the majority of the hazardous active substances in

a limit for maximal exposure for each individual sub- the NIOSH list are antineoplastics, active substances from
stance is not feasible, it is still an ambition. For several other classes are included, such as phenytoin and tacrolimus
substances, mainly those to which many workers and [8]. As part of the categorisation some reference is given
the general public may be exposed, reliable occupa- about which hazard is the main reason for being included in
tional exposure limits (OELs, see Sect. 26.7.2) have the list. This NIOSH list is updated regularly which is a great
been determined. If these OELs are related to other advantage, however as said only the most hazardous
characteristics of those substances, the OELs could substances are included.
virtually be put into the categorising systems. By
doing so, the categories of the system could be
provided with ‘approximate OELs’. 26.3.6 Categorisation of Hazards of Products
Categorisation of pharmaceutical preparations (within the

As an example Table 26.5 gives per category about
field of occupational safety and health seen as mixtures)
10 active substances that have been categorised following
into hazard categories is relevant because exposure to it
Table 26.4, with expert interpretation.
can occur in practice. This happens for example when
dissolving a mixture of freeze-dried substances or by the
26.3.5.2 Categorisation by NIOSH crushing of tablets for patients who cannot swallow.
The National Institute for Occupational Safety and Health Customising H-statements from substances to products
(NIOSH) of the United States has developed a categorisation though is not simple. The GHS sets a calculating method for
system for ‘hazardous substances’. NIOSH defines hazard- fixing the health hazard of mixtures of substances. The
ous pharmaceutically active substances using six criteria: hazard of a mixture depends on the type of hazard and how
1. Carcinogenicity the concentration of the substances affects the hazardous
2. Teratogenicity or other developmental toxicity properties in the preparation. The GHS gives per separate
3. Reproductive toxicity H-statement, if relevant, on how to determine whether the
4. Organ toxicity at low doses in humans (<10 mg/day) or H-statement is maintained, changes or expires depending on
in animals (<1 mg/kg/day) the concentration in the mixture. For instance for a property
5. Genotoxicity such as corrosiveness, a 10 % content in a mixture may lead
6. Structure and toxicity profile of new active substances to a tenfold decrease of hazard. But for a property such as
that mimic existing active substances determined hazard- mutagenicity, although the content in a mixture may be only
PRODUCTION
ous by the above criteria 0.1 %, the hazard may be classified as large as with a 100 %
NIOSH reviews each active substance on an individual basis content [30].
and does not group them into classes. The review process
is accounted for in [29], from which it can be concluded
that: 26.4 Exposure Routes and Protection
• Safe handling recommendations from the manufacturer
of a medicine is followed without requiring further Different routes may lead to exposure to hazardous
review. substances at the workplace:
• Peer reviewers and stakeholders are independently – Inhalation
reviewing the status of specific active substances. – Eye contact
• NIOSH experts made the final determination; some sci- – Skin contact; primarily with the substance or secondarily
entific principles that are followed in that process are via contaminated surfaces
given in [8]. – Ingestion
• Draft conclusions are published for public review. – Injection
Table 26.5 Hazard categorisation of substances according to the model described in this section: some examples per categorya
Category (hazard class) Examples of active substances and excipients
1 Aluminium magnesium silicate, borax, ethanol, magnesium oxide, paracetamol, peppermint oil, sodium citrate
2 Acetylsalicylic acid, aspartame, caffine citrate, isoniazide, lidocaine, nitrazepam
3 Butylhydroxytoluene, clioquinol, cocaine hydrochloride, hydrocortisone acetate, phenytoin, omeprazole, salicylic acid,
tetracycline hydrochloride
4 Atropine sulphate, boric acid, ethinylestradiol, lithium carbonate, testosterone propionate, thioguanine, tretinoin
5 Coal tar, colchicine, ganciclovir, methotrexate, mitomycin, paclitaxel, vincristine
a
For more information or an update the second author can be approached
26.4.1 Inhalation Respiratory protection products or respirators are

classified on the basis of the achieved applied protection
When an individual breathes in polluted air, any substance factor (APF). This is the factor by which the exposure by
may enter the respiratory tract causing direct harm to the inhalation is reduced as the protection equipment is used in
respiratory system and indirect harm due to uptake via the required manner. Dust filters are positioned in three
ingestion. Especially sensitising substances may require classes: FFP1, FFP2 and FFP3, usually called P1, P2 and
attention. As airways and the lung cannot be closed off, P3 respectively. They provide protection against powders or
only ventilation (exhaustion) and filtration of inhaled air aerosols or both.
remain as protective measures, such as working in safety Respirators should comply with national or European
cabinets and wearing masks with air filters (respirators). standards such as EN 143 for Particulate filters and EN
Ventilation, at which the air that is contaminated with the 149 for Filtering half masks to protect against particles.
substance is carried away from the operator, reduces the Distinction has to be made between suitability for solid or
exposure. Filtration may be necessary to prevent the with- liquid particle filtration.
drawn air from contaminating people elsewhere. Ventilation FFP1-filters have an APF of 4 for solids, FFP2-filters
or exhaust can be achieved with the following measures of have an APF of 10 and FFP3-filters have an APF of 20.
increasing effectiveness; also increasing containment is Quarter masks (which cover a quarter of the face), half-face
attained: masks and full-face masks can be discerned. The half- and
• Ventilation of the work space full-face masks can, if provided with a combined filter for
• Use of powder exhaust unit or a fume cupboard both gas and dust, attain an APF of 40. In addition, quarter or
• Use of safety cabinet half-face masks if provided with filters for both gas and dust
• Use of isolator have an APF of 10 for liquids. Full-face masks have an APF
Powder and vapour (fume) exhaustion is the first measure of 20 for liquids.
to protect the respiratory system of the operator against the In pharmacy practice employers sometimes choose to pro-
hazards of substances. See Sect. 28.3 for a discussion about vide respirators instead of buying safety cabinets or isolators.
the equipment and its effectiveness. Section 27.5.1 goes into This is against the general principles of risk mitigation (see
the air handling (HVAC) of premises when the product Sect. 26.7.1) and may only be accepted if preparation scarcely
should be protected from the operator (with aseptic pro- takes place. Some specific situations however rely on personal
cesses) as well as the operator from the product. respiratory protection by respirators:
For protection of the airways to inhalation of substances, • As an additional measure to working in a safety cabinet
respirators can be used. Effective respirators however are not with solid (powdered) substances of the highest hazard
pleasant to wear, as the worker never breathes freely and category (which is 4 or 5 depending on the model) for
they may be rather heavy as well. Many mouth masks are example with the preparation of capsules
provided with an in- or exhalation valve or both which eases • Processing heavily corrosive substances
breathing, see Fig. 26.3. • In case of calamities
Fig. 26.3 Examples of FFP2

disposable respirators
It is not necessary to wear a respirator when working in an together in order to avoid contaminating the product and
isolator except when the containment is breached for exam- causing an accident with rotating equipment. Wearing hair
ple during the maintenance operations. and possibly beard caps is part of the clothing regime.
In aseptic processes in pharmacy specific clothing is
required to protect the product against micro-organisms
26.4.2 Eyes from the operator (see Sect. 31.3.3). This may include the
wearing of non-shedding suits or coats (depending on the
With regard to eyes corrosive substances are most feared. classification of the environment), hair cover, shoe covers or
The wearing of safety glasses can protect eyes rather well. dedicated clean room shoes, gloves, and a respirator cover-
The glasses should fit well and protect the eyes completely. ing the nose and mouth.
Wearing safety glasses is in any case necessary when: If also protection from substances is required it is
– Operating the ampoules machine recommended to wear suits or coats made of polyethylene-
– Working with glass equipment under pressure coated polypropylene (which is nonlinting and non-absorbent).
– Filling out corrosive substances This material is recognised to offer better protection than
– Cleaning up spilt corrosive substances polypropylene against many antineoplastic substances. The
Wearing of safety glasses is minimally indicated when suits must have closed fronts, long sleeves, and elastic or knit
the substance bears specific H-statements, see Table 26.4, closed cuffs. They must be disposed after each use. Moreover,
row ‘Acute toxicity’: H314, H318 and H319. disposable sleeve covers are recommended to protect the wrist
area and be removed after the task is complete.
26.4.3.2 Gloves
26.4.3 Skin
Wearing gloves for protection of the skin is increasingly
common practice with pharmacy preparation. In the risk
Corrosive substances are most feared because of their direct
assessment model of Sect. 26.7.3 it even replaces any effort
harmful effect on the skin. Antineoplastics are most feared
of estimation of skin exposure. Gloves are minimally
with regard to absorption via the skin. The skin of operators
indicated when the substance bears specific H statements,
may be primarily contaminated by the substance, but also
see Table 26.4, rows Irritation (skin, respiratory tract and/or
secondarily via contaminated surfaces. Contamination of
eyes) and Sensibilisation (skin and or respiratory tract).
surfaces is very difficult to avoid, so potentially also con-
Gloves are available made from different material and
tamination of skin of operators, cleaners and even staff who
having different thickness. They must comply with
PRODUCTION
are working in adjoining areas (see further Sect. 26.5.4).
European standards (for instance [32]). The choice for a
The wearing of the appropriate clothing and gloves can
particular type depends on:
protect the skin rather well. Proper cleaning should diminish
• The mechanical properties of the glove (abrasion resis-
the surface contamination and thus the secondary exposure
tance, flexibility)
of the skin.
• The chemical properties (resistance to the substance from
which protection is required)
26.4.3.1 Protective Clothing • The permeability of the material for the substance from
Clothing may protect the body from hazardous substances. which protection is required
The risk for dermal exposure depending on personal clothing Substances potentially penetrate gloves, thereby exposing
was investigated [31], and can be summarised as Table 26.6; the skin. Specific studies assessed dermal exposure to
a low score is aimed at. antineoplastics with regard to the use of gloves
Corporate clothing that covers the clothes should always [33–38]. The permeability of the gloves is expressed as
be worn during preparation processes, and should be breakthrough time, the time that a substance needs to pass
changed according to a fixed regime: for example, daily through the polymer layer. Permeation is related to a variety
and immediately after spillage. Long hair should be bound of factors, such as glove composition, glove thickness, expo-
sure period, and the physical characteristics of the substance
Table 26.6 Hierarchy in dermal exposure risk with clothing
[39–41]. Due to the large number of substances and kinds of
Personal cloth protection Score gloves, only limited data on permeation of specific
No clothing 1 substances are available.
Woven clothing 0.3 In practice, for pharmacy preparations the required gloves
Non-woven clothing-permeable 0.1 are of natural rubber (see Sect. 24.2.4) or thick plastic
Non-woven clothing impermeable 0.03 (polyvinyl chloride or polyethylene, see Sect. 24.2.3) if
working with corrosive substances. Gloves of thinner mate- 26.4.5 Injection

rial (latex, nitrile rubber, polyvinyl chloride) may be suitable
for working with other substances. People who are allergic Percutaneous injuries can result from needlestick injury, cuts
to natural rubber (latex) can try gloves of nitrile butadiene or abrasions from contaminated items. These exposures are
rubber, vinyl or neoprene. particularly serious because of the potential for immediate
Gloves are expected to be more permeable as they entry of the solution into a bloodstream. Hazards are not
come into contact with alcohols, for example during disin- only related to toxic substances but also to micro-organisms.
fection of the workplace. However some authors All sharps items should be handled and disposed of as noted
investigated permeation of antineoplastics when using in Directive 2010/32/EU (see Sect. 26.10).
alcohol and did not find increased permeation with the
investigated gloves. Permeability of gloves to selected
antineoplastics after treatment with ethanol or isopropyl 26.5 Exposure Levels
alcohol is given in [42].
A gloving procedure should take into account: 26.5.1 Necessity of Models
• Glove material and thickness; suppliers of gloves with a
CE label supply on suitability for types of substances, Exposure has to be quantitated to be able to quantify the
protection time (if no other damage has occurred). health risk of a specific activity with a specific substance
• Change time, this is the time that gloves will be changed (risk ¼ hazard exposure).
even if no damage has occurred; 30 min is often taken Exposure by inhalation is of most concern and is the
for this. prime topic of this section. Exposure via skin and eyes will
• Inspection; the worker has to be aware of and actively be treated at the end.
search for any damage that may occur; any damage The inhalation exposure level is the amount of substance
should lead to changing the gloves. per m3 in the breathing zone of the worker, which is the
• Single or double gloving; double gloving increases volume of air within 1 metre in any direction of the worker’s
barriers but diminishes precise feeling. head). Measuring the exposure level of each activity would
The outcome of these considerations may differ. For be the ideal approach to assess the associated risks. But this
handling antineoplastics in many countries in Europe single is not realistic, not in general and especially not for small-
gloving is the standard in practice, which has to be warranted scale situations [45]. The accurate measurement of health
by frequent change and frequent inspection. The European risk through atmospheric monitoring requires many samples
Society of Oncology Pharmacy [43] seems to prefer double in order to take into account within, and between, worker
gloving, however without being explicit about the other sources of variability [46–48]. The cost and practical
variables (changing time, thickness, frequency of inspec- difficulties associated with atmospheric monitoring repre-
tion). NIOSH recommends [44] double gloving when work- sent an often insurmountable obstacle for companies, espe-
ing with NIOSH ‘hazardous substances’ (see Sect. 26.3.4: cially for small and medium enterprises (SMEs). A model-
this represents a high toxicity class) as well as a changing based approach remains as a possibility.
time of 30 min. In the last decades some models have been developed, the
In chapter Aseptic handling (see Sect. 31.5) product pro- most well-known probably being COSHH Essentials [28],
tection results in single gloving and change after 30 min or INRS [27], Stoffenmanager [49] and especially the
earlier when damaged. Advanced REACH tool [50].
26.5.2 Advanced REACH Tool (ART)

26.4.4 Ingestion
Since 2010 a new, international, model has become avail-
Ingestion may occur unnoticed after inhalation or skin con- able: the Advanced REACH Tool [50], with a thorough and
tact. Workers have to be taught not to touch their face during highly recommended explanation of the method and its
preparation. Direct ingestion of hazardous substances may backgrounds [45].
occur accidentally and can usually be prevented by prohibi- This interactive tool helps to estimate the exposure level
tion of food and drink in all preparation areas of the phar- for a huge variability of work situations, in the chemical and
macy (see Sect. 27.7). Hand to mouth ingestion is food industry, transport but also small-scale situations.
particularly well known in smoker population. Hand wash- ART takes, apart from the amount to be handled, into
ing with soap when leaving preparation area is a basic, account nine ‘principle modifying factors’ that influence
efficient measure to remove chemical contamination. inhalation exposure level [51]:
• Substance emission potential (e.g. fine powder, granules, • Dispersion (e.g. indoors/outdoors, room size, ventilation
liquids, etc.) rate)
• Activity emission potential (e.g. mixing, pouring, • Personal behaviour
weighing, etc. but also milling, compressing powders, • Surface contamination (cleaning)
picking objects, bending metal tubes, hammering) • Personal enclosure
• Localised controls (e.g. local exhaust, containment, glove • RPE (¼ respiratory protective equipment).
box, open, etc.) The tool uses some of these factors as configurable variables.
• Segregation By changing input variables it is easy to assess their
Ope r a tion a l Condition s
Subst ance em ission pot ent ial
Act iv it y em ission pot ent ial
PRODUCTION
Surface cont am inat ion
Dispersion
Risk M a n a ge m e nt M e a su re s
Localised cont rols
Dispersion
Fig. 26.4 Example of a report following an ART exposure scenario

influence on the outcome, the estimated exposure level band. The ventilation, exhaust and containment facilities during
In this way it can be discovered which measures will con- pharmacy preparation that have been investigated concerned
tribute most to a lower exposure. four different types (see Sect. 28.3 for description of equip-
ART takes volatility of liquid substances into account, ment). The effectiveness decreases from 1 to 4:
however not yet the volatility of solid substances. 1. Isolator
ART cannot be used yet for dermal exposure (but is 2. Safety Cabinet
developing it). Also integration of ART predictions with 3. Powder exhaust unit (solids and non-volatile liquids) or
tools for modelling internal dose is foreseen. fume cupboard (fumes)
As an example of assessing the exposure level during 4. Work bench without any form of local ventilation
the preparation of capsules the ART report is given in The investigations showed the level of inhalation exposure
Fig. 26.4. depending on:
• The physical form of the substance(s): solids (powder or
crystalline) can blow and are easier to be inhaled than
26.5.3 Exposure at Pharmacy Preparation semisolid and liquid substances
• The quantity of the substance(s)
26.5.3.1 Preparation from Raw Materials • The duration of the operation
Exposure during pharmacy preparation from raw materials • The ventilation and exhaust measures taken to remove
can be estimated with the ART, which is not surprising as substances from the breathing air
outcomes of specific exposure measurements during phar- The types of handling (weighing, rubbing, crushing, mixing,
macy preparation, described in this subsection, have been shaking, and stirring) turned out to have a minor influence on
used to develop and calibrate the ART. the exposure level.
Pharmacy preparation from raw materials or through The preparation activities that have been investigated
adapting of products, as well as reconstitution of medicines covered 2 amounts of the active substance: < 10 g and
accounts for numerous different preparation methods, batch 10–100 g. So for working with either very small amounts
sizes and operators. Some exposure measurements have (< say about 100 mg) or higher amounts > 100 g, this
been performed with these methods for small-scale prepara- specific model may not offer the most suitable solution.
tion in pharmacies [52], which led to a specific exposure Working with very small amounts occurs, for instance,
model for small-scale preparation in pharmacies for inhala- within pharmacies, hospitals or nursing homes where
tion exposure. employees crush tablets for patients with dysphagia (see
The investigations considered small-scale preparation of Sect. 37.6.2) or reconstitute antibiotic mixtures or
capsules, cutaneous preparations, aseptic handling in a parenterals (see Sect. 26.5.3).
safety cabinet with laminar down flow. The inhalation expo- The investigation [52] assessed which ventilation and
sure was measured by filtration of the air in the breathing exhaust measures decreased exposure and to what extent.
zone, see Fig. 26.5a and b. If, for example, 10–100 g of material is used, working in a
Fig. 26.5 (a and b) Measuring inhalation exposure level by filtration of the air in the breathing zone (photos Ruud Briedé)
no dedicated fume cupboard, safety

ventilation: isolator
ventilation dust exhaust cabinet
physical
appearance: solid semisolid, solid semisolid, solid semisolid, solid,
liquid liquid liquid semisolid,
liquid
amount:
10-100 g < 10 g 10-100 g < 10 g
exposure:
high medium low medium low low low very low very low
Fig. 26.6 Inhalation exposure model for different ventilation situations at pharmacy preparation from raw materials (Adapted from [52] with
permission)
very low ¼ GM (geometric mean): 0.1 microgram/m3
low ¼ circa 10 – tens of microgram/m3: GM 13 micrograms/m3
medium ¼ circa 100 – hundreds of micrograms/m3: GM 71 micrograms/m3
high ¼ >1 mg/m3: GM 329 micrograms/m3
PRODUCTION
Fig. 26.7 (a and b) Exposure of investigational gloves during the filling of hard gelatin capsules (test substance riboflavin) (photos Ruud Briedé)
safety cabinet instead of in a powder exhaust unit, changes however is taken from the literature [23]. The isolator turns
the exposure class from medium to low (see Fig. 26.6). each type of physical appearance into a very low exposure.
Four exposure classes have been discerned: See further Sect. 28.3.
• Very low Dermal exposure was investigated as well. It appeared
• Low that exposure of the hands was extensive (see Fig. 26.7a
• Medium and b).
• High The difference with inhalation exposure however is that
Within assumptions the levels have been quantified. Each the skin of the hands can easily be protected by wearing
exposure class corresponds to an amount of micrograms/m3 gloves (see Sect. 26.4.3). The wearing of gloves with all
dust. These values represent the so-called geometric mean pharmacy preparation activities is thus strongly advised by
(GM). The GMs of the low, medium and high levels are thus the occupational health professionals.
supported by measurements. The GM of the class ‘very low’
exposure of operators, other healthcare personnel and

The RISKOFDERM Dermal Exposure Model [53] is a cleaners. Tests on surface contamination (wipe tests) illus-
model for estimating potential dermal exposure, trate spreading of contamination and the difficulty of proper
i.e. the total amount of a substance coming into contact cleaning of surfaces; contamination is often found on objects
with the protective clothing, work clothing and and premises a fair distance from the primary source. The
exposed skin. It is based on statistical analysis of external surface of vials for antineoplastic parenteral
data gathered in the RISKOFDERM project, a medicines for instance represent a significant source of con-
European project on dermal exposure. The model tamination that spreads into the entire working environment
originally consists of a set of equations as reported in including the outside of safety cabinets and isolators by
the deliverables of the RISKOFDERM project. These contact via contaminated materials (gloves, sleeves, etc.)
equations have been entered into a user-friendly [59, 62, 64]. These results may be expected to be valid for
spread sheet in Excel. vials of other medicines such as antibiotics for which maxi-
As said ART is developing a tool for dermal expo- mal mitigation of exposure is indicated due to their
sure as well, taking into account the RISKOFDERM sensitising potential.
model. Surface contamination is apparently not influenced by
ventilation or filtration of air. Skin contact through surface
contamination would therefore probably pose people in
adjoining areas to a greater risk than exposure by inhalation.
26.5.3.2 Reconstitution
Exposure from antineoplastics in hospital pharmacies and
wards during reconstitution of parenteral medicines is moni- 26.5.4.1 Wipe Tests
tored and evaluated by assessing contamination levels in air, At a wipe test a sample is taken with a tissue or a swab from
on surfaces or personnel (blood, urine). Publications origi- a surface, after it has been cleaned. The tissue must be
nate from all over the world, for example in the Netherlands moistened with a liquid in which the substance to be
[33–37, 54], in Sweden [55], Germany [56–58], UK [59], expected will dissolve. The sample is then analysed for
Italy [60, 61], France [62–64], US and Canada [65, 66] and example for radioactivity or traces of substances used.
Japan [67]. Results of wipe tests may be in the order of 0.1
These studies confirmed the presence of antineoplastics nanograms/cm2, very much depending on the method of
in blood and urine samples of workers. However, there is no sampling and method of analysis. A reference value (thresh-
direct correlation with personal health risk. Biological mon- old guidance value) can therefore only be set in relation to a
itoring may be used for occasional assessment but not for specific method of sampling and analysis. A general consen-
routine evaluation. sus isn’t available yet.
The studies demonstrate the persistent spreading of sur-
face contamination. They also establish notions about The USP <797> recommends surface monitoring on a
acceptable contamination levels although the main aim of regular basis initially for benchmarking and at least every
measuring surface contamination remains monitoring 6 months, locations to be assessed are the working area of
(benchmarking). It appears that the benchmarking strategy the safety cabinet or isolator (see Sects. 28.3.6 and 28.3.7)
enables improvement of the protection of the workers. For and adjacent areas, including floor directly under the
example the biological monitoring by urine sampling working area, the counter top where final preparations
(assessing platinum), in pharmacies using isolators, are placed, and the ward. Cyclophosphamide, ifosfamide,
highlighted the importance of handling procedures in the methotrexate, fluorouracil are recommended as represen-
background area of isolators [59, 64]. tative antineoplastics. If chemical contamination is found
Additional attention had to be paid to the implementation the root cause shall be investigated and corrective
of personal protective measures and the significance of the measures implemented. These may involve thorough
investigational results. See further Sect. 26.5.4. cleaning with an alkaline soap and water, training and
supervising. Improvement of the effectiveness of local
exhaust equipment has to be considered as well.
26.5.4 Surface Contamination USP warns that levels greater than 1 ng/cm2
of cyclophosphamide were found to cause human
Contamination on outer surfaces of medicines containers as uptake.
well of working places (table tops, safety cabinets) leads to
Table 26.7 Threshold Guidance values for 5-fluorouracil and Plati- and health of their workers in the workplace to a reasonable
num in hospital pharmacies (Adapted from Schierl et al. [58]) measure and that the workers must enable their employer to
5-fluorouracil (pg/cm2) Platinum (pg/cm2) comply with these duties.
<5 <0.6 In the context of this textbook legislation is discussed that
5–30 0.6–4 affects preparation in pharmacies, mainly concerning expo-
>30 >4 sure to chemical substances. Legislation provides the logic
for determination of ‘safe levels’, for which risk acceptance
26.5.4.2 Threshold Guidance Values by Society takes part.
Assessment of surface contaminations brought some authors
to suggest guidance values to improve working practice.
Fluorouracil, cyclophosphamide and platinum are currently 26.6.1 Occupational Safety and Health
used as tracers. Threshold Guidance Values (TGVs) for Directives
platinum and cyclophosphamide, were proposed based on a
large investigation of 102 hospital pharmacies (see The European Framework Directive on Safety and Health
Table 26.7) in Germany [58]. TGVs were based on the 50th at Work (Directive 89/391/EEC [72]) provides the funda-
and 75th percentiles of contamination values. mentals of European safety and health legislation. On the
The MEWIP program, which was a large-scale investiga- basis of the Framework Directive nearly twenty individual
tion in Germany [68], investigated several antineoplastics directives have been developed, covering a range of risk
(cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, factors and different categories of workers [73], for example
gemcitabine, ifosfamide, methotrexate, and paclitaxel). The the Carcinogens Directive (see Sect. 26.6.4) and the Preg-
program led to a substance-independent performance-based nant Workers Directive (see Sect. 26.6.5). The OSH Frame-
target value of 0.1 ng/cm2 based on the 90th percentile of the work Directive continues to apply in full to all the areas
contamination values. covered by the individual directives, but where individual
Sessink [69] purposed guidance values for cyclophospha- directives contain more stringent and/or specific provisions,
mide based on wipe and urine samples collected in the these special provisions of individual directives prevail.
Netherlands based on 90 % (<0.1 ng/cm2) and 99 % The Framework Directive sets out minimum require-
(<10 ng/cm2) wipe sampling results. No positive urine ments and fundamental principles, such as the principle of
samples were found at contamination levels < 0.1 ng/cm2, prevention and risk assessment, as well as the responsi-
which is an indication that no measurable exposure of the bilities of employers and workers. Member States of the
PRODUCTION
healthcare workers has occurred. Therefore Sessink [69] European Union have all transposed a series of directives
suggested that the reference value 0.1 ng/cm2 reflects a into their national legislation. Member States are free to
safe situation and 10 ng/cm2 is not acceptable (Table 26.8). adopt stricter rules for the protection of workers when trans-
For this last situation immediate corrective measures must posing EU directives into national law, and so legislative
be implemented and its efficacy should be evaluated. In requirements in the field of safety and health at work may
between-values would need monitoring and searching for vary across EU Member States.
root causes in order to reach the target ‘green’ level.
Swedish investigations [55] led to a suggestion for
‘hygienic guidance values’ (HGVs). The Netherlands has transposed EU directives into its
national occupational safety and health act [70]. Since
2007 the authorities do not regulate the health safety
policy anymore on detailed level. This policy should
26.6 Legislation
be established within companies, so customisation is
possible. As far as European regulations permit, the
Occupational safety and health legislation regulates the
Dutch authorities determine the targets to be achieved.
standards of workplace safety and health with the aim of
How employers and workers achieve the targets, can
preventing workplace accidents, injuries and diseases. It
be regulated per sector. The idea is that trades unions
details responsibilities of employers and workers. Generally,
the legislation requires that the employer protects the safety (continued)
Table 26.8 Guidance values (Adapted from Sessink [69])
Cyclophosphamide monitoring Target risk level Prohibitive risk level
Urine (micrograms/24 h) <0.02 0.02–0.2 0.2–2 >2
Wipe sample (ng/cm2) <0.1 0.1–1.0 1.0–10 >10
and employers’ organisations compile a so-called • Take the necessary measures for first aid, fire-
Safety and Health Catalogue where it is indicated fighting, evacuation of workers and action required
how and with what means companies can achieve the in the event of serious and imminent danger
target requirements. In the Netherlands there is a • Keep a list of occupational accidents and draw up,
health and safety catalogue for working in the commu- for the responsible authorities reports on occupa-
nity pharmacy [71]. For workers in the hospital phar- tional accidents suffered by his workers
macy, the Health and safety Catalogue for (Dutch) • Inform and consult workers and allow them to take
hospitals applies. It sets out in more detail the situation part in discussions on all questions relating to safety
of exposure to hazardous substances in the hospitals, and health at work
for example the risks of working with antineoplastics, • Ensure that each worker receives adequate safety
radiopharmaceuticals and anaesthetic gases. and health training
The worker shall:
• Make correct use of machinery, apparatus, tools,
Employers should map and evaluate all the risks of the
dangerous substances, transport equipment, other
work, suggest and implement measures that assure an
means of production and personal protective
improvement in the level of protection and evaluate the
equipment
policy. This is called the RI&E-procedure, RI&E being the
• Immediately inform the employer of any work sit-
abbreviation of Risk Inventory and Evaluation. The
uation presenting a serious and immediate danger
employers should inform and instruct the workers about
and of any shortcomings in the protection
the risks and the measures taken to manage the risks.
arrangements
Workers must follow the safety instructions and use the
• Cooperate with the employer in fulfilling any
provided protective equipment.
requirements imposed for the protection of health
The labour inspectorate can impose penalties if an insti-
and safety and in enabling him to ensure that the
tution or company does not comply with the legislative
working environment and working conditions are
requirements. In the event of incidents they always hold an
safe and pose no risks
inquiry.
Health surveillance should be provided for workers
Further information on European legislation, its imple-
according to national systems.
mentation and other practical documents on safety and health
at work can be found on the website of The European Agency
for Safety and Health at Work (EU-OSHA) [72]. To the best of our knowledge there are no guidelines or
standards elaborating general OSH guidelines specifically
Employers’ and Workers’ Obligations [72] for (hospital) pharmacies on a European level.
The employer shall:
• Evaluate all the risks to the safety and health of
workers, inter alia in the choice of work equipment, 26.6.2 European Regulation REACH
the chemical substances or preparations used, and
the fitting-out of work places OSH directives address only health risks at the workplace
• Implement measures which assure an improve- and are mainly process-oriented. Other regulations address
ment in the level of protection afforded to workers product-oriented health and environment risks on a
and are integrated into all the activities of the European level such as the European Regulation REACH
undertaking and/or establishment at all hierarchi- and the CLP regulation (see Sect. 26.6.3).
cal levels REACH (Registration, Evaluation, Authorisation and
• Take into consideration the worker’s capabilities as Restriction of Chemicals [77]), applies to chemicals that
regards health and safety when he entrusts tasks to are manufactured, imported, placed on the market or used
workers in the EU. REACH has two main aims: to ensure a high level
• Consult workers on introduction of new of protection for human health and the environment, includ-
technologies ing by improving knowledge and information about
• Designate worker(s) to carry out activities related chemicals; and to enhance the competitiveness of the
to the protection and prevention of occupational European chemical industry [78].
risks REACH came into force in all EU countries on 1 June
2007 and states the obligations for the whole supply chain:
(continued)
manufacturers, importers, downstream users and distributors to all possible ways of exposure routes (including the skin),
of chemicals. All categories are obliged to register their use and to persons at particular risk. The employer shall reduce
of chemicals and to have information on its hazards. Prepar- the use of a carcinogen or mutagen by replacing it with
ing pharmacies belong to the category downstream users. substance not or less dangerous. If replacement of
substances is not possible (see also Sect. 26.7.1), the
employer shall use engineering measures, mainly contain-
26.6.3 GHS and CLP ment. If a closed system (total containment) is not techni-
cally possible, the employer shall reduce exposure to
Different classification and labelling systems for the hazards minimum.
of substances are currently used throughout the world. The The Directive adds a series of detailed guidelines for
same substance may thus be classified as ‘toxic’ in the employers to minimise exposure, inform employees,
United States, ‘harmful’ in the European Union and ‘moder- reporting workers that may be exposed, reporting incidents
ately dangerous’ in China. To eliminate disparities a Glob- (also to the authorities).
ally Harmonised classification and labelling System (GHS) The Carcinogens Directive is the origin of two notions in
was developed under the auspices of the United Nations. It pharmaceutical practice: the ALARA (as low as reasonably
was formally adopted in 2002 by the United Nations Eco- achievable) principle at the processing of carcinogenic
nomic and Social Committee (UN ECOSOC) and revised in substances and the registration of working with carcinogenic
2005 and 2007 [78, 79]. substances.
GHS aims to:
• Define physical, health and environmental hazards of
The Directive requires that an employer of employees
chemicals
exposed to carcinogenic or mutagenic agents registers
• Create classification processes that use available data
the following, in addition to the data of the general
on chemicals for comparison with the defined hazard
mandatory registration:
criteria
• The reason why the carcinogenic or mutagenic
• Improve the communication on hazard information, as
agent is used and cannot be replaced
well as protective measures, on labels and Safety Data
• The quantity of the substance used per year
Sheets (SDS).
• The type of work done involving the substance
• The number of employees who could be exposed to
26.6.3.1 GHS Implementation in Europe: CLP
the carcinogenic or mutagenic agent
The GHS is a set of international recommendations. As GHS
PRODUCTION
• The measures to minimise that exposure
is non-binding rather than legally binding, it had to be
• The personal protection equipment in use
adopted through a suitable national or regional legal mecha-
• The situations in which carcinogenic and muta-
nism to ensure it becomes legally binding. That’s what the
genic agents have been replaced
CLP Regulation does for Europe. CLP is the regulation on
This registration requirement should be converted in
Classification, Labelling and Packaging of substances and
pharmacies into a practical procedure because the vast
mixtures (EC No 1272/2008), it came into force in
number of carcinogenic substances, the number of
2009 [80].
employees and the large variations in processes.
GHS is also known as EU-GHS in Europe. As of 2015,
when GHS will be fully in force, all substances and mixtures
(products are considered as mixtures) must meet the new As REACH does not overrule this Directive, the approach
classification, labelling and packaging requirements CLP. of controlling workplace exposure should comply with
ALARA [10]. See Sect. 26.8 for further interpretation.
26.6.4 Carcinogens or Mutagens Directive
One of the individual directives under the Framework Direc- 26.6.5 Pregnancy Workers Directive
tive is the directive on the protection of workers from the
risks related to exposure to carcinogens or mutagens at work: The Directive on the introduction of measures to encourage
Carcinogens or Mutagens at work Directive (2004/37/EC) improvements in the safety and health at work of pregnant
[74]. This Directive obliges the employer to assess and workers and workers who have recently given birth or are
manage the risk of exposure to carcinogens or mutagens. breastfeeding, The Pregnant Workers Directive (92/85 EEC)
This assessment shall be renewed regularly and data shall be [75], has been attached to the Framework Directive
supplied to authorities on request. Special attention is made (Sect. 26.6.1). These guidelines treat, apart from risks from
hazardous substances, also risks from physical movements • Assess the risk by using categorisation
and postures, mental and physical fatigue and other types of • Prioritise risks for which mitigation is most necessary
physical and mental stress. Employers’ duties include “the • Convert priorities into actions keeping general risk miti-
identification of specific chemical substances and categories gation principles in mind
of chemical substances and reducing the use of, and expo- This chapter subsequently discusses general mitigation
sure to chemical substances that may affect a pregnant or principles, exposure limits and working with a risk
breastfeeding worker”. In practice, also workers with a categorisation model.
desire to have children (men and women) should be taken
into account, since some substances may be harmful to the
fertility or harm in the very first stage of a pregnancy. That is 26.7.1 General Principles
why it is important to point out that workers report as soon as
possible that they are pregnant. They also need to know that In an ideal situation the health risk is known and preventa-
reporting a desire to have children, men and women, may be tive and protective measures can be taken to control the risk.
of interest to their own safety. However if the risk is only guessed or put relative to another
Each pharmacy must draw up a maternity policy. The risk, it is possible to perform control measures.
pharmacist needs to identify in the Risk Inventory and Eval- Occupational hazards and exposure can be controlled by
uation (RI&E) which substances are present that may cause a variety of methods.
damage, and which activities otherwise could be dangerous Four general categories of control measures in widely
for pregnant women (such as lifting heavy boxes). accepted order of effectiveness are (see Fig. 26.8):
• Elimination or substitution: eliminate the exposure before
it can occur
26.7 Risk Mitigation • Engineering controls (or: collective protective measures):
require a physical change to the workplace
Investigating hazard and exposure means to mitigate the • Administrative controls (collective protective measures);
health risk of workers (risk ¼ hazard exposure). require worker or employer to change work flow or
In an exceptional situation the actual exposure can be organisation
determined (see Sect. 26.5.3), the hazards of the substance • Personal protective equipment (PPE, or: individual pro-
has been defined sufficiently (see Sect. 26.3.5) and above all, tective measures); requires worker to wear a device
the exposure limit to the substance has been set by the Control measures mentioned as first option should be con-
competent authority. This may apply for instance to working sidered before the next ones because they are most effective.
with ethanol, see also Sect. 26.7.2. In such an ideal situation The reason for a better effectiveness is that measures that
it is possible to claim completely safe working conditions or, protect the whole of the workplace and everyone who works
in case of genotoxic and sensitising substances, safe with a in there (collective protective measures), are more effective
societally accepted minor health risk (see Sect. 26.7.2). In than individual protection. The measures will be dealt with
practice for pharmacy preparation and reconstitution in order of decreasing effectiveness.
medicines hardly any exposure limits exist at the moment.
In most situations risk mitigation means: 26.7.1.1 Elimination or Substitution
• Analyse the working situation Elimination is the most effective measure to remove the
• List potentially harmful situations hazard completely. This measure should be used whenever
Fig. 26.8 Hierarchy of

consecutive control measures to elimination or substitution
control and minimise the risk
associated with the hazard and the
exposure, adapted from Quality engineering
Systems Toolbox, software and controls
services for quality management
www.qualitysystems.com, with administrative
permission controls
increasing PPE increasing participation

effectiveness and supervision
and sustainability needed
possible but will be hard to achieve in pharmacies. If it is

possible, this step needs to be taken at the time the pharmacy • Clean contaminated exteriors of containers (bottles
receives the request for a preparation. It is part of one of the and jars).
assessment models of a prescription (see Sect. 2.2.3). • Make sure all containers, weighed quantities and
Replacing a hazardous substance or work process with a intermediates are also recognisable from others,
safer substance or work process is also an option. Choosing e.g. by a label.
a different dosage form, such as an oral liquid instead of • Prevent the spread of the substances as much as
capsules, is also a way of substitution to decrease the hazard. possible by working on a clearly delimited place.
Preparing an oral liquid than capsules generally creates less • Keep contaminated material (glassware, mortars,
dust whereby the exposure by inhalation will be decreased. vessels etc.) separated from clean equipment.
Using semisolid concentrates of active substances in derma- • Prevent contamination of items that are not imme-
tological preparation is not only advantageous for an effective diately necessary for work (such as logbooks,
dispersion (Sect. 29.7.2) but also for mitigating exposure. instructions, pens).
• Grip vials with antineoplastic parenteral
preparations with the (gloved) hand put in a sand-
26.7.1.2 Engineering Control Measures
wich bag that is discarded afterwards.
Engineering controls require implementation of physical
change to the workplace which eliminates or reduces the
risk on the work process. Examples of engineering controls
are:
• The use of ventilation measures (exhausting, see Sect.
26.7.1.3 Administrative Control Measures
Administrative control measures include for example job
28.3; pressure regime, see Sect. 27.4.2)
scheduling to limit exposure, posting hazard signs,
• Isolation or containment of the work processes
restricting access and training. Job scheduling in pharmacy
• Change the engineering of work processes to minimise
preparation however is not always desirable from the point
contact
of view of routine which is considered advantageous for
• Proper cleaning procedures, including monitoring
pharmaceutical quality. A pharmacy example of an admin-
The numerous investigations on spreading of contamination
istrative control measure is the relocation of reconstitution
with antineoplastics have increased the insight about measures
of medicines with class 4 and 5 substances from the ward
to counter it. The establishment and observance of good
to the hospital pharmacy where better protection can be
cleaning, clothing and gloves protocols and workers’ aware-
provided.
PRODUCTION
ness are important measures, as well as training of operators,
other healthcare personnel and cleaners in the proper
handling of contamination. For cleaning procedures see 26.7.1.4 Personal Protective Equipment
Sect. 34.16. Personal protection equipment is the least desirable but may
The performance of wipe tests (Sect. 26.5.4) may help to still be effective. Personal protective equipment (PPE) may
investigate sources of contamination and monitor work and be indispensible for instance:
cleaning procedures. • When handling substances at places where no engineer-
ing controls reasonably can be provided (for instance on
wards)
General rules to minimise spreading of contamination
• In emergency situations, see Sect. 26.9
are:
In Sect. 26.4 personal protective equipment (respirators,
• Close containers with (raw) material directly after
goggles, gloves, clothing) are described related to the route
use.
of exposure.
• Place containers which require specific storage (for
example a safe) back in the store immediately after
use. 26.7.1.5 Combination of Measures
• Do not eat, drink and chew in the preparation areas A combination of measures usually provides a safer and
and also do not keep food and drinks in those areas. healthier workplace than relying on only one method. A
• Move all objects at an even pace and avoid quick strategy of combination of methods is given in Fig. 26.9. It
movements that cause turbulence in the airflow. combines quantity, occupational health hazard, task duration
and physical form of the substance.
(continued)
Fig. 26.9 Combination of occupational health hazard

control measures (After Donna
Heidel with permission) low/reversible severe/irreversible
kilograms 8 hours
engineered local high containment
exhaust ventilation
task duration
isk
quantity
r
sure
po
ex
open systems closed systems

miligrams 15 minutes
slurry/suspension agglomerated highly disperse
physical form
26.7.2 Exposure Limits This should be the case even if exposure to the substance at
that level occurs repeatedly or over a long period of time,
If the level of exposure is known, whether by measurements even a worker’s entire working life (8 h a day, 40 years).
in the air that the worker breathes or by estimation via an Some authors proposed the use of Dermal Occupational
exposure level model, would this level be safe enough to Exposure Limits (DOEL) [81].
prevent health damage? If exposure cannot be prevented, is OELs are not absolute limits, but time-weighted averages
it necessary to control it not exceeding that acceptable level? measured over an 8-h period. During this period, exposure
An exposure limit reflects the concentration of a sub- may at times exceed the OEL, providing that lower levels
stance at the workplace that is considered safe for the balance such higher levels of exposure, so that the average
worker. This concentration has to be specified: level for the 8-h period does not exceed the OEL. An OEL
• Is this concentration valid for a short period, a working can also be defined as a 15-min time-weighted average
day (how many hours?), a week or even a lifelong (expressed as TWA-15 min). OELs may also be defined by
employment? a ceiling value (expressed as OEL-C). This is an absolute
• Does it apply to the inhalation route, dermal route or even OEL that must not be exceeded at any time.
another route? OELs are considered as levels, thresholds, that guarantee
• Is it quantified based on scientific evidence or is it the safety: no-effect levels. From a scientific viewpoint it may
qualitative approach ‘as low as possible achievable be considered impossible however to give advice on an
(ALARA)’? absolute safe limit. Some uncertainty has to be taken into
• Which body has set the limit? account but that is merely about interpretation of scientific
• Is feasibility in the social context taken into account? studies. Two specific adverse effects however cannot be
For working situations in Europe the most relevant exposure connected with a no-effect level: genotoxic carcinogenicity
limits are the OELs. They are elaborated and the relation and sensitisation on inhalation.
with DNELs and DMELs is shortly given. For surface con- According to the Body who prescribes them, two types of
tamination currently no standards exist but threshold values OELs exist:
are proposed (see Sect. 26.5.4). • Public (i.e. statutory) OELs, set by the competent
authorities
• Private OELS, set by companies or other bodies
26.7.2.1 Occupational Exposure Limit (OEL)
An Occupational Exposure Limit (OEL) is the maximum
permissible concentration of a given gas, vapour, fibre or 26.7.2.2 OELs for Genotoxic and Sensitising
dust in the air in the workplace [76]. It is intended to be the Substances: Target Risk Levels
level at or below which a given substance can be present in For genotoxic carcinogens no no-effect level (a safe thresh-
the air in the workplace without harming the health of old) can be determined (see Sect. 26.3.3). The only way to
workers and their offspring, based on current knowledge. eliminate any risk would be to impose a complete ban.
However, as long as such substances are indispensable 26.7.2.3 Public OELs

(or put differently as long as Society accepts the use of The European Commission is advised about OELs by the
such substances, e.g. many antineoplastics), the risk of expo- Scientific Committee on Occupational Exposure Limits
sure, and thus the risk of cancer, cannot be completely (SCOEL) [83]. As a result legally binding as well as
avoided. The same applies to limits for sensitising indicative OELs (as an indication of what should be
substances (see Sect. 26.3.3). Limiting the risk level is the achieved) are laid down in European Directives. Each
general approach for these substances. Limits are set based Member State in the European Union establishes their
on an accepted risk of 10-p (the value of p being decided own national OELs, based on the European Directives.
upon by Society). The corresponding national lists usually include more
Instead of an OEL, then, a target risk level will be substances than the Directive. National OELs can again
identified by governmental bodies, feasibility will be be legally binding or indicative limits.
discussed, and a discussion will be repeated every 4 years
where necessary [10]. The target risk level states the extent
Ethanol
to which exposure must be minimised in order to ensure that
Hazard type: EU listed as carcinogenic and reprotoxic.
the extra risk of harm is negligible or will be reduced to a
Many public OELs exist, for instance 260 mg/m3
natural background risk. The feasibility discussion focuses
(TWA-8 h) and 1,900 mg/m3 (TWA-15 min) in the
not only on technical feasibility, but also on operational and
Netherlands.
economic feasibility.
Risk mitigating in pharmacies (disinfection at asep-
tic processes) can be attained by:
In the Netherlands (also in Germany and Switzerland) 1. Substitution/elimination: don’t use ethanol for
for instance use is made of a system of ‘feasible’ risk cleaning purposes.
levels: a ‘prohibitive risk level’ (prohibiting an addi- 2. Engineering controls: apply ventilation and
tional risk of cancer higher than 104 per substance per exhaust.
year) and a ‘target risk level’ (106 per substance per 3. Administrative and work practice controls: provide
year). For sensitisation the target risk level job rotation, perform disinfection only when
corresponds to a 103 extra risk of sensitisation necessary.
owing to exposure to an inhalant allergen beyond any 4. Respiratory protective equipment: wear appropriate
inherent sensitisation to the substance. gloves.
Thresholds for sensitisation are so low that they in Expert Advice about meeting the OEL:
PRODUCTION
most cases, with the current state of scientific knowl- • Contact with the raw material at preparation: the
edge, cannot be determined. The Dutch Health Coun- wearing of gloves and working in fume cupboards
cil [82] prefers to start from ‘risk numbers’ being air (anyway because of risk of explosion) is sufficient;
concentrations associated with a predetermined • Disinfection of LAF units and safety cabinets:
accepted (extra) chance that an employee is sensitised – Moisten a cloth, don’t spray (except for wrapped
by occupational exposure for that particular allergen. utensils with a rough surface, but only if abso-
In determining the predetermined chance, political, lutely necessary).
social and political aspects are taken into account. – Use only just enough.
Based on this consideration the H-statements – Exhaust and discharge on outside environment.
317 and 334 lead for the time being to classification – Background ventilation at least 2 h1 but prefer-
in danger class 3 in Fig. 26.4. Active substances with ably 5 h1.
the H-statements 317 and 334 are found in a wide – If in very small rooms: leave the room after
range of therapeutic classes, such as hydrochlorothia- disinfection and return after a quarter of an hour.
zide, methadone, cefuroxime, chloramphenicol and
polymyxin.
As feasibility is an economical or cultural concept rather 26.7.2.4 Private OELs

than a scientific one, differences in OELs for genotoxic As so few public OELs are established but the employer is
substances between countries may be expected. responsible for the occupational safety and health of his
In the case of non-genotoxic carcinogens (see workers, he has often to decide on OELs. This is of course
Sect. 26.3.3), a safe threshold, OEL, can basically be an extremely difficult and expensive job, not within reach of
defined. These OELs have the same status as OELs for common companies or institutions. Within REACH (ECHA
‘normal’ health-damaging substances. guidance) however procedures have been developed for
establishing private OELs, more specifically called DNELs 26.7.2.6 Threshold Values for Surface
and DMELs [10, 84]. Contamination
A DNEL is a Derived No-Effect Level and a DMEL is a The proposals for threshold values for surface contamina-
Derived Minimal Effect Level. A DNEL applies to tion, especially directed at antineoplastics, have been
non-genotoxic substances and a DMEL to genotoxic discussed in Sect. 26.5.4. These levels very much depend
carcinogens and substances sensitising by inhalation. Note on the method of sampling and analysis. The establishment
the principal difference between the two approaches that is of these threshold values are yet on the level of best
reflected in the terminology: a DNEL is connected with practices, see also Sect. 26.8.
absence of effect; a DMEL is connected with a (low and
accepted) effect level.
Some private OELs for pharmaceutical substances may 26.7.3 Risk Matrix Models
be available in the GESTIS database [12] such as:
• Theophyllin: 0.5 mg/m3 (private OEL from Latvia) A risk categorisation model combines hazard categories with
• Hydroquinone: OELs from 0.5–2 mg/m3 (several exposure categories for the identification of those situations
countries) that require most attention to be improved. The risk matrix
model which have been developed with the hazard and
26.7.2.5 Information Sources of Exposure Limits exposure categorisation given in Sects. 26.3.5 and 26.5.3
For Europe a very promising database has been created for will be given as an example. It applies to inhalation risks
retrieving existing OELs and DNELs: the GESTIS (Interna- of small scale pharmacy preparation. This approach is simi-
tional limit values for chemical agents Occupational expo- lar to those by the INRS [27] and COSSH [28].
sure limits (OELs) database) [12]. The first step of a risk assessment is to determine the
hazard category of the substances involved, the second step
is to determine exposure via inhalation or skin and the third
GESTIS database provides workplace-related DNELs step involves combination of others into a risk category by
which have been established by manufacturers and the equation: risk ¼ hazard exposure.
importers under their own responsibility and have Table 26.9 depicts the risk matrix obtained.
been published by the European Chemicals Agency The indicative occupational exposure limit values are
(ECHA), in the first instance without review. Key data depicted horizontally as well as their midpoints (derived from
for each substance are also listed for its identification Table 26.4). The limit values correspond to the amount of
(synonyms, index numbers, formulae) together with a substance, in micrograms per m3 air to be maximally inhaled
link to further substance data. as an average on an 8-h working day. Analogously a table can
The GESTIS DNEL Database currently contains be made with limit values valid for a 2-h working day. The
for about 1,300 substances DNELs for workers (local geometric exposure averages are given vertically, associated
and/or systemic effects in the event of inhalative long- with the measured exposures at the investigations of pharmacy
term exposure) with additional information. Should preparation (see Sect. 26.5.3). Each exposure class corresponds
different DNELs be published for one and the same to specific ventilation measures, as given in Fig. 26.6. It
substance, they are stated side-by-side without evalu- follows that if the hazard class of a substance is known, as
ation. These data are also available in the form of an well as the physical form and quantity, then a workplace advice
Excel file. The DNEL values are gathered from vari- can be given on the necessary ventilation and exhaust measures
ous EU member states and about 10 other countries in order to achieve an acceptable (low) health risk.
worldwide. As an example, Table 26.10 gives the workplace advice for
No DMELs are published in this database. The 8 h preparing pharmacies for substances with hazard class 3.
crucial framework is therefore missing (as feasibility Ventilation and personal protection measures should be
depends very much on societal decisions that will be implemented on the batch preparation instruction to inform
country specific). Since the corresponding cancer the operator.
risk is not generally stated for DMEL values in the As explained in Sect. 26.5.3 this model can be used for
ECHA registration entries and the procedure for small-scale preparation with quantities from about 100 mg
their derivation is not transparent, DMEL values up to 100 g. For higher quantities reference is made to ART
will not be incorporated into the GESTIS DNEL (see Sect. 26.5.2) for estimating the exposure. Having the
Database. exposure will enable to use the matrix of Table 26.9 for the
risk determination.
Table 26.9 Estimated inhalation risks in three classes: small, moderate and high
Hazard class 1 2 3 4 5
> 5,000 5,000−1,000 > 10−1,000 > 1−10 ≤1
Limit value
micrograms/m3 micrograms/m3 micrograms/m3 micrograms/m3 microgram/m3
5,000 3,000 505 5.5 1
Midpoint
micrograms/m3 micrograms/m3 micrograms/m3 micrograms/m3 microgram/m3
Very low
GM = 0.1 Small Small Small Small Small
microgram/m3
Low
GM = 13 Small Small Small High High
Exposure
micrograms/m3
Medium
GM = 71 Small Small Moderate High High
micrograms/m3
High
GM = 329 Small Moderate Moderate High High
micrograms/m3
Table 26.10 Workplace advice for 8 h preparing pharmacies for processing substances with hazard class 3
Workplace Physical form Measures
Type 1 (isolator) and 2 (safety cabinet) Solid, semisolid or No additional measures
liquid
Type 3 (fume cupboard, dust exhaust) Solid <10 g substance: no additional measures
10 g substance: use substance in another physical form (semisolid or liquid)
or:
Wear respirator with APF 4
Liquid and semisolid No additional measures
Type 4 (no dedicated ventilation) Solid Use substance in another physical form (semisolid or liquid)
or:
PRODUCTION
<10 g substance: wear respirator with APF 4
10 g substance: wear respirator with APF 20
Liquid and semisolid No additional measures
not using OELs, by professional organisations. This best

26.8 Hazardous Substances in Hospital practice should be open for review by the Competent
Pharmacy Practice Authority.
The key question is: do all precautions, procedures and

Best Practice Class 5 Substances (Example)
monitoring lead to a safe work situation? Safety is a
As an example the following best practice may be
matter of risk acceptance. If there exists a public OEL to
formulated for a country such as the Netherlands.
refer to, one could speak of a ‘safe’ situation on behalf of
The categorisation model given in this chapter (see
Society. However hardly any OELs for pharmaceutical
Sect. 26.3.5) applies the REACH approach to the
substances have been set (see Sect. 26.7.2 for the ethanol
hazard classification of any substance. Sufficient
example), and if so the extent of the exposure has to be
investigations on the exposure at working with up to
measured to be able to find out if the OEL has been met.
100 g of substance in situations with different ventila-
Even then, it is only possible to know something about safety
tion options, led to the use of the risk matrix of
with reference to inhalation, because most OELs refer only
Sect. 26.7.3 in practice, as basis for an interactive
to exposure by inhalation and not to skin exposure. The next
tool (called RiFaS) resembling ART, see Table 26.10
option is to use a private OEL or to decide for a private OEL
for an example of a RiFaS working place advice.
together with other professionals. This approach is more
or less equivalent to the formulation of a best practice, (continued)
manipulated in the pharmacy, not on the ward or in nursing

Due to uncertainty about the validity of homes.
measurements of inhalation exposure when working
in safety cabinets and isolators and because the aware-
Keep in mind: not all antineoplastics belong to hazard
ness about the significant role of skin exposure via
categories 4 or 5 (see Sect. 26.3.3), and the other way
surface contamination, processing class 5 substances
round: some other active substances (such as
are to be dealt with in a less straightforward manner.
ethinylestradiol, lithium carbonate, ciclosporin, coal
A best practice for handling class 5 substances
tar, metronidazole and tacrolimus) belong to class
(to which most antineoplastics belong) could be pro-
4 or 5.
posed as:
• Try to avoid the need of processing solid class
5 substances, by pushing back individual dose
corrections or by developing liquid formulations.
• Aseptic handling of solutions with class 26.9 Calamities with Hazardous Substances
5 substances in a safety cabinet or an isolator is
safe for inhalation exposure. A calamity with a hazardous substance may occur during
• Preparation of capsules (working with solid preparation, but also before (transport, unpacking of incom-
substances) with class 5 substances requires apart ing goods) and afterwards (delivery). It is therefore neces-
from working in a safety cabinet the wearing of a sary that all employees of the pharmacy, and if applicable
respirator type P3, or should be performed in an the employees of the institution where the pharmacy
isolator (positive or negative pressure) (see Sect. belongs, are well aware how they should act during a spill
28.3.7). or release of hazardous substances. It also concerns
• Monitor surface contamination in order to minimise logisticians, delivery personnel, nurses and cleaners.
skin exposure; follow trends in the own hospital
and benchmark with other hospitals. Agree upon
target and prohibitive levels (see Sects. 26.7.2 and 26.9.1 Procedure
26.5.4) in relation to type of analysis.
A consequence of agreeing on a best practice is that The policy in an emergency must be recorded in one or more
risks (not being nil) and costs of the approach are procedures and should be trained for, regularly. As for any
apparently accepted by Society. calamity, a company safety officer must be warned as soon
as possible. Every institution must have one or more safety
officers who are trained in the measures to be taken in case of
By agreeing to best practices the legal requirements for calamities. The safety officer judges in case of calamities if
carcinogenic and sensitising substances (ALARA As Low the pharmacy must be cleared and coordinates the measures
As Reasonably Achievable) are generally fulfilled. to clean up the spilled substance. The employee that has
‘Reasonably’ implies a level of risk acceptance. Risk caused the calamity, or sees it first, ensures that:
acceptance includes the notion that application of any fur- • He places himself in safety.
ther precautionary measures may lead to either risk increase • The safety officer is warned.
on other aspects as well as to financial consequences that • Other colleagues stay out the contaminated area.
society don’t want to bear (see also Sect. 21.4.3). Risk • Close the door(s) to adjoining areas to allow dilution by
acceptance will mean at a hospital level that other situations room ventilation to enter into force and thus prevent
where antineoplastics are handled have to be taken into distribution of particles in the air.
account. It may for instance be conceived that implementing The procedure should prescribe how to clean up the
safety measures for other healthcare workers in hospitals spilled substance and the personal protective equipment
(such as the advice of no reconstitution of class 4 or (gloves, respirators) that should be worn in such a case.
5 substances on the wards) have a higher priority than further Specific emergency kits are used in hospital pharmacies
improving safety in pharmacies. and wards where antineoplastic medicines are handled and
A similar idea exists on the manipulation of oral solids in administered. These ready-to-use kits, also called spill
homes for the elderly. Although exposure levels have not boxes, are commercially available A standard content is
been measured, the same advice may be valid: licensed oral provided by the ESOP (European Society of Oncology
solid medicines with class 4 and 5 substances are to be Pharmacy) [85].
26.9.1.1 Background Pressure

In areas where aseptic processes are performed in a safety
cabinet, an overpressure in the background area may be kept
relative to the adjoining areas to keep micro-organisms out.
However in a calamity with hazardous substances in a back-
ground area with overpressure, particles in the air can spread
to adjoining areas when opening doors. The dilemma is
whether the aseptic requirements or the eventual spread of
hazardous substances will dominate the pressure regimen. A
reasoning could be that if the exposure in the air in a
calamity ends up in the adjoining areas, this exposure will Fig. 26.10 Example of an active safety device: a cap snapping over
be lower than in the preparation and background areas the needle
because of the clean-up of the contamination, the behaviour
of particles (precipitation), the technical specifications of the The aseptic processing of medicines such as
areas and the ventilation system, and the occurrence of antineoplastics may expose the operator to hazardous
dilution. Moreover these calamities occur, at most, once a substances via NSI. An aseptic non-touch technique involves
year and the duration of exposure is short, the impact of this frequently recapping of needles which is banned under the
temporary higher exposure on the total cumulative exposure Sharps Directive. Consequently, procedures will need to be
is likely to be minor. As a result of this reasoning the reviewed and alternative products, such as blunt fill needles/
overpressure for aseptic process will dominate. This filters and recapping blocks, should be considered [87].
reasoning precludes a good calamity instruction. Another As pharmacists are responsible for the purchasing of
or additional option may be the installation of a switch that medical devices, they will be involved with risks for other
can stop ventilation when a calamity occurs. healthcare workers as well. They may know that the best
The outcome of reasoning may however be different if it prevention against NSI is the use of safety-engineered sharp
doesn’t concern a safety cabinet but an isolator. Firstly the devices (SEDs). There a two kind of SEDs [88]:
need of having an overpressure in the background area is less • Active devices (manual, semi-automatic): require the
severe. Secondly a calamity may not only concern hazardous user to activate the safety feature. For example: snapping
medicines but also the sterilisation gases in isolators (hydro- a cap over the needle (see Fig. 26.10). Active devices are
gen peroxide and peracetic acid). In some countries there- only as good as the operator using them. If the operator
fore a negative pressure in the background area is decided fails, for whatever reason, to activate a safety feature,
PRODUCTION
for. Additionally a provision may be created for increasing then the device is not protected and, therefore, the
the ventilation rate during a calamity. healthcare worker is at risk from a NSI.
• Passive devices (fully automatic): the safety mechanism
is integral to the device design, requiring no any addi-
tional actions by the user to activate the safety feature.
26.10 Needlestick and Sharp Injuries For example, self-sheathing needle.
The EU Directive to prevent needlestick and sharps injuries The main requirements of a SED are:
in the hospital and healthcare sector (Sharps Directive) During use
2010/32/EU [86] implements the Framework Agreement • The safety feature can be activated using a
on prevention from sharps injuries in the hospital and one-handed technique.
healthcare sector signed by the European social partners • The safety feature does not obstruct vision of the tip
HOSPEEM (the European hospital and healthcare of the sharp.
employers’ association) and EPSU (the European Federation • Use of the product requires the use of the safety
of Public Services Unions). feature.
Needlestick and sharps injuries (NSI) are a common • This product does not require more time to use than
occupational hazard for healthcare workers. Although nurses does a non-safety device.
are most at risk from needlestick and sharps injuries, it may • The safety feature works well with a wide variety of
also affect pharmacy staff, for instance at the collection and hand sizes.
handling of patients’ waste (i.e. insulin syringes) and at
aseptic processes. (continued)
• The device is easy to handle while wearing gloves. restricted area and the vapour itself mixes well with
• The device does not interfere with uses that do not air, a lighter source that is far apart from the liquid can
require a needle. cause the fire. Due to the high concentration of inflam-
• The device offers a good view of any aspirated fluid mable mixture the inflammation will involve an explo-
• The device will work with all required syringe and sion: in a short time a lot of heat is given off.
needle sizes.
• The device provides a better alternative to tradi-
The flash point of flammable substances (see Table 26.11)
tional recapping.
gives an indication whether measures should be taken to pre-
After use
vent fire. Especially if the flash point of a substance is lower
• There is a clear and unmistakeable change (audible
than about room temperature, it is necessary to ensure that there
or visible) that occurs when the safety feature is
are no incendiary sources that may come into contact with the
activated.
vapour near the liquid. Incendiary sources used in preparation
• The safety feature operates reliably.
processes may be a gas flame, but may also be electric devices
• The exposed sharp is either permanently blunted or
that are not automatically explosion-proof, such as some oint-
covered after use and prior to disposal.
ment mills, rotor-stator mixers and refrigerators.
• The device is no more difficult to process after use
Many preparations with flammable and explosive
than are non-safety devices.
substances can be carried out in a fume cupboard or in a
Training
safety cabinet with discharge to the external environment.
• The user does not need extensive training for cor-
Preparation on a larger scale, such as filling out of bulk
rect operation.
flammable liquids in containers, is not possible in a fume
• The design of the device suggests proper use.
cupboard and therefore ventilation of the work area itself
• It is not easy to skip a crucial step in the proper use
must sufficiently reduce the concentration of the vapour.
of the device.
Whether an explosion risk exists at a preparation process
can be calculated taking into account the ventilation rate of
the room. The following properties must be known:
• The flash point of the substance
• The vapour pressure from which combustion is possible
26.11 Fire and Explosion
(¼ lower explosion level, LEL)
• The temperature of the room
Some raw materials are inflammable or explosive. It is
• The amount of liquid in relation to the size of the room
necessary to know what steps are needed to take in order to
• The saturated vapour pressure (¼ the maximum concen-
control these hazards.
tration of the vapour in the air at a specific temperature)
• The vapour density
Fire is the reaction between the vapour of a substance The concentration C of a given substance, which can be
and oxygen from the air. So from a liquid or solid maximally achieved at a given temperature is the saturated
substance vapour has to be formed to cause fire. The vapour concentration (in mg/m3). This can be derived from
flash point of a liquid is the lowest temperature at the saturated vapour pressure p (a value that often can be
atmospheric pressure (1,013 mbar) at which the liquid found in the substance properties) using the following
gives off so much vapour (on or near the surface of the formula:
liquid) that this vapour can become lighted by a flame
or a spark. C ¼ ðM=22:4Þ ð p=1013Þ ð273=TÞ 106 ð26:1Þ
Fire is initially limited to the immediate
surrounding area of the flammable substance. An Table 26.11 Flash points and the lower explosion levels (LEL) of
exception is ether. The vapour of ether mixes very some common organic solvents
slowly with air because due to its high density it Substance Flash point LEL
drops to the ground and it spreads quickly over there. Ethanol 100 % v/v 12 C 3,4 % v/v
At a relatively large distance from the fluid the ether Ethanol 95 % v/v 14 C 3,4 % v/v (ethanol)
vapour can be lighted. Ethanol 70 % v/v 21 C 3,4 % v/v (ethanol)
Liquid can evaporate quite some time before a Acetone 19 C 2,3 % v/v
flame or spark lights the vapour. If this happens in a Ether 45 C 1,7 % v/v
Isopropanol 12 C 2,0 % v/v
(continued)
T ¼ temperature in Kelvin, and M ¼ molecular weight. At A warning for fire danger remains relevant because of the
20 C this equation leads to: 41 M p20 mg/m3. low flash point (14 C).
The explosion limit is usually specified in volume% in When working with larger quantities, a fume cupboard
air. The amount that at least must evaporate in order to reach (see Sect. 28.3.2) is needed.
the LEL in a room filled with air can also be calculated. The
vapour pressure in mbar is related to volume% in air as
follows: 26.11.2 Fire Prevention and Handling Measures
p ¼ volume% 1013=100
Premises have to enable public, staff and goods moving

From the LEL, the related concentration (at 20 C) can be easily in and out of the pharmacy, this applies even stronger
calculated with (26.1): to abnormal conditions of fire (and other) accidents. Areas in
which inflammable substances are processed, must have two
C ¼ ðM=22:4Þ ðLEL=100Þ ð273=TÞ 106 exits as far apart as possible. At least one of the two must
offer a good and accessible escape route. If the area is not on
¼ 416 M LEL unit : mg=m3
the ground floor, the escape route can be realised with a
landing with a caged ladder. Escape routes and fire escapes
For the maximum allowable concentration of the flammable must be clearly indicated, should never be blocked and
vapour a safe margin can be taken such as 10 % of the LEL. should be made antiskid. The emergency exit doors must
This takes into account that the mixing is not optimal, open outwards and preferably have a panic snap. This is a
whereby locally the explosion limit can be exceeded. In system with a horizontal and a vertical rod, with which the
that case, the maximum allowable concentration will be: door can always be pushed open outwards.
41.6 M LEL (in mg/m3). If possible equipment and lighting should be explosion-
The amount of liquid that can evaporate up to this maxi- proof; if not, the amount of inflammable substance to be
mum (or should not be exceeded in order to prevent an handled has to be minimised (see Sect. 26.11.1). In the
explosion in the preparation area taking place), can be cal- laboratory a gas flame or a gas stove may only be used in
culated by multiplying the obtained numbers with the size of the fume cupboard.
the preparation area in m3. The risk of fire in the pharmacy is largest where flammable
substances such as ethanol, ether and petroleum ether may be
present: the laboratory, storage area and, to a lesser extent, the
PRODUCTION
26.11.1 Work Example production area. Any area with flammable substances should
have at least one extinguisher per exit. The staff should know
The saturated vapour pressure of ethanol is 58.5 mbar and the positions and should be trained in its use. An emergency
the lower explosion level is 3.4 vol.%. shower in such areas may be useful, as well as providing a fire
At 20 C and atmospheric pressure, a maximum of blanket. Fire alarm can be given manually (with or without
41.1 46 58.5 ¼ 110,600 mg ethanol vapour in 1 m3 automatic notification to the fire department) or fire can be
air can be present. automatically detected. The emergency telephone number
For an explosion, however, a concentration of 416 46 (112 in the European Union except the UK which uses 999)
3.4 ¼ 65,062 mg/m3 may be sufficient and the safety may be put on phones and fire extinguishers.
approach requires that not more than 6,506 mg/m3 ethanol
vapour should be present in the area, so 6.5 g/m3.
So, in an area of 3 3 3 m3, 1,760 g of ethanol has to References
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Premises
27
Willem Boeke and Paul Le Brun
Contents 27.6.3 Floors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606

27.6.4 Ceilings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
27.1 Processes as a Starting Point for the Design of Areas 27.6.5 Heating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
and Installations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 27.6.6 Furniture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
27.2 Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 27.7 The Implementation Phase of Building or Rebuilding 607
27.2.1 Main Layout Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
27.2.2 Sterile Stock Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
27.2.3 Aseptic Stock Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
27.2.4 Aseptic Extemporaneous Preparations . . . . . . . . . . . . . . . . . . . 588
27.2.5 Non-sterile Stock Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
27.2.6 Non-sterile Extemporaneous Preparations . . . . . . . . . . . . . . . 588 Abstract
27.2.7 Storage Rooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 This chapter outlines the general aspects of premises
27.3 User Requirements Specification . . . . . . . . . . . . . . . . . . . . . . 589 designed for pharmaceutical preparation activities and
the steps to consider in order to achieve a justified design,
27.4 Functional Specification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
27.4.1 Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 construction and qualification of these premises. Also the
27.4.2 Classification of Premises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 built-in technical facilities are discussed. Premises and its
27.4.3 Interlock Systems for Air Locks . . . . . . . . . . . . . . . . . . . . . . . . . 593 technical facilities are an essential link in achieving good
27.4.4 Communication and Interior Design . . . . . . . . . . . . . . . . . . . . . 593 preparation practice. Their design and qualities should be
27.4.5 Routing and Gowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
derived from the kind of products that will be produced
27.5 Built-in Installations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 in it.
27.5.1 Installations for Heating, Ventilation and Air
European and WHO GMP define in general terms
Conditioning (HVAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
27.5.2 Installations for Storage and Distribution preconditioned criteria that have to be met by premises,
of Pharmaceutical Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 including storage areas, weighing areas etc. However this
27.5.3 Provisions for Pressurised Air, Vacuum and Various chapter does not define exactly what is appropriate in any
Gasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
27.5.4 Electrical and ICT Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
specific facility. The emphasis is on the interrelationship
27.5.5 Building Control Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 between the demands, the building, the installations and
the provisions. The scope is general so that all small-scale
27.6 Detail Specification and Building . . . . . . . . . . . . . . . . . . . . . . 604
27.6.1 Inner and Outer Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 production facilities for healthcare establishments and
27.6.2 Doors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 preparation centres are covered in the discussion. Also
ready-made premises or modules can be assessed by
comparison of their qualities with the ones mentioned in
this chapter.
Based upon the chapter Ruimten en Installaties by Willem Boeke, This chapter’s arrangement follows the general
Marco Prins and Jeannine van Asperen in the 2009 edition of approach of best practices in qualification. Important
Recepteerkunde.
subjects covered are:
W. Boeke (*) • Processes that underlie the necessity to build a prepa-
Klinische Farmacie Ziekenhuisgroep Twente, Hengelo,
ration facility
The Netherlands
e-mail: [email protected] • Products and the legislative framework
• Routing of goods and personnel and communication
P.P.H. Le Brun
Apotheek Haagse Ziekenhuizen, The Hague, The Netherlands • Specification and classification of premises
e-mail: [email protected] • Built-in installations for HVAC, water and gasses

586 W. Boeke and P.P.H. Le Brun
• Detail specification and building execution them having substantial knowledge in their fields. Still the
• Walls, doors, floors, ceilings, heating, fixtures and specific knowledge of the design and qualification of a
fittings pharmaceutical preparations facility and its installed equip-
ment might be insufficient among those parties, unless a
Keywords specialist company is chosen for the design and building.
Premises Building HVAC Construction Built-in Conversely consulting engineers are important for the
facilities Water incorporation of every aspect of safe building which usually
is an unfamiliar topic for the pharmacist. This should prevent
failures in construction stability, escape routes, fire and
explosion prevention, etc.
27.1 Processes as a Starting Point
It should be decided which categories of products are to
for the Design of Areas and Installations
be prepared and on what scale. The products involve prepa-
ration processes that basically determine what is necessary
At the initial design stage for a new preparation facility
for a specific facility, taking into account legislation.
attention should be paid to a variety of subjects, such as:
Pharmacy preparation processes can arbitrarily be
• The type and product range of medicines that will be
subdivided into the following categories each with their
required from the facility
own specific premises:
• Developments within the pharmaceutical and medical
I. Extemporaneous sterile and non-sterile preparations
environments and possible future product and process
Examples of this kind of preparations are: Aseptic
demands
handling, i.e. uncomplicated operations with sterile
• The production scale and the batch volumes per product,
medicines in closed containers after which they get a
considering peak loads and annual volume
very short usage period, reconstitution of sterile and
• The scope of the facility and its requirements, e.g. to
non-sterile authorised medicines and extemporaneous
supply other pharmacies with pharmacy prepared
non-sterile preparations from raw materials.
medicines
II. Extemporaneous preparations involving specific risks,
Whatever motives there might be for a (re-)building project
such as complex aseptic handling and preparation with
it should always be kept in mind that the design is specific to
hazardous substances. Involved in this category is aseptic
the type and volume of products for which it is built. Cutting
handling with most antineoplastics, medication cartridges,
out one detail might ruin the possibilities to achieve a
radiopharmaceuticals, biological or advanced therapy
validated production process.
medicinal products (ATMP’s).
III. Sterile and non-sterile stock preparations. Involved are:
Small Detail; Big Consequences. . . • Non-sterile stock preparations
Standard doors will always have certain tolerances in • Sterile stock preparations (sterilisation in final
their rate of warping. However the entry doors to container)
premises with an air pressure hierarchy, as required • Sterile aseptic stock preparations
by the production process, must be checked for this The products to be prepared can be organised into a table as
property in advance. This is to avoid the almost in Table 27.1, related to their categories. This may help to
unsolvable problems in the qualification of the air estimate the extent of provisions and the level of required
pressure hierarchy due to leakages by not perfectly standards that are necessary per product type.
closing doors. Neither the suppliers of doors nor
contractors are usually aware of the importance of
assessing these tolerances in advance. After all, if
this air pressure hierarchy really was required but 27.2 Design
could not be qualified as such, a validated production
process will not be achieved. 27.2.1 Main Layout Considerations
Starting from the classification of preparation processes a

Therefore, at the initial design stage in the construction of rough preliminary design is drafted indicating the position of
premises for pharmaceutical preparations the responsible production areas, their interrelationship and logistics. The
pharmacist or an advisor who has proven capabilities in relations between departments and premises, flow of goods
this specific area must have a decisive input and a coordina- and persons are plotted. This start document is preferably
tive role. He will have to deal with architects, companies of formulated by the one who will be responsible in future for
consulting engineers, (sub-)contractors and installers, all of the preparation processes.
27 Premises 587
Table 27.1 Categorisation of products for designing premises

A. Stock preparations Categories A correct constructional design has to be derived from
A1 Sterile the process and will prevent any confluence or cross-
Aseptic preparations (vials, ampoules, infusion fluids III ing of routes. However, in practice crossing cannot
in bags, prefilled syringes) always be avoided. In that case procedural solutions
Autoclavable preparations (vials, ampoules, infusion III should warrant that all goods are to be labelled and
fluids in bags or bottles)
packed securely (e.g. in closed boxes) before being
Eye drops III or II
exposed to crossing lines. Routing questions at the
Sterile ointments and creams III
design of a layout of premises will frequently be with
A2 Non-sterile
regard to processes such as weighing raw materials,
Packaging e.g. in Unit Dose III
Tabletting III
sampling, input and output to and from any temporar-
Fluids (solutions and suspensions) III
ily deposit store for intermediates or quarantine,
Ointments and creams III cleaning of reusable utensils and label printing.
Suppositories III For example, it is important to consider if the weighing
B. Extemporaneous preparations process will or will not be carried out in a centralised
B1 Sterile weighing room thus requiring subsequent transport of
Aseptic handling (complex, see Sect. 31.3.2) II the labelled portions to the preparation room. In a
Total parenteral nutrition, medication cassettes centralised weighing room, thorough precautions
Aseptic handling (hazardous, see Sect. 31.3.5) should be taken to prevent cross contamination of the
Antineoplastics, radiopharmaceuticals raw materials. The same goes when two workers use
Simple aseptic handling; short shelf-life I the same set of weighing apparatus in a pharmacy.
B2 Non-sterile
Capsules, suppositories, fluids, ointments and creams I
Reconstitution of licensed pharmaceutical preparations I • The location of the preparation department in relation to
logistic functions, etc. For example radiopharmaceuticals
(see Sect. 15.6.1) should be prepared nearby or at the
nuclear medicine department.
The preliminary design should be drawn up based on the • The required apparatus and utensils, the preparation pro-
following considerations: cesses they are used for and the required provisions such
• The extent of the preparation department: Available as air conditioning, clean water, electricity, compressed
premises usually are confined. However, sufficient room
PRODUCTION
air and gasses. For extremely hazardous preparations
must be available for apparatus and materials. Apparatus (antineoplastics, radiopharmaceuticals, see Sect. 26.3.5)
should be stored in a way that minimises contamination. and for sterile preparations separate premises may be
Therefore, a separate accommodation near the prepara- required to protect products and operators adequately, as
tion premises is preferred over the placement in the is also laid down in GMP. Scaling up of the processes
preparation room itself. may lead to partitioning of the rooms into areas for
Sufficient room should be available for the operators to dedicated functions.
work efficiently and safely. After classifying the preparation processes and the corres-
• Avoiding crossing routes for personnel and goods: In a ponding premises and its outlines the preliminary design will
pharmacy several products are usually being prepared on be drafted. Some examples are given below for a few prepa-
the same day. This brings about a higher risk of cross ration processes.
contamination when compared to a large pharmaceutical
industry producing only one product on a dedicated pro-
duction line. Inadvertent mixing up of a sterile and a not 27.2.2 Sterile Stock Preparations
yet sterilised product or of products of different batches
constitutes a similar threat. Separate rooms are necessary for the preparation and for
• Entrance: The entrance to premises for preparation filling into e.g. infusion bags or ampoules prior to final
should be provided by means of, preferably heat sterilisation. In addition, one or more sterilisers with
sex-separated, gowning rooms for staff and a separate corresponding technical rooms (including the access) are
air locked entrance exclusively for goods. If necessary needed.
the separation of the sexes might be achieved by The premises for the most critical preparation steps
separating in time. However it should be realised that (e.g. filling) must be built as a clean room (see Sect. 27.3)
this may jeopardise the efficiency of the production. and require a controllable air conditioning installation.
Those premises must comply with GMP class C (see hazardous products, may require dedicated rooms and con-
Sect. 27.4.2 and Table 27.2) [1]. tainment conditions (see Sect. 26.7).
Sterile stock preparations usually require such high For aseptic handling in closed systems a cabinet with
volumes of water that separate technical installation unidirectional airflow (LAF or safety cabinet) or an isolator
premises are required to accommodate the installation for can be used (see Sect. 28.3). The requirements for the back-
the production of water for injections. ground room depend on national guidelines and on the types
Finally, premises for examining and for packaging and of containment in the cabinets. Adjustments are allowed but
labelling are necessary. must be based on a risk assessment.
Appropriate rooms (laboratories) for pharmaceutical
microbiological control and for chemical quality control
Strictly, air quality class A cannot be claimed if the
should not be left out. However the possibility of
background qualification is less than class B. However
microbiological contamination from this laboratory requires
this class A safeguard is strictly only required for
a completely separated air handling.
aseptic stock preparation and any aseptic handling
Alternatively the microbiological control could be out-
that is executed with non-closed systems. Under spe-
sourced implying yet other, more procedural complications
cific conditions a class C condition as background
such as the need for Service Level Agreements and meeting
might be acceptable. On the basis of a thorough risk
the requirements of GMP Chap. 7 (Outsourced activities).
assessment and a monitoring and validation program
even a class D background for well-defined aseptic
handling may be justified, see Sect. 31.3.4.
27.2.3 Aseptic Stock Preparations
In premises for aseptic preparation from sterile raw materials

the preparation room usually is combined with the filling
27.2.5 Non-sterile Stock Production
room because carrying the bulk product into another room
will introduce an additional contamination risk. In this situ-
This department can be divided into separate premises for
ation a separate room for preliminary operations, e.g. disin-
solid (dusty), semisolid and fluid preparations. Preparation
fection of utensils and surfaces of containers, is required.
processes with inflammable substances may require specific
At the most critical places, especially at the filling point
provisions such as a fume cupboard or more intensive venti-
of the aseptic fluids, the premises must meet GMP class A
lation. Premises for tableting and similar dust-producing
conditions [1]. A class A condition usually needs a back-
preparation processes should be equipped with a suitable
ground condition of class B to be able to maintain the class A
installation for air conditioning and dust exhaustion. Apply-
condition during operation. However exceptions to this rule
ing a negative pressure will prevent dust from active
can be warranted, e.g. using an isolator.
substances escaping from the preparation room. Even for
Classified premises are expensive both in procurement
repackaging activities (e.g. into unit dose package) a sepa-
and maintenance. Therefore, it is justified to analyse each
rate room is to be preferred. Specific GMP classification
preparation process for all critical steps and to limit their
A-D is not required for non-sterile preparations. However
number as far as possible.
the GMP principles such as cleanability are applicable.
Premises for examining and for packaging and labelling
Therefore, in practice, facilities for non-sterile preparation
can be combined with those for sterile stock preparations.
are often classified as grade D.
27.2.4 Aseptic Extemporaneous Preparations 27.2.6 Non-sterile Extemporaneous

Preparations
Also in this situation a separate room is required for prelim-
inary operations, e.g. disinfection of utensils and surfaces of The underlying principles for premises for non-sterile stock
materials. In the preparation room medicines are preparations should be used for extemporaneous prepara-
reconstituted, e.g. filling of syringes, infusion bags, medications as well. Preparation activities in a community phar-
tion cartridges, disposable infusion pumps and irrigations. In macy usually are confined to reconstitution, aseptic
addition, parenteral nutrition fluids, antineoplastics, handling, manipulation of licensed medical products and
radiopharmaceuticals and eye preparations may be prepared non-sterile preparation from raw materials. The avoidance
in these premises. Radiopharmaceuticals and other very of crossing process lines in small-scale situations is a
27 Premises 589
challenge but it is almost impossible to prevent crossing with dust or even insects. So either only complete units have
lines just by the layout of the premises. Routing has to be to be used or the remaining materials should be rewrapped or
specified by procedures and organisational measures have to repacked.
be taken, e.g. working with trays or closed boxes per Storage rooms should be kept clean at a normal house-
activity. hold level and vermin-free. No specific additional demands
The requirements for the premises may turn out to be are made because the package of the products should protect
quite moderate, provided that they are based on a well- them sufficiently against any contamination.
documented risk assessment. It will at least imply that
premises shall be exclusively dedicated for preparation
activities, e.g. shall not give direct access to toilets and
27.3 User Requirements Specification
will have to be physically separated from any public area.
The layout should not compromise a logical sequence of
As soon as the draft design, the program of requirements and
activities. Specific gowning and cleaning procedures must
a thorough (risk) analysis of the anticipated production
apply.
activities is gathered, this information should be ’translated’,
Attention should be paid to the ventilation of any premise
usually by professional advisors, into a keynote document or
and its upkeep. In newly built premises, the ventilation
user requirements specification (URS). This document
capacity might have been minimised due to energy saving
should describe and specify in detail the required situation
policy, especially in northern countries. Therefore the risk
after the (re-)building. It should clearly underpin the listed
has to be assessed that the ventilation might fail to meet
demands and points of departure, which for their part should
minimal requirements. Any so-called ’natural ventilation’
be traceable to relevant legislation. In addition the URS
might clear the way for insects to enter, unless specific
should, after realisation of the building, offer direct control
measures are taken (e.g. insect screens). Air quality can be
points to all critical aspects of the intended processes. The
improved by using a recirculating dust exhaust cabinet
conformity of the final situation to the original plan must be
which should be available in every community pharmacy,
proven which only can be done by checking systematically
e.g. for the reconstitution of antibiotic oral liquids.
all critical control points of the completed premises to the
original plan as previously specified in the URS.
The delivery of this evidence is called the performance
27.2.7 Storage Rooms qualification (PQ), see further Sect. 34.15. It is important to
pay attention to the future PQ as, in contrast to other
PRODUCTION
Apparatus to achieve specific, usually low temperature, stor- qualifications, the PQ cannot be outsourced. A well-
age conditions are described in Sect. 28.9. The design of formulated URS takes account of the implementation of
storage rooms should take into account that the temperature the future PQ tests and therefore its tenor extends far beyond
should not exceed 25 C for prolonged periods (see Sect. a more trivial ’Plan of Demands’.
36.9.4). This may involve the necessity of air conditioning. The URS should account for regulatory demands of
Additional provisions should be provided to avoid long GMP, Occupational Safety and Health and Environmental
lasting humidity levels over 60 % RV or below 20 % RV Care. Additionally preparation demands, required apparatus,
or penetration of direct sunlight. HVAC (installations for Heating, Ventilation and Air Con-
Specific conditions, like lockable safety cupboards, may ditioning) controls, routing of personal and goods as well as
be required for the storage of any specific class of hazardous gowning and cleaning instructions should be specified. It
(e.g. inflammable or poisonous) products. should be stated explicitly which regulations (e.g. GMP,
A properly considered location of storage rooms, ISO standards, Occupational Safety and Health legislation)
separated quarantine storage and laboratory may ease rout- do apply, thus delimiting the legislative framework. By
ing very much. adding the prefix ’c-’ (current) to the name of any law
There should be ample space for input and output of goods (e.g. c-GMP) it is stated that the regulation may be develop-
without the need of rearranging the goods at each occasion ing during the life of the premises and that always the most
(first-in first-out principle). Especially the manoeuvring of recent version has to be consulted.
pallets should be accounted for. Clean rooms are usually involved in the design of a
Empty packing material is usually wrapped in airtight pharmaceutical production facility. The term ’cleanroom’
wrappings or transport casings. However after opening the is specified in detail in the ISO standards 14644 (parts 1, 2,
wrap, packing materials are open to the rather unconditioned 4, 5 and 7) and 14698 (parts 1 and 2) [2–5]. Particularly ISO
environment of the storage room and thus open for pollution 14644 part 4 deals with the design, the construction and the
initial start-up of a clean room and includes a useful be proved at any moment and place, measures are prescribed
checklist [4]. that should guarantee this absence with substantial safety
margins:
• The inlet air should be filtered, through HEPA (Highly
Efficient Particulate Air) filters.
27.4 Functional Specification
• A specified air replacement factor per hour (ventilation
factor; see Sect. 27.5.1 HVAC) should be achieved.
27.4.1 Contents
• The premises must be kept clean in relation to lower
classified neighbouring premises by the application of
Next step in the design process is drawing the functional
pressure differences.
requirements specification (FRS), also called the physical
Annex 1 of the GMP applies. This document specifies four
requirements specification. The FRS documents elaborated
grades for low particulate premises: A, B, C and D. See
demands for connections, heat burden, floor load, acoustic
Table 27.2.
demands, specifications of the walls, HVAC etc.
GMP Annex 1 states that a certain air quality class can
The heat burden is the amount of heat that is generated in a
only exist when the access to the room is achieved through
room per unit of time by humans and apparatus. Provisions for
an air lock in which the same class prevails. The Annex
air supply have direct impact on product quality. In the FRS
1 classification refers to the ISO classification (see
for clean rooms the limits are specified for the allowable
Table 27.3) that define intermediate air quality specifications
number of particles at rest and in operation, i.e. the clean
by decimal class designations.
room class (see Sect. 27.4.2 below), along with desired turbu-
According to ISO 14644–1 the air classification scheme is
lence limits, limits for air pressure and microbiological limits.
distinguished by a mathematically coherent approach and
It provides the final specifications for premises, fixtures and
based upon a formula:
fittings and a map with the positions of furniture and appara-
tus. The FRS contains also technical or procedural measures
Cn ¼ 10N ð0:1=DÞ2, 08 ð29:1Þ
to prevent cross contamination or crossing lines for personal
or goods [5]. Obviously all specifications in the FRS are
where
substantiated at the base of their application. As an example,
Cn ¼ maximum number concentration of particles per m3
in premises intended for complex aseptic handling or recon-
with diameter the considered particle diameter,
stitution of hazardous sterile medicines, any choice for the
rounded to a maximum of 3 digits;
classification of the background conditions should be justified.
N ¼ ISO classification number;
D ¼ considered particle diameter;
0.1 ¼ the reference diameter, a constant with the
27.4.2 Classification of Premises
dimension mm.
The idea behind GMP is to preclude any factor with an As the ISO classification is defined by a continuous
unpredictable or undetermined impact on the production pro- formula with the particle size as a variable and the GMP
cess as this impairs the process validity. Particles, micro- grades are defined in discrete counts for specific particle
organisms and (gaseous) chemical contaminants arising sizes, the comparison between GMP grades and ISO
from the air from outside might constitute such a factor, classifications is formally not possible. Additionally ISO
especially relevant for the process of producing sterile and classifications can be formulated in decimals where the
aseptic preparations. Therefore, GMP requires that premises GMP grades cannot. However as a practical approach the
for this kind of preparations must be classified. Since the comparison is possible as e.g. grade B at rest will match ISO
absence of invisible micro-organisms and dust is hard to 5 for most practical purposes.
Table 27.2 Grades of air conditioning according to GMP

Maximum permitted number of particles per m3 equal to or greater than the tabulated size
At rest In operation
Grade 0.5 μm 5.0 μm 0.5 μm 5.0 μm
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520,000 29,000
D 3,520,000 29,000 Not defined Not defined
27 Premises 591
Table 27.3 ISO 14644–1 classification of air cleanliness

Maximum permitted number of particles per m3 equal to or greater than the tabulated size
(in operation)
Class 0.1 μm 0.2 μm 0.3 μm 0.5 μm 1 μm 5 μm
1 10 2
2 100 24 10 4
3 1,000 237 102 35 8
4a 10,000 2,370 1,020 352 83
5(GMP B at rest) 100,000 23,700 10,200 3,520 832 29
6 1,000,000 237,000 102,000 35,200 8,320 293
7 (GMP grade B in operation, Grade C at rest) 352,000 83,200 2,930
8 (GMP grade C in operation, Grade D at rest) 3,520,000 832,000 29,300
9 35,200,000 8,320,000 293,000
a
EU GMP Grade A meets ISO 4.8
How Is the Classification of the Premises Actually cabinet is at least class B. The background room for
to be Derived from the URS? aseptic reconstitution or handling in a LAF, or safety
A basic principle is that raw materials, intermediate cabinet may have a lower classification than B,
products and final products that are not yet in their provided that it is based on risk assessment. Confor-
final, primary package should never be exposed to any mation to the latest views of inspectorates and profes-
unconditioned air. The primary package is the airtight sional associations e.g. PIC/S [1] is advised.
enclosing package of the final product that is in direct
contact with the product. Should therefore also
non-sterile extemporaneous preparations (Category I;
community pharmacy or small hospital pharmacy) be For premises designed for non-sterile preparations over-
prepared in a classified premise? The principal objec- pressure is preferable to prevent any penetration of uncon-
tive is that during preparation of non-sterile products no trolled air. For premises designed for sterile or aseptic
contamination from whatever source can occur. To that preparations this is required by GMP.
end adequate procedures should be organised such as a Generally working with hazardous substances – as almost
PRODUCTION
warranted adequate maintenance (cleaning, prevention all active substances are – requires containment. In the
of impairment) and also warranted procedures should specific case of radiopharmaceuticals, Nuclear Energy legis-
apply to prevent disturbances such as any opening of lation requires the application of negative pressure (see Sect.
doors or windows during preparation activities. Under 15.6.3). In the situation of aseptic handling, which requires
such conditions, a specific classification of premises has positive pressure, with radiopharmaceuticals, this results
limited meaning and usually can be left out. After all essentially in contradictory pressure demands. A solution
Class D only specifies a maximum number of particles may be achieved by putting the whole complex of prepara-
at rest which is usually easy achievable except when a tion rooms with air locks at negative pressure relative to its
current badly functioning ventilation system is in action environment. The system of walls, floors and ceilings should
or during specific (weather) conditions, incurring a high be completely airtight in that case. Pipe entries, electrical
concentration of fine particles or pollen. sockets as well as porous stone in the wall parts above the
Also if products are sterilised in their primary pack- ceiling are frequent sources of (substantial) leakage of
age a low microbial starting contamination is essential. contaminated air. Thus all chinks and gaps have to be filled
Therefore products to be sterilised must be filled under and porous stone has to be coated.
class C conditions but the preparation of the bulk By now putting the air locks at some additional negative
solution may take place under class D conditions. pressure a relative overpressure in the preparation premises
Aseptic handling and preparation must be executed is created relative to the admission air locks. The deeper
under class A conditions, usually a LAF (Laminar Air negative pressure in the air lock will however lead to a
Flow) cabinet, a LDF (Laminar Down Flow) cabinet, a vigorous influx of contaminated air as soon as the outer
safety cabinet or an isolator see Sect. 28.3. The back- door is opened, contaminating the lock and compromising
ground room for stock preparations in a LAF, or LDF its function. To prevent this an additional ’front air lock’
should be considered. The front air lock should have a slight
(continued)
negative pressure relative to the environment and will be Weighing of solid substances will release dust. A dust
supplied with clean HEPA filtered air. Alternatively, a clean extract cabinet, equipped with a High Efficiency Particulate
air lock or corridor giving access to other (positive pressure) Air (HEPA) or Ultra Low Particulate Air (ULPA) filter (see
premises can serve as a front air lock to a negative pressure Table 27.4) in the rear wall or in the exhaust, or both, will
premise. See Fig. 27.1. limit the exposure of operators to active substances. Addi-
tional options are the wearing of respirators (see Sect.
26.4.1) and a closed weighing vessel.
In many respects the hazards of many antineoplastics
The air turbulence from a dust extract cabinet may disturb
and radiopharmaceuticals for staff are similar. Also the
the functioning of electronic balances. A dedicated construc-
required skills for aseptic handling are similar. This
tion in each of the preparation premises to manage this is
may lead to the consideration of designing a standard
layout for all premises for handling with extremely
hazardous substances. However, for antineoplastics Table 27.4 Survey of HEPA and ULPA filters
no formal requirement for pressure applies (see Sect. Filter class according
26.8). Therefore, the viewpoint that overpressure to EN 1822:2009 Efficiency % Penetration %
warrants a better microbiological air quality usually E10 85 15
will prevail. In addition the validity of negative pres- E11 95 5
sure premises may be impaired as a result of almost E12 99.5 0.5
unavoidable air leakages. H13 99.95 0.05
The objective can also be achieved with the use of H14 99.995 0.005
negative pressure cabinets sited in positive pressure U15 99.9995 0.0005
rooms. U16 99.99995 0.00005
U17 99.999995 0.000005
Fig. 27.1 Model plan for

pressure hierarchy around
negative pressure premises.
Adapted from Recepteerkunde
2009, #KNMP
clean air corridor

+15 Pa
sliding
door LDF
underpressure
cabinet
gowning lock -30 cleanroom -15 Pa
Materials
lock
surrounding area; 0 Pa
27 Premises 593
expensive and therefore cannot always be achieved. If for

this reason a separate weighing chamber is designed all intercom apparatus. A ‘voice actuated system’ - the
measured portions should be transported in well-closed and voice of the speaker actuates the communication line -
identified vessels. might be a better solution. Background noise
(e.g. from LAF cabinets) however may impart the
correct functioning of such a system. A wireless head-
27.4.3 Interlock Systems for Air Locks set or a mobile telephone that stays within the premise
and is cleaned / disinfected daily may be an
For the maintenance of an air pressure regime and an air alternative.
quality class of a preparation premise an air lock is required.
It controls access from any lower qualified premise. Person-
nel locks should be discriminated from materials locks. In
personnel locks the required gowning regime has to be
determined in advance. In most cases this results in the 27.4.5 Routing and Gowning
requirement of sex-separated gowning locks.
For materials locks the prevailing transport direction and The FRS design document should consider the usual tracks
the usual volume of materials is important. If possible the of personnel. Routing of personnel and thus required
transport direction should be assured for instance by means gowning rooms are principally independent of the routing
of a catch that transmits a standardised vehicle (e.g. a crate) of materials. Therefore, materials locks or transmission
in only one direction. cabinets are indispensable in a good design. A correct
All air locks must be equipped with a so-called interlock gowning procedure for personnel can hardly be maintained
system. This system ensures that both doors of the air lock when employees have to use the changing lock for material
will never be opened at the same time. transport.
For a gowning lock the following requirements can be put
Different interlock principles exist: forward:
• Both doors are permanently closed by magnets, • A clear division between the ’dirty’ and the ’clean’ part,
necessitating a separate hand operated switch to preferably by means of a step-over bench
open one of them. • A correct location of a washbasin and a dispenser for
• Both doors are permanently unlocked, in which hand disinfectant
• Drains (from washbasins) should not be sited on the
PRODUCTION
case the opposite door is locked by opening the
other door. ’clean’ side of the lock
Considerations for the choice are: the hand operated • A cabinet for clean, unused clothing, and a bin for used
switch is a potential source of cross contamination, clothing is provided
magnets consume electricity and emergency escape • A locker to stow away personal belongings
routes depend on easy access. Toilets should not be accessible directly from a preparation
premise from the clean part of a gowning lock [2].
For the design of the routing and communication it might
be useful to have well in advance the future staff ‘virtually’
preparing the products, based on concept drawings and let
27.4.4 Communication and Interior Design them document all of their detailed activities. Together they
should properly review all process steps in detail to find out
Employees who are working in separate rooms within the which provisions have to be taken.
premises should be able to communicate with each other. If
no well-designed communication resources were in place the
personnel would be forced to communicate to each other
27.5 Built-in Installations
through windows, locks, opened doors, etc. Routing of per-
sonnel and goods will then be seriously jeopardised.
Built-in installations that will be dealt with in this chapter
are:
Mobile telephones in preparation premises are notori- • Air conditioning installations
ous sources of cross contamination and thereby not • Installations for storage and distribution of pharmaceuti-
appreciated. The same goes for a hand operated cal water
• Provisions for pressurised air, vacuum and gasses
(continued)
• Electrical installations (power supply, emergency power its own separate air inlet and outlet. In practise overflow
supply, signalling and ICT provisions. grids are used frequently to transport air from one room with
In a community pharmacy (category I preparations; see relative high air pressure to an adjacent room or air lock with
Table 27.1) usually limited provisions will be sufficient, a lower air pressure. However, in that case no independent
e.g. if water of suitable pharmaceutical quality is purchased control of the air pressure or the ventilation factor is possi-
in bottles. See also subsection 27.2.5. ble. So during the design it is necessary to consider any
possible contamination of overflow air from an adjacent
room and the limitations to control it.
27.5.1 Installations for Heating, Ventilation In principle a HVAC installation consists of three
and Air Conditioning (HVAC) components, i.e. the preliminary treatment installation
(make-up casing), the recirculation- and control installation
A HVAC installation is quite space consuming as air ducts (recirculation casing) and the distribution network with fine
usually must be voluminous to warrant the distribution of the tuning per room. See the example in Fig. 27.2.
required air volumes within acceptable noise nuisance
limits. In existing constructional premises the layout of the 27.5.1.1 Preliminary Treatment Installation
air ducts often is not possible without any compromise. The make-up casing draws in fresh air through a bird grid
Ideally, but expensive, each room is to be equipped with and a rough dust filter. Subsequently the air is, according
11
P
6 7 9 10
2
3 4 5
1 8
12
P
13
19 17 16 15
14
20 20 20 18
21 21 21
22 22 22
Legenda Figure 27.2

1. Bird grid (air inlet) 12. Recirculation ventilator
2. Coarse dust filter 13. Restriction with pressure difference measurement (Dp)
3. Inlet ventilator 14. Regulating valve
4. Restriction with pressure difference measurement (Dp) 15. Steam injector (moistening)
5. Regulating valve 16. Heat exchanger for heating
6. Steam injector (moistening) 17. Heat exchanger for cooling and drying
7. Heat exchanger for cooling and drying 18. Drain for condensate
8. Drain for condensate 19. Dust filter
9. Heat exchanger for heating 20. Heat exchanger for temperature adjustment in the premise
10. Dust filter 21. HEPA filter and inlet grid
11. Pretreatment installation 22. Premise
Fig. 27.2 Schematic representation of a HVAC installation for clean rooms

27 Premises 595
to weather conditions, heated, cooled, moistened or dried.

In the (almost) airtight classified clean rooms, with or laminar airflow, having a velocity of about 0,4 m/s.
recycled air, atmospheric humidity can easily increase Higher velocities soon give raise to turbulence of the
above limits by water vapour or exhaled human air. This air; lower velocities displace any particles too slowly.
will not level with environmental air conditions as quickly The airflow rate (volume per unit of time; D) can be
as usual in normal, non-airtight buildings. Drying of derived from this air velocity s and the area A of the air
(inlet or recirculated) air is achieved by condensing inlet grid [5]: D ¼ s A.
over a cold heat exchanger placed in the air stream. It has to be decided whether the total airflow rate to
Provisions for drying and moistening are critical installa- be distributed over the premises is controlled by a
tion parts because moist air can easily foster growth of so-called fixed volume controller or by a variable
accumulating moulds. A well-designed control plan volume controller. A fixed volume controller main-
should prevent this. tains a constant pressure fall over a fixed constriction
in the main air transportation channel. The controller
thus serves to maintain a steady air volume per unit of
27.5.1.2 Recirculation- and Control Installation
time independent of variations in input air pressure
To save energy, as well as to control air quality a substantial
(wind!), pressure fall over filters and leakage through
portion (usually 80 %) of air returning from the premises is
chinks and gaps. A variable volume controller delivers
reused by means of a recirculation ducting. The remaining
the air at a slightly variable flow rate as this controller
20 %, leaving the premises by leakage and by direct exhaust
directs the airflow at the basis of a specific air pressure
to the outside of the building has to be replenished by the
in one or more reference rooms.
make-up ducting. The recirculation ducting controls air
The consequence of a fixed volume controller is
quality by:
that small variations in the amount of air leaking
• Filtering the supply air through a central HEPA filter
through chinks and seams soon give raise to substan-
• Adjusting temperature and humidity
tial differences in the air pressure hierarchy. In this
• Adjusting airflow rates (volume of air per unit of time) to
case pressure steps between different rooms need a
the distinct rooms
level of 15 Pa to cope with any unavoidable variations
The air drying over cold heat exchangers makes independent
in leakage.
control of humidity and temperature difficult. Apart from
With a variable volume controller there is a direct
that the circulation of air through filters generates frictional
feedback from the air pressure in each separate room.
heat. The prediction of the amount of heat and moisture
Small variations in air leakages will result in adjusting
PRODUCTION
generated from the production process therefore is both
the air control valve in such a way that the air pressure
complex and important design information.
differences are maintained. Usually a smaller pressure
The HEPA filter makes the distributed air (almost) free
step between rooms, e.g. 10 Pa, will be sufficient to
from particles (see Table 27.4). Preferably the pressure fall
maintain the pressure difference and airflow. The ISO
over the filter is continuously monitored to signal leakages
standard 14644-4 mentions pressure steps of 5 – 20 Pa.
(pressure fall is too low) or blockage by pollution (pressure
However it should be borne in mind that 1 Pa
fall is too high and has usually gradually increased).
(1/100.000 bar) is a very small pressure difference,
The volume of each room and the required ventilation
which is hard to control. In the design therefore a
factor determine the airflow rate that has to be achieved in
certain margin should be observed. GMP specifies a
the room. The ventilation factor or replacement factor is the
guidance value of 10–15 Pa between rooms.
number of times that the volume of a room is completely
Although at first glance a variable volume control-
replaced with fresh air. In the ISO standard 14644-4 [4]
ler would be preferred it has a drawback that the
advisory ventilation factors are given in relation to the air
recovery time of a clean room after the introduction
quality class in a classified premise. Occupational safety and
of contaminating particles at validation will not easily
health legislation will also add requirements to the ventila-
show reproducible results.
tion factor.
An additional problem may be raised by the con-
troller. The opening of a door for instance will create a
Air Velocity, Ventilation Factor and Airflow Rate zero pressure difference. If the controller reacts too
Control fast overcompensation of the feedback loop takes
Starting from ISO class 5 no ventilation factor is given place resulting in fierce auto-reinforcing fluctuations
as this class can only be achieved by a unidirectional of air pressure [5].
Exhaust
Apart from the fixed volume controller and the
variable volume controller also hybrid controllers are
available: a variable volume controller with a limited
range of variation or a fixed volume controller with a
variable controlled exhaust volume. Which type suits a
specific clean room depends on the level of control of
the flushing pattern of the air inside the room, the air Ceiling
pressure differences and the recovery time.

One-way
valve
27.5.1.3 Distribution Net and Fine Tuning

For the design of preparation premises an air balance per
room should be drafted regarding: Exhaust
• The free volume of the room (room volume minus the ventilator
volume of fixtures and fittings)
• The required overpressure relative to linked premises LDF safety workbench
• The required ventilation factor
• Any volume of direct exhaust (e.g. through safety
cabinets)
• The heat burden (amount of heat generated by apparatus Floor
and humans)
Additionally the required air quality class (GMP, see Fig. 27.3 Draught diverter
Table 27.2 or ISO, see Table 27.3) must be documented
and it should be documented that the pattern of air flushing
through the room is effective at all functionally relevant the designed air balance within the room. The use of a
spots. The actual air sweep will have to be validated after draught diverter facilitates the possibility to switch off the
construction and must meet the specifications. cabinet itself as the extraction ventilator will then bypass
The ventilation factor and the room pressure determine it. The functioning of the extraction ventilator should be
the volume of air that has to be let in and thus the dimensions interlinked with the HVAC installation in such a way that
of the air duct, the number of inlet grids and the position of if the latter fails or is switched off, the capacity of the
the metering valve of the involved supply channel or the area extracting ventilator should be adjusted, or, in case of fire
of the involved overflow grid. The heat burden and the alarm, switched off. In addition any direct or indirect failure
admitted airflow rate furthermore determine the maximum of the extracting ventilator must lead to an alarm condition
inlet air temperature or the required capacity of any after- as this impairs directly staff safety.
heating radiator.
The air quality class determines the type of HEPA filter
(see Table 27.4) mounted in the inlet grid and the thereby Principle Draught Diverter
raised air friction. All HEPA filters should be entered into a When a so called draught diverter is implemented the
maintenance plan; at least once a year a leakage test and a exhaust channel is placed over the outlet of the equip-
filter integrity test should be performed [5]. ment like an inverted funnel. At switched-off status,
In premises equipped with direct external exhaust it has to air will be sucked out from the room, bypassing the
be determined in advance if the connection to the exhaust equipment. When switched-on the air leaves the room
duct will be fixed or achieved by means of a so called mainly through the equipment. Accounting for the
draught diverter (Fig 27.3). volume of air that passes through the equipment is
Examples of equipment with an external exhaust are necessary in the calculation of the air balance. For
e.g. fume cupboards and flue gas exhausts, fitted to an the air pressure or ventilation factor in the room it
ampoule filling machine or to an atom absorption spectro- doesn’t matter whether the equipment is switched on
photometer. Also a safety cabinet or a non-recirculating dust or off.
suction cabinet (e.g. Wibojekt®) and negative pressure In any case it should be warranted, whether the
isolators have external exhausts. When the equipment has a equipment is fitted with a draught diverter or with a
fixed connection the exhaust ventilator must be switched on
continuously and thus the equipment has a direct impact on (continued)
27 Premises 597
knowledge of the specifications of pharmaceutical quality

fixed outlet connection, that never, e.g. in the case of water. The most important characteristics and the
breakdown of the external exhaust ventilator, outside categorisation of pharmaceutical water, according to the
air can enter the preparation premise. The opposite European Pharmacopoeia, is discussed in Sect. 23.3.1.
should be prevented as well: if a safety cabinet shuts The leading principle in storage and distribution of phar-
down the exhaust should close at the same time, maceutical water in bulk is continuous circulation in a loop
because otherwise environmental air could exchange that includes at least the following:
with the air from within the premises, thus • Apparatus for the measurement of temperature, conduc-
contaminating the HEPA filter. A well-designed tivity and TOC (Total Organic Carbon; i.e. the total
draught inverter with a one-way valve provides all carbon load of organic, carbon containing substances)
those functions. • A storage vessel
• Filter(s) in the production part of the installation and for
pressure levelling out with air from the outside of the
system
27.5.2 Installations for Storage and Distribution
• Apparatus for heating
of Pharmaceutical Water
• Apparatus for cooling
• Taps
In this subsection only built-in installations required for
• Apparatus for disinfection (only for cold water systems).
storage and distribution of pharmaceutical water are
See Fig 27.4
discussed. Apparatus for the production of pharmaceutical
Distinct requirements that apply for different qualities of
water are discussed in Sect. 28.4.
pharmaceutical water will be discussed below.
Water of pharmaceutical quality is used as a raw material,
excipient, solvent, and as cleansing agent. In addition the
pharmaceutical production facility needs water for (thermal)
disinfection or sterilisation and for the preparation of phar- 27.5.2.1 Purified Water in Bulk
maceutical quality reagents [6]. The most commonly used systems for the production of
Engineering of installations for the storage and distribu- purified water deliver water with temperatures around
tion of pharmaceutical water can only be understood with room temperature. Therefore adequate measures have to be
PRODUCTION
tank vent with
air filter UV-lamp (only cold
water systems)
temperature conductivity temperature
conductivity
taps
spray ball
Ozon generator (only

apparatus for water purification level measurement cold water systems) restriction
cold
water
tap
tap
cooler
pre-filter
storage vessel
Softener or RO
drinking water supply apparatus or EDI distiller flowmeter
via non-return valve apparatus or any
and break tank combination of those drain pump
Fig. 27.4 Schematic diagram of water storage and distribution systems. Source Recepteerkunde 2009, #KNMP
taken to manage and control total viable aerobic counts 27.5.2.3 Design Criteria for the Quality of Water
during preparation and storage (see Sect. 23.3.1). For the chemical specifications of pharmaceutical water see
The design capacity should be balanced with the Sect. 23.3.1. A sufficient low conductivity, specified in the
predicted need per instance, e.g. for the most water consum- Ph. Eur., warrants that any metals, ions and inorganic
ing activity and the predicted need over time. Involved are contaminants will be practically absent. During the produc-
considerations of production time per batch, investment tion, storage and distribution Water for Injections in bulk is
costs and the time to re-fill the storage vessel. It should be tested continuously at conductivity, temperature and at TOC
taken into account that drawing off or flushing out the water content. TOC can be measured either in-line, involving a
will curtail the ongoing growth of micro-organisms. metering sensor that is permanently mounted into the loop,
During transport through the loop the water passes sev- or off-line, implying periodical measurement in tapped
eral valves in which biofilm formation may occur (see Sect. water samples [7]. Water samples should be tested off-line
19.3.5). This biofilm can easily extend beyond the valve as periodically on nitrates, aluminium (especially in water
the system for purified water usually is not heated. Therefore intended for dialysis applications), heavy metals and bacte-
the most critical place in the loop is the point beyond valves, rial endotoxins. Purified water in bulk should be monitored
i.e. where the water runs back into the storage vessel. That is at the same parameters. The (expensive) TOC assay might
the right spot for placing critical measurement apparatus in be partly replaced by periodical testing on oxidisable
the loop, such as for temperature and conductivity. substances. Bacterial endotoxins in purified water should
be monitored, especially when the water is used in
27.5.2.2 Water for Injections in Bulk haemodialysis. In purified water additional monitoring
The Ph. Eur. specifies that ’water for injections in bulk is might be indicated, e.g. of ozone (during and after disinfec-
obtained from water that complies with the regulations for tion), the hardness of the feeding water and the luminosity of
water intended for human consumption or from purified the UV source (decaying ozone).
water by distillation in an apparatus of which the parts in
contact with the water are of neutral glass, quartz or a
Suppliers of equipment usually use American termi-
suitable metal and which is fitted with an effective device
nology in their documentations, including the term
to prevent the entrainment of droplets.’ So the quality of this
“sanitisation” referring to disinfection methods that
water is essentially defined by the very specific way it is
are known to be effective to sterilisation processes,
produced. The reason for this is that there is no reference
however in which (formally defined) sterility as a final
water quality to compare.
result will not be proven.
During production and storage adequate measures should
be taken to monitor and control the total viable count (see
Sect. 19.6.3). This can be measured in freshly tapped water
for injections in bulk (maximum 10 CFU/100 ml). Ph. Eur.
27.5.2.4 Measuring Conductivity
actually gives this value as an action limit, but to control
Measurement of conductivity during production, storage and
microbial contamination it is better used as a maximum
distribution of (highly) purified water and water for
value. During production by means of distillation, water
injections is indispensable. One conductivity sensor usually
for injections reaches a temperature between 94 and 99 C.
will be mounted into the pipe that carries the hot, freshly
By maintaining high temperatures in the storage vessel and
distilled water from the distiller into the storage vessel.
the loop any growth of micro-organisms is prevented. In this
Usually this sensor is combined with a temperature sensor.
way the content of endotoxins (see Sects. 19.3.4 and 32.8)
Additionally a conductivity and temperature sensor must be
can be kept low (standard: less than 0,25 IU/ml), as well as
mounted into the return flow of the loop. This is necessary to
the total viable count.
prove that the water that runs back into the vessel still has
The water for injections limit for conductivity is lower
adequate quality.
than that for purified water. At 80 C water for injections
may have a conductivity of maximal 2,7 microSiemens/cm.
Usually only the storage vessel and not the loop is heated. Ph. Eur. extensively describes the procedure for the
So during the passage of the loop the water will cool down measurement of conductivity, the calibration of the
gradually. Additionally any inadvertent leakage of a valve conductivity sensor and the calibration of the system.
(e.g. the one that provides a washing machine with water for The measurement is complicated as there is no refer-
injections) may impair the quality of the water in the system. ence for low-level conductivity measurements. When
These facts underline the choice of the most critical spot for the off-line conductivity turns out to be too high a
all measurements being the place where the water runs back
into the storage vessel. (continued)
27 Premises 599
transport pipes made of stainless steel or synthetic materials,

second measurement is prescribed after previously the inner side of storage vessels, taps and membranes in
stirring atmospheric carbon dioxide into the water. valves.
When this second measurement still reads too high a
third step is prescribed adding a potassium chloride
27.5.2.7 Systems for the Storage
solution and measuring pH. Only then a conclusion
of Pharmaceutical Water
can be drawn about the quality of the conductivity
At the design of the pharmaceutical water installation the
measurement.
capacity of the storage vessel should be determined based on
the maximum daily consumption, the average consumption
and the maximum peak consumption per product batch. The
water consumption by sterilisers and washing / disinfection
27.5.2.5 Total Organic Carbon (TOC)
machines should also be taken into account.
TOC is an indicator for any existent (decayed) organic
The higher the peak water consumption, the larger the
material in the water, often originating from living or dead
storage vessel. If the demand for water has a more steady
micro-organisms. A low TOC (less than 0.5 mg/ml) may be
character then the vessel can be smaller. In case of a large
interpreted as a useful indicator that the water has a proper
vessel the available floor area and its load capacity must be
microbiological quality [7, 8]. This assay can be performed
accounted for. Continuous production implies that one or
easily and immediately before use.
more tanks are being filled and drained continuously. Qual-
ity control should take place in a continuous way, completed
27.5.2.6 Microbiological Quality of Water with intermittent additional tests. After maintenance and
Operations, storage and transport methods all can influence also periodically the system should be disinfected. The fre-
the growth of micro-organisms. quency of the disinfection depends on the results of the
In practice microbiological quality of water is monitored process validation [9, 10]. Further specifications of the sys-
by action and alert levels. Thus the user will be early notified tem follow the required water quality. The required storage
about any deviation of critical parameters. For instance temperature also plays a role:
an alert level might be put at a factor 10 below an action • Cold storage implies storage conditions between 4 C and
level. To determine these levels a good set of total viable 10 C at which micro-organisms grow very slowly. Cold
aerobic counts, endotoxin assay results and TOC assay storage renders the system effective and reliable. Disin-
results should be available. For the collection of these fection occurs only occasionally and can be performed
PRODUCTION
results, particularly in the start-up phase very frequent with hot water. Drawbacks are the expense of a cooling
measurements must be executed. installation and its considerable energy consumption.
The development of a biofilm (see Sect. 19.3.5) in the Stainless steel, PVDF, polypropylene and polyethylene
water production system has to be prevented. The rougher cross-linked (PEX) all are suitable as a material for the
the surface the easier a biofilm will develop. Nevertheless storage of purified water at low temperatures. The design
even onto polished metal, synthetic materials, glass and in of the vessel should be aimed at the lowest possible total
streaming water it may develop, therefore the micro- viable aerobic count. This implies that all surfaces, pipe
biological quality of the water has to be controlled fre- holes, valves, etc. should be accessible and made of very
quently. In demineralised water the growth proceeds faster smooth material.
than in distilled water as a consequence of more available • Storage and distribution at ambient temperatures (15 C -
nutrients. As soon as a biofilm causes contamination the 30 C) is reasonably effective and reliable and the invest-
term biofouling is used. The best way to eliminate a once ment and operation is comparatively cheap. However the
formed biofilm is mechanical cleaning, which is becoming risk of building up a biofilm is substantial. Therefore,
more and more common in industry. However, when the non-cooled storage systems should be disinfected fre-
surface is not accessible for mechanical cleaning, other quently by flushing with hot water or by adding ozone.
cleaning methods must be applied, such as flushing with Materials for loop and storage vessel are similar as for
hot alkaline followed by hot acetic acid or flushing with cold storage [9, 10] however the method of disinfecting
concentrated sodium chloride solution followed by hot acid can limit the choice. More aggressive methods such as
solution or hot alkaline. The microbiological safety of the treatment with steam are preferable, but require expen-
installation thus not only depends on the application of heat sive materials such as stainless steel.
but on the (im-)possibilities to dispose of any formed biofilm • Hot storage and distribution means storage and distribu-
as well. Risky surfaces are demineralisation resin, tubes, tion at a temperature continuously kept over 70 C [1]. In
practice an ample safety margin is implemented and

usually the actual storage and distribution temperature is Only during tapping the heat exchanger is temporarily
well above 85 C. Hot storage is the most effective and flushed with cold water, locally chilling the pharma-
reliable way to prevent growth of micro-organisms. With ceutical water. Only a very limited amount of the
the aid of well mounted isolation material in the heating chilled pharmaceutical water will return to the loop
mantle a storage vessel can be kept at high temperature at by means of mounting a so-called restriction disc just
low expense. The loop piping should also, preferably, be before the junction. So chilled product water will
insulated. Taps should be placed at short distances from hardly mix with the main stream in the loop. When
the loop. Before use the tap has to be flushed with hot no chilled water is tapped sufficient water will pass the
water. Hot storage involves relative high investment costs heat exchanger, the tap valve and the restriction disc to
and moderate running costs. It introduces a specific risk maintain this part of the loop at the required
of rouging. Hot storage does not diminish the content of temperature.
endotoxins. The distribution loop can be combined with
taps equipped with sanitary coolers to deliver the phar-
maceutical water at ambient temperature.
The water level in the storage vessel has to be controlled
continuously, preferably with the aid of a building control
Rouging
system (see Sect. 27.5.5). Thus a low level signals to restart
At sustained exposure to very pure hot water or steam
the production, however a very low level should produce an
a thin red, reddish brown, orange, light blue or black
alarm signal shutting down the complete installation to pre-
deposit (tarnish) might built up. This is seen particu-
vent, among other things, the circulation pump running dry.
larly at less polished spots, e.g. burrs, scratches, sharp
A high level will stop the production and an extra high level
edges, material transition areas or bad welds and is
should give an alarm signal to alert the risk of overflow
called rouging. In fact rouging is an oxidation process.
through the vent filter.
When metal ions in micro-caves dissolve into the
The storage vessel and the loop for water for injections is
water potential differences might occur at a micro-
preferably made of stainless steel AISI 316 L and polished to
scopic scale leading to hydrolysis and oxidation. The
a roughness grade of 0.4-0.6 μm mean pore diameter [9,
coloured material consists of iron oxide, iron carbon-
10]. The water should return from the loop into the vessel
ate or iron hydroxide or any combination of these.
through a (rotating) spray ball. By this means the empty
Rouging itself doesn’t yield any immediate hazard.
upper part of the vessel will be kept hot and germ free. The
However once rouging has been built up it might
vessel or at least the lowest point in the loop should be
expand and eventually lead to development of rust in
equipped with a sanitary bottom valve ensuring that after
which case the smoothness of the texture is affected
complete draining (e.g. for maintenance purpose) no tainting
and the risk of biofilm formation increases. Therefore,
water will stay behind in the system [10].
highly polished stainless steel constitutes a barrier
both against rouging and biofilm formation. Removal
of rouging is a very expensive process involving Tank Vent
experts [10, 11]. A level control system can only be used if the system
has been designed according to GMP. Tapping of
water from the storage vessel will lower the level in
the tank. The sucked-in air entering the vessel has to
be filtered through a 0.2 μm hydrophobic membrane
filter that can be tested and which should be mounted
Tap for Cooled Water in a stainless steel casing onto the vessel. A pressure
A tap cooler mounted into a hot distribution loop safety provision is mounted to safeguard against any
requires a special design. The loop and the storage possible overpressure in the vessel. The filter has to be
vessel must be kept at high temperature while no replaced at least once yearly as a preventive measure.
long branches filled with stationary (colder) water During the hot storage of pharmaceutical water the
can be accepted. Therefore the loop splits near the filter also has to be kept at a high temperature to
cold tap into two parallel pipes both continuously prevent the occurrence of condensate. This condensate
being flushed with the hot pharmaceutical water. In would provide an ideal substrate for micro-organisms
one of the two branches a heat exchanger is mounted. which might grow through the filter.
(continued)
27 Premises 601
27.5.2.8 Maintenance and Disinfecting Water usually consists of continuously monitoring the intensity of
Storage and Distribution Systems the UV light. An alarm signal should indicate when the lamp
Biofilm will emerge especially fast on ion exchange resins, has to be replaced [9, 10].
Reversed Osmosis (RO) -membranes and piping made of
stainless steel or plastics. Therefore, systems for pharmaceu- 27.5.2.11 UV-light for Germ Reduction
tical water should not contain stationary water and should be UV-light with a wavelength of 200–300 nm not only
disinfected at start-up and after each maintenance process. degrades ozone but also reduces the total viable aerobic
Even systems for the preliminary treatment of feed water count in pharmaceutical water, especially in systems with
have to be constructed as a recirculating system [10]. cold storage and distribution. UV-light disrupts the DNA of
Cold water systems usually cannot be steamed. Instead micro-organisms and thus obstructs their growth. Irradiation
chemical disinfection or disinfection using ozone is custom- with UV-light is not intended to replace any disinfection
ary. An important benefit of ozone treatment compared to method. The effectiveness of the irradiation process depends
other chemical methods is that it can be executed on water quality, light intensity, flow rate of the water,
automatically. duration of the irradiation and the identity of the micro-
Frequent hot water disinfection is a good alternative as a organisms in the water and thus is difficult to validate
preventive measure, provided that all materials are sufficient [9, 11].
heat-resistant. It is carried out at a temperature of 90–95 C
during at least 2 h of exposure. This process must be 27.5.2.12 Clean Steam
validated [10]. The problems to remove a once formed Only the USP includes a monograph for pure steam [12],
biofilm is discussed above in Sect. 27.5.2.6. also called clean steam. Clean steam is obtained from
RO membranes may not be exposed to ozone. The pro- purified water heated over 100 C and brought into the
ducer of the membrane should indicate how to treat and vaporised phase in such a way that no drops of feeding
disinfect it in a correct way. water are carried over. In any situation where steam or
steam condensate might stay in immediate contact with
27.5.2.9 Chemical Disinfection critical, product affecting surfaces, clean steam must be
If the equipment is provided with adequate connection utilised. An example is the interior surface of a filling appa-
systems a chemical disinfection is possible. Commonly a ratus. Technical steam is steam generated at some central
solution of hydrogen peroxide and per-acetic acid is diluted location in the building. The quality is defined with pressure
to 8-10 % and then flushed through the equipment. The and temperature. Clean steam may be utilised during prepa-
system must be thoroughly rinsed afterwards.. The method ration, in steam sterilisation and during controlled steaming
PRODUCTION
is quite effective, however it involves the additional efforts of installation as a sterilisation method after cleaning [13].
of purchasing, storage and handling of the disinfecting Quality control of clean steam is carried out on its con-
agent. densate. Additional requirements are in force when the
steam is utilised for sterilisation (see Sect. 30.5.1).
27.5.2.10 Ozonisation
Ozonisation is a specific means of chemical disinfection as 27.5.2.13 Transport Systems for Pharmaceutical
the active agent (ozone) is generated in the equipment itself. Water
Ozone is used for the periodical disinfection of pharmaceu- A system for transport or distribution of pharmaceutical
tical water installations when disinfection by steaming or water should meet at least four requirements:
with hot water is not possible. Ozone is a strong oxidising • It should deliver water that meets all quality requirements
agent and kills micro-organisms in water. To obtain suffi- (see Sect. 23.3.1).
cient disinfecting power ozone should be present in the • The water should always flow at the required flow rate,
water for a sufficient time and in an adequate concentration, especially at the instance of drawing off.
according to the guidance of the producer of the ozonisation • The water should be delivered at the temperature required
apparatus. Concentrations with a maximum of 10-50 ppm for the process at hand.
(sometimes even less) are most common. The ozone genera- • The system should function at acceptable investment and
tor that is mounted in the loop produces the ozone gas. running costs.
However after ozonisation the utilised pharmaceutical
water must be freed of ozone again. Therefore, UV lamps 27.5.2.14 Piping
are included in the loop at a spot that is transparent to UV By means of a sanitary pump and a flow rate meter showing
light. UV light of 254 nm degrades ozone turning it into the flow rate, the water circulates in a loop through a sanitary
oxygen. Thus quality control of the lamp is necessary; it (hygienic, well-disinfectable) piping system. Unused water
runs back into the storage vessel. Micro-organisms, corro-

sion, (hidden) construction flaws and aging can all affect the oxygen-rich water, diluted nitric acid or oxalic acid.
loop system. The loop should not contain any branches in When all residues of acid are flushed away with water
which water is stationary. For this purpose specific calcula- for injections the installation can be steamed and put
tion schemes exist. Generally the length of any branch in the into operation.
loop never should exceed 6D (diameter of the loop pipe) The welds in a stainless steel loop never should
but in practice 3D or even 2D is to be preferred. Also corrode, leak or become a source of rouging or biofilm.
purified water as feeding water for a distiller installation Welding work therefore should be inspected closely
should recirculate when nothing is drawn off. and be thoroughly documented. Specialised instruments
The support and mounting of the piping should be are being used for this purpose. The welder must be
constructed in such a way that no sagging occurs, a risk qualified. All handmade welds should be fully con-
that is more prominent with synthetic materials at higher trolled; in orbital welded pipework usually 20–30 %
temperatures than with stainless steel. Preferably the piping of the welds are tested.
is mounted at a slight slope with the bottom valve at its Other, also demountable, fittings between pipes and
lowest point. The usual angle of the slope of horizontal installations are of the type clamp, flange or screw
piping at short distances is advised at 2 % and at 0,5-1 % fitting.
for greater lengths. For transport of water for haemodialysis and
Joints must never be mounted at a residual strain because purified water, plastics may be used for the tubing.
that could cause leakages, which can lead to considerable However for these materials it is also required that
damage. The support system for the piping must not cause connections are meticulously welded, inspected,
any galvanic corrosion. The distribution system must be documented and cleaned. The use of glues (e.g. the
immune to ozone or the heat of steam. It has to resist a glue to join classical grey plastic, PVC, tubes for
specified water pressure and turbulence as well. The interior non-pharmaceutical use) introduces an unacceptable
of the piping should have a surface as smooth as possible to uncertainty because residues of the glue and solvents
prevent corrosion and formation of a biofilm. Stainless steel may contaminate the water. Analysis of this kind of
piping must be polished at the inside for this reason. Piping contaminants preceding the formal acceptance of the
of synthetic materials used for the distribution of pharma- system is not a realistic option [9, 10].
ceutical water are smooth plastics like PVDF, polypropylene For pharmaceutical water guidelines of, among
or PEX. The piping may not release any substances or others, FDA and DIN 11864 apply for these kind of
(metal) ions and should be corrosion resistant [9, 10]. fittings. Anyhow, the number of fittings should be kept
as low as possible.
Welding, Mordanting and Passivation
Stainless steel contains chrome that generates a tarnish
of chrome dioxide, which protects against rust. How-
ever over time some form of corrosion will develop; 27.5.2.15 Pump
totally non-rusting steel does not exist. A circulation pump should have a highly polished finish and
The installer should weld the piping work orbitally. should be well cleanable. It must resist any disinfecting
Orbital welding is the partly automated method of process, preferably steaming. Also the pump must allow
welding highly alloyed steel pipes together using a complete drainage. The latter implies that no water residue
tungsten electrode under inertial gas, also indicated must stay behind when the complete loop is drained during
as TIG-welding (tungsten inert gas). By this method maintenance.
a very smooth weld develops. Subsequently the instal- The pump should be able to generate a flow rate of
lation must be cleaned, mordanted, passivised and 1–2,5 m per second in the loop, still achieving an acceptable
finally be flushed and steamed. Cleaning after welding water pressure. The pressure depends also on the loop resis-
is done by flushing with caustic detergents and water. tance. Usually a restriction disk mounted in the loop serves
Mordanting implies that the corrosion resistant tarnish to prevent a major pressure drop when water is withdrawn by
is removed temporarily using strong acids (chromic opening a tap. The flow rate causes the flow to be turbulent
acid or strong nitric acid). Immediately thereafter the and thus prevents the risk at (almost) stationary water
reactive metal alloy is passivised by oxidising in the e.g. near valves and other small bulges in the loop. After
air. Passivation is also executed by flushing with all, any stationary water would substantially increase the risk
of building up biofilm [9, 10].
(continued)
27 Premises 603
27.5.2.16 Tapping Points Requirements depend on the use and therefore may differ
Membrane valves must be completely drainable and from those to medical gasses. Gasses that are in direct
disinfectable, preferably by steam. The membrane made of contact with the (end-) product should meet the requirements
plastic should be replaced 1–2 x per year. Sometimes globe derived from the product itself.
valves are used to shut off steam pipes, because they are
more wear-resistant.
The requirements for medical gasses may differ from
A sufficient number of sample tapping points should be
those for pharmaceutical gasses. As an example,
available. The tapping of water during any dysfunction
requirements to safeguard continuous availability
(e.g. deviation of temperature, deviation of conductivity or
carry more weight with the clinical process of artificial
low level) of the water installation must be prevented. This
respiration than with a pharmaceutical application.
can be done by automatically blocking all tapping points at
But the chemical purity of e.g. nitrogen used for filling
the basis of any alarm signal originating from the installation
ampoules will be more important in pharmaceutical
[9, 10].
than in medical applications. Purity has to be backed
by traceability of the origin. Certain suppliers there-
27.5.2.17 Responsibility for the Validation
fore provide cylinders with designations such as ‘trace
and Qualification of Water Systems
pharma’.
The validation of this equipment has to account for its built-
in status. Therefore the validation plan already has to be part
of the design and realisation phase of the installation. The requirements for gasses can be:
The person responsible for the water quality to be used in • Technical (capacity, pressure, availability)
pharmaceutical preparations usually is the pharmacist who is • Chemical (content assay, contaminants, moist content)
also responsible for the preparation processes. This person is • Physical (absence of particles and oil)
accountable for all procurement, validations, qualifications, • Microbiological
maintenance, deviations and changes of the installation(s). A low moisture content (dew point) in a gas under pressure is
He should always be fully informed about all those aspects. most important because at expansion moist could lead to
This also applies when the water preparation installation is condensation, which would enable micro-organisms to grow
installed outside of the premises of the pharmacy e.g. in the [9, 13].
premises of the technical services or any laboratory [11].
27.5.3.2 Vacuum
PRODUCTION
A vacuum installation may have impact at the final product,
27.5.3 Provisions for Pressurised Air, Vacuum
e.g. when vacuum is used to prevent air being beaten into a
and Various Gasses
viscous mass or to remove air from it. A choice has to be
made between a central installation and a local one such as a
27.5.3.1 Gasses and Pressurised Air
water jet pump or an electrical vacuum pump. At a centrally
Medical gasses (including medical air) are gasses that as
placed installation a provision has to prevent the pressure
such are used in the treatment of patients. Medical gasses
inside the tubes rising above a predefined value. Otherwise
administered to patients are medicines [13], see also Sect.
contaminated air could enter a negative pressure room if the
23.13.
pump were to break down.
Gasses used in production processes are called pharma-
ceutical gasses. They are applied as:
• Gasses that are immediately immersed into the interme-
diate medicinal product, e.g. nitrogen as a means to dispel 27.5.4 Electrical and ICT Provisions
oxygen from aqueous solutions or pressurised air to carry
over fluids. At the design of preparation premises the availability of
• Gasses that are necessary at the preparation or filling electrical and ICT provisions should be well considered in
process, but are not directly in contact with the product, advance. Sufficient data and electrical sockets should be
e.g. natural gas and oxygen for opening and sealing of provided in walls and at worktops.
ampoules. Keyboards and mouses should easily be cleaned and
• Gasses used for pharmaceutical analyses, such as acety- disinfected and therefore must be chemically resistant. The
lene for atomic absorption spectrophotometry and helium casings of the computers should be installed in such a way
for gas chromatography. that accumulation of dust is diminished, for the protection of
• Gasses (usually pressurised air) for technical purposes the computer as well as the pharmaceutical product. The air
such as pneumatic operation of installations. in classified rooms will hardly carry any dust, but
nevertheless the casing should be opened at least once a year of independent alarms. Also rules have to be implemented
to remove any dust. The casing should also being placed as regarding the procedure for the resetting of any alarm and for
far from the critical places as possible, if possible outside of the documentation of its actual follow-up.
the room. Wireless tablets may circumvent all difficulties
with cables and fans. Cleaning and disinfecting of worktops
is much easier when cables are tucked in cable ducts or 27.6 Detail Specification and Building
under the worktop.
For each apparatus or installation it should be considered The documenting of the functional specification (FRS) of a
whether it has to be provided with emergency power supply preparation facility is followed by the detail specification
or preferential power supply. Therefore, the risks of any (DS) or tendering specifications. A subtle difference between
short or longer lasting power cut should be analysed in DS and tendering specifications is that the latter will be
advance. Especially the consequences of any disturbance drafted for the purpose of contracting-out. However the DS
of air pressures and the breakdown of exhaust installations is primarily aimed at verifiability during the IQ phase. Usu-
must be considered. ally just one document will serve both functions. In this
document choices are made (usually a professional advisor
does the job) for floor and wall covering, ceiling materials,
27.5.5 Building Control Systems etc. The HVAC installation will now be specified in full
detail, communication means are specified and detailed
Apart from the pharmaceutical installations, already men- building and arrangement maps are drafted and updated.
tioned in this chapter, buildings are generally equipped with The choices must comply with the FRS, which in turn
heating and cooling equipment, fire prevention equipment, must comply with the URS. Therefore each choice should be
burglar security systems, personal access control, sun blinds, well documented and justified at this basis.
elevators, sewage pumps, etc. What should be attended to in the assessment of the DS?
So altogether the building incorporates a vast multitude In premises intended for sterile and aseptic preparations
of technical systems, several of them influencing each other. (clean rooms) the most severe requirements apply to the
This might raise a need for an overall monitoring and control walls, doors, floors, ceilings, heating and furniture, see fur-
system. ther subsections. Premises which are only intended for
Usually control and monitoring are integrated in one non-sterile preparations can do with less far-reaching
system providing a central point from which the functioning demands. Nevertheless in practice it might be wise to
of all systems can be monitored, registered and adjusted. apply the requirements for sterile premises also for
Furthermore, failure alarm signals are channelled through non-sterile premises if both are at stake. In the first place in
the building monitoring system. a new building the itemisation of methods and materials
When pharmaceutically critical systems (refrigerators, between premises meant for sterile preparation and for
HVAC systems, purified water systems, etc.) are to be mon- non-sterile preparation usually doesn’t yield much cost
itored by a building monitor system it has to be independent reduction. Additionally many of the starting points for the
from more general systems in the building and its validity requirements for sterile preparations more or less apply to
has to be assessed in advance. Additionally systems for the ’non-sterile’.
registration of measurements must be independent of
systems that operate the installations and all installations
(i.e. their sensors, adjustment tuners and alarm signals) 27.6.1 Inner and Outer Walls
must be fit to be connected to the building control system.
All possible alarm signals have to be listed and Where premises for preparation are adjacent to any outer
documented regarding alert- and action levels, hysteresis wall a specific problem emerges. Constructional walls, also
(to prevent them from switching on and off continuously at outer walls, never will be completely airtight. In case of
a non-stable parameter) and timeliness (providing short- wind pressure always air from outside will influx, bringing
termed deviations without unnecessary alarms or providing pollen (in spring), mould spores (in autumn) and fine partic-
a reaction time before exciting the alarm). A scheme of ulate dust (in winter). This can only be prevented by building
procedures has to be defined to be followed after any alarm a double wall system, i.e. by complete separation of the
is triggered. The follow-up instruction after any alarm preparation premises from all outer walls (so-called box-in-
should include an indication about its urgency, e.g. if imme- box principle) which is usually accomplished by building a
diate action is obligatory when the alarm occurs in the night gallery corridor. If this is no option, then at least a separate
or in the weekend. No alarm signal should be overruled, secondary glazing is necessary in the windows of outer walls
covered up or left invisible in case of concurrent triggering to level out any wind pressure. Such a secondary glazing
27 Premises 605
At places where damage could occur the wall should usually as a metal corner bracket or metal u-moulding,
be made of impact-proof and scratch-proof material, which must be protected against rust. This again
e.g. melamine resin sheet material like Trespa®. At requires early planning of the right layout of any
other places, e.g. above breast height, cheaper gypsum suspended cupboards, worktops, etc.
board walls can be used, provided that they are treated
with a specific water-resistant coating that can also
resist the chemicals used for cleaning and disinfecting.
Seams, e.g. at places where fixed cupboards are
concrete floor
placed against the wall, should be closed with a well-
chosen acid-resistant joint sealant. Any seam should
have a width between 2 and 4 mm to safeguard that the
sealant will stick firmly into the joint. Wall connectors profile
for electricity and ICT provisions must not give entry for
compression
contaminated air or vermin. Therefore the interior sup- ribbon
ply pipes should be made airtight with sealant. In prac- coating
tice usually a hollow wall modular construction is used gypsum
for clean room building (‘Metal Stud’, see Figure 27.5) double board
with all pipework and tubes sealed within the wall. version
All pipework and tubes (electricity, water, gasses,
air ducts, etc.) should be documented by photographs
25 12,5
before the wall is finally closed during construction.
Those pictures can demonstrate later that the finished 45
construction indeed does correspond with the as-built
drawings. As-built drawings are the drawings that 82,5
exactly represent the finally built constructive reality.
At places where the wall should be loaded with objects
to be mounted, the constructor should apply back Fig 27.5 Metal Stud wall. Source: Recepteerkunde 2009,
styles. These are fortifications introduced in the wall, #KNMP
PRODUCTION
(continued)
introduces a wasted space between the inner glazing and the Light switches, as being touched by many persons, can be
outer one, in which at some time vermin will emerge. best placed outside of the room e.g. at the entrance to
Cleaning might be facilitated by having the outer glazing personnel gowning locks. In that way an important source
accessible from the outside. of cross contamination is ruled out.
If carrying in or out large apparatus must be possible, a
demountable, resealable, partition in the wall should be
27.6.1.1 Inner Walls
considered.
A requirement for premises for sterile preparations (clean
rooms) is that walls are free from any ledges and seams to
enable effective cleaning and disinfection. The provision of
ample glazing for supervision and well-being of personnel 27.6.2 Doors
should be considered. The ledge free and seamless mounting
of windows and doors into walls is known as ’flush fitting’. Doors in clean rooms must be flush mounted, smooth, clean-
In order to adequately flush the room with clean air the able, if necessary disinfectable and as far as possible seam-
exhaust should not be positioned near the inlet grids in the less. This especially goes for doors in GMP classified
ceiling. Special inlet grids (diffusers) should generate turbu- premises as indicated in Sect. 27.4.2. Points of special inter-
lent airflow. In air class B exhaust at floor level is mostly est are:
preferred. A hollow wall construction offers the possibility • Air leakage through chinks between doorframe or thresh-
of incorporating air ducts (exhaust channels) within the wall. old and a shut door will render the air pressure within the
These may make, however, other provisions on that particu- room out of control and it may raise an annoying wheezing
lar part of the wall impossible. noise. Therefore, doors should close firmly and not warp.
Fig. 27.6 Dropseal. Source

Recepteerkunde 2009, #KNMP Floor Covering Materials
The choice for floor covering materials depends on the
kind of activities. As an example, in a preparation
room where iodine or organic solvents will be
processed, the floor should be chemically resistant in
the first place. When processing inflammable products
the generation of sparks due to static electricity has to
be prevented. For aseptic handling chemical resistance
of course is much less important. The primary empha-
sis for a floor in a premise for handling radiopharma-
ceuticals or other very hazardous substances, is on
suitability for thorough and effective decontamination
and disinfection.
A synthetic floor covering, e.g. like marmoleum or
a good quality of vinyl, laid in strips or tiles and sealed
• Air leakage by the bottom of the shut door may be with synthetic laces is a quite frequently used material.
prevented by implementing dropseals mounted within As an alternative a floor made of epoxy resin (a
the bottom part of the door (see Fig. 27.6). A pawl at so-called cast floor) can be considered, with its
the hinge side actuates a lever mechanism at shutting the advantages of high load bearing capacity, smooth sur-
door. This mechanism pushes a rubber strip against the face and absence of seams. A drawback is its slipperi-
floor. At the opening of the door a spring mechanism ness, especially if wet there is a risk of skidding.
pulls the strip back up again into its casing. Additionally it is very critical to have the cast floor
• Doors should never shut against the air pressure, as the applied completely free of dust or dirt.
higher air pressure behind the door may raise leakages. If The floor covering material preferably should butt
the preferred turning direction is not feasible, e.g. in case to the walls by means of a hollow skirting. Fitted
of an emergency route from a positive pressure room, the furniture that is not mounted hovering over the floor
door should seal on all sides, including top and bottom, should be placed upon pre-mounted dado’s, after
into a soft rubber groove. In some cases the preferred which the floor covering can be installed with a hollow
turning direction of a door based on function is opposite skirting against the dado.
to the preferred turning direction based on air pressure
hierarchy. A sliding door may solve that problem,
provided that it is equipped with an effective push mech-
anism when shut and is well cleanable.
27.6.4 Ceilings
27.6.3 Floors Ceilings are preferably completely closed, i.e. manufactured

from fixed mounted, smooth and cleanable sheets.
Floors must be easily cleaned and disinfected. Drains should Pipework should be tucked away behind the ceiling,
be avoided, as these are important sources of contamination. because otherwise dust builds up. If possible pipes or
If a drain is unavoidable because the equipment demands it, tubes transporting water should be avoided at the top of
it should be equipped with a sanitary valve, preferably a type any preparation premise because leakage would have disas-
that closes automatically when the connected equipment is trous consequences. This is in regard not only to pipes
shut down. Such a drain requires a well-documented disin- transporting pharmaceutical water but also to the sewer
fection procedure. system, rainwater drains, condensate drains and steam
Floors should be practically seamless because seams can pipes. The possibility of the occurrence of condensate on
easily become filthy. However each type of floor covering cold water pipes during warm weather should also be con-
will come with seams and dilatation joints are necessary to sidered. If the pipes cannot be avoided, any leaking water
allow for any shrinkage or dilatation, also in clean rooms. At should drain off by a gutter. Regular maintenance of the
least any seams and dilatation joints must be avoided near pipework and timely replacement of gaskets will be neces-
the most critical places. sary as well.
27 Premises 607
substances. The flow pattern in a safety cabinet can easily

System Ceilings or Closed Ceilings be disturbed by an incorrectly placed or ill-chosen air inlet
A lowered, so-called system ceiling can be used, how- grid in the ceiling [5].
ever it has several snags: the joining to the walls
usually results in a right angled corner that is difficult
to clean. Additionally the system sheets, lying rather
27.6.6 Furniture
loosely within the frame, can easily snap open, espe-
cially when air pressure jolts occur at the opening or
The upper side of cupboards should join to the ceiling, or
closure of doors. If that occurs unpredictable amounts
alternatively a slant finishing should connect the upper side
of dust and dirt will enter the room. Even special clips
to the ceiling. Personnel should not be able to place objects
to fix the ceiling tiles cannot prevent this completely,
on top of a cupboard. As far as cupboards are made from
as after maintenance work those clips are frequently
wood, plywood or chipboard these parts should be laminated
not replaced. Sealed ceilings are free of those
on all sides, e.g. also at the backside of shelves. Holes to
drawbacks and they force the designer of the building
adjust shelves in height should be filled up. ‘Open’ wood or
to create an alternative entry to the space above the
chipboard may release spores. Workbenches should prefera-
ceiling. This entry will not come from the preparation
bly hover or be attached to the wall. Floors under worktops
room, but by means of an admission hatch e.g. from a
must be well accessible for cleaning. Fixed furniture prefer-
neighbouring gallery corridor or by means of a trap-
ably should be placed upon pre-mounted dado’s.
door from an upper storey. The benefit of this is that
Refrigerators and freezers within the preparation premise
maintenance or repair work, e.g. at pipework or the
are unwanted for several reasons such as that the expansion
replacement of lamps, situated behind the ceiling, can
radiator at their backside cannot be cleaned. If a refrigerator
be executed without entering the premise itself. If
or freezer in the preparation premise is indispensable it
completely sealed ceilings are not feasible in all
should be airtight separated from the room, e.g. by means
rooms entrance to the space above the ceiling from
of a flat shaft of sheets up to the ceiling or a throughput
gowning rooms or connection corridors are preferred;
through the wall.
the ceiling should never be entered from the prepara-
Chairs should not possess seats made of wood or covered
tion room itself.
with textile. The undercarriage should be easily cleanable.
Light fittings do easily attract dust as a consequence of
PRODUCTION
their static electricity. Therefore they should be incorporated 27.7 The Implementation Phase of Building
in the ceiling and be shut off by means of a glazed or or Rebuilding
transparent synthetic sheet. In classified premises no sub-
stantial air leakage must occur past the fitting. During the execution phase of newly built or rebuilt phar-
maceutical premises (including clean rooms) the building
control department should take a few particularities into
27.6.5 Heating account. The ISO 14644-4 standard [4] specifies those
particularities for clean rooms.
The cleaning of heating radiators is very laborious and not • Verification of matters that cannot be demonstrated after
very feasible in practice. Therefore, they are unsuitable for implementation. Design drawings should be continuously
pharmaceutical preparation premises. If they nevertheless updated such as to be finally correct ’as-built’ drawings.
cannot be avoided, sheet radiators mounted at sufficient Pictures of the inner part of hollow walls can support the
distance from the wall to allow effective cleaning, are to verification process. The sealing of any pipe holes or
be preferred. However, in GMP classified premises as meant cutaways must be checked systematically.
in Sect. 27.4.2 even sheet radiators are absolutely undesir- • Special attention should be paid to prevent the fouling of
able. Heating and cooling in that case should be achieved by air channels during their mounting. Air channel
means of the ventilation system (see Sect. 27.5.1). components must be supplied clean and closed on both
In using air for heating, attention should be paid to the ends. Partly mounted air ducts again must be shut at the
type of inlet grid. In a well-designed preparation premise a open end to keep them clean inside. The building area
high ventilation factor will prevail. If not a specific whirl should be swept clean daily.
grid is mounted draught will occur. This is not only annoying • Eating, drinking and smoking in the building area has to
for those working within the premise, it also may lead to be forbidden and this ban should be enforced strictly to
inadvertent displacement of weighed portions of active prevent that any organic material (like bread or tobacco
crumbs) are left in hollow walls, under or behind rooms after disturbance is checked, viable and non-viable
cupboards or in air channels. particles are counted, temperature- and humidity are
As a consequence of its high costs the execution phase of measured, etc.
a building usually is very tight. Especially in the end phase The IQ and OQ are usually executed by the contractor in
this can result in working against the clock. A common cooperation with the customer. When this phase is
completion process assumes the premises to be put into completed, the work is delivered up to the customer and
operation immediately after completion, accepting the doc- accepted. Then the performance qualification (PQ) is
umentation of a few residual points that will be settled later, executed by the customer. In this phase it will be proven
in practice already during operation. For clean rooms this is that the premises will work as they were meant to be work-
not possible. The starting-up procedure involves many steps ing as defined in the URS. Installations will function and
that must be planned well in advance and are described in a classifications of the rooms are met (see Sect. 34.15).
Validation Plan. This plan encompasses general examina- The validation requires time and manpower. For a small
tion, qualification and validation. During examination the scale preparation facility a time frame of 3 to 6 month is not
as-built premises are checked against the detail specification uncommon. It is quite obvious that the start-up process to
(DS). In addition some of the specifications will be checked operational status of preparation premises will never allow
that are described in the FRS and even the URS e.g. the time for any delayed activity for a constructive residual point
smoothness of the walls. The control of all these such as the mounting of another light fitting afterwards.
specifications is also called as-built verification. If all Planning in advance is paramount.
specifications are met the premises and built-in equipment
is qualified. Next all systems such as HVAC are put in use
and checked for their proper operation and safety. The air References
balance is adjusted. Calibration of e.g. pressure difference
meters is performed. This phase is also called commission- 1. PIC/S Guide to Good Practice for the Preparation of Medicinal
Products in Health Care Establishments. PE 010–3, 2008
ing and is usually executed by the contractor.
2. NEN-EN-ISO 14644 Cleanrooms and associate controlled
All deficiencies found during commissioning have to be environments; parts 1, 2, 4, 5 and 7
solved. The premises and installations are cleaned and sub- 3. NEN-EN-ISO 14698 Cleanrooms and associated controlled
sequently the validation can start based on procedures environments - Biocontamination control; parts 1 and 2
4. NEN-EN-ISO 14644-4:2001(E) Cleanrooms and associate con-
approved by the owner, usually the pharmacist. Validation trolled environments part 4: Design, construction and start-up
has several standard structures with the main subjects: IQ, 5. NEN-EN-ISO 14644-5:2004(E): Cleanrooms and associate con-
OQ and PQ (Sect. 34.10). Validation is a formal GMP trolled environments; part 5: Operations
requirement. 6. Note for Guidance on quality of water for Pharmaceutical use.
EMEA 2002
In case of a (new) building with installations the IQ and
7. Bader K, Hyde J, Watler P, Lane A (2009) Online Total Organic
OQ phase comprises a verification of the checks done during Carbon (TOC) as a process analytical technology for cleaning
the as-built verification and the commissioning including the validation risk management. Pharm Eng 29(1):8–21
check of all GMP critical aspects. It is not necessary to 8. Collentro WV (2007) Pharmaceutical water, system design, opera-
tion and validation. Informa Healthcare, Richmond
repeat all tests of the commissioning. Some additional tests
9. ISPE Water and Steam Systems; Baseline guide. ISPE, 2001
are done such as challenging critical limits of documented 10. Mathiesen T, Rau J, Frantsen JE, Terävä J, Björnstedt P-A, Henkel
functional specifications in practice and adjusting them if B (2002) Using exposure tests to examine rouging of stainless steel.
necessary, provided that they still comply with the FRS. Pharm Eng 22(4):90–97
11. ISPE Good Practice Guide: Commissioning and Qualification of
Also the documentation is completed such as manuals, Pharmaceutical Water and Steam Systems. ISPE, 2007
cleaning, disinfecting and maintenance procedures, 12. Pure Steam (2014) USP Unites States Pharmacopoeia 27:5176
instructions, a monitoring program. Microbiological (con- 13. NEN-EN-ISO 7396-1:2007(E) Medical gas pipeline systems – part
tact) samples (see Sect. 31.6) are taken, recovery time of the 1: Pipeline systems for compressed medical gases and vacuum
Equipment
28
Marco Prins and Willem Boeke
Contents 28.6.3 Planetary Mixer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632

28.6.4 Mortar with Pestle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
28.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 28.6.5 Beaker Mixer/Blender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
28.2 General Requirements and Qualification 28.6.6 Three Roll Mill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
of Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 28.6.7 Coffee Grinder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
28.2.1 Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 28.6.8 Topitec and Unguator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
28.3 Local Air Filtration and Exhaust Units . . . . . . . . . . . . . . . 611 28.7 Filling and Apportioning Apparatus . . . . . . . . . . . . . . . . . . 638
28.3.1 Functionalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 28.7.1 Small Scale Filling Apparatus for Fluids . . . . . . . . . . . . . . . . 638
28.3.2 Fume Cupboard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 28.7.2 Suppository Molding Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . 640
28.3.3 Moveable Exhaust Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 28.7.3 Capsule Filling and Closing Apparatus . . . . . . . . . . . . . . . . . . 642
28.3.4 Powder Exhaust Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 28.7.4 Tube Filling Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
28.3.5 Laminar Airflow Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 28.8 Cleaning Apparatus (Dishwasher) . . . . . . . . . . . . . . . . . . . . . 646
28.3.6 Safety Cabinets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 28.8.1 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
28.3.7 Isolators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 28.8.2 Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
28.4 Apparatus for the Production of Pharmaceutical 28.8.3 Operating Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 28.9 Apparatus for Cooled Storage . . . . . . . . . . . . . . . . . . . . . . . . . 646
28.4.1 Water Softeners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 28.9.1 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
28.4.2 Demineralisation Apparatus Based on Ion Exchange . . . 621 28.9.2 Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
28.4.3 Apparatus for Reverse Osmosis . . . . . . . . . . . . . . . . . . . . . . . . . . 622 28.9.3 Operating Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
28.4.4 Apparatus for Electro-Deionisation . . . . . . . . . . . . . . . . . . . . . . 623
28.4.5 Distillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
28.5 Ultrasonic Baths and Heaters . . . . . . . . . . . . . . . . . . . . . . . . . . 625
28.5.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
28.5.2 Ultrasonic Baths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 Abstract
28.5.3 Gas Stove and Gas Burner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 This chapter is about the design, quality and application
28.5.4 Electric Heating Plate, Immersion Heater and Heating
Mantle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
of equipment for the preparation of medicines in a phar-
28.5.5 Water Bath . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 macy or for preparation in small scale pharmaceutical
28.5.6 Heating Lamp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 industry. The type of pharmaceutical equipment needed
28.5.7 Microwave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628 depends on the type of products to be produced, on the
28.6 Grinding, Mixing and Dispersing Apparatus . . . . . . . . . 629 required productive capacity and the batch size. A list of
28.6.1 Stephan Mixer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 essential and critical equipment for production and qual-
28.6.2 Rotor-Stator Mixer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630 ity control must be included as attachment in the URS
(User Requirements Specification) of any facility. In this
chapter only equipment commonly used for preparation
Based upon the chapter Apparatuur by Willem Boeke, Marco Prins and in pharmacies and small scale industry is discussed. The
Jeannine van Asperen in the 2009 edition of Recepteerkunde.
equipment, requirements, qualification methods, main
A.M.A. Prins (*) applications, maintenance and cleaning procedures are
Jeroen Bosch Ziekenhuis, s-Hertogenbosch, The Netherlands
described for:
• Powder exhaust units, Laminar airflow units, Safety
W. Boeke
cabinets and Isolators
Klinische Farmacie Ziekenhuisgroep Twente, Hengelo,
The Netherlands • Pharmaceutical water production
e-mail: [email protected] • Heating and Ultrasonic water baths

610 A.M.A. Prins and W. Boeke
• Grinding, mixing and dispersing • Provided with accurate and complete technical and oper-
• Filling, dosing and closing for liquids, suppositories, ational documentation
capsules and tubes • Provided with essentials spare parts
• Fridges and freezers It must be proven that a device will be suitable for the
intended function in the preparation process by appropriate
validation or qualification, see Sect. 34.15. Qualification and
Keywords validation must be planned, described and documented.
Equipment Maintenance Exhaust equipment LAF Responsibilities must be clear before the validation process
Water production Mixers Filling equipment Fridges starts. Tests, calibrations, inspections and acceptance criteria
URS FRS FAT SAT must be laid down in a pre-approved qualification protocol.
Raw and processed data, test results and conclusions must be
documented. The result is the qualification or validation
report, including test results and conclusions. Qualification
28.1 Orientation
effort are highly dependent on the criticality of the equip-
ment and the direct or indirect effect (impact) of the device
What type of equipment is needed in the pharmacy or prep-
on the quality of the preparation process and product. When
aration facility depends on the type of products to be
purchasing a new device it is often possible to ask the
prepared or manufactured, the required production capacity
supplier (by quality agreement) to qualify the equipment.
and the batch size. The choice of apparatus discussed in this
This involves, usually, the Installation Qualification (IQ) and
chapter is arbitrary. Larger apparatus and installations such
the Operational Qualification (OQ), sometimes also parts of
as large stainless steel autoclavable mixing tanks are
the Performance qualification (PQ), although usually the
intentionally not discussed, neither are infusion fluid pro-
user of the equipment has to take the responsibility for the
duction lines, filling lines for injection vials, syringes and
execution of the PQ (see Sect. 34.10).
ampoule machines. Larger machines usually consist of many
Preferably the essential list of equipment is included as
components assembled on client specifications, resulting in
attachment in the so called URS (User Requirement Specifi-
many variations.
cation) of the facility, as discussed in Sect. 27.3.
In this chapter we discuss the main applications of equip-
ment that is commonly used in pharmacies and small scale
industry as well as the maintenance and cleaning procedures
or installation. Small equipment and materials such as volu-
28.2.1 Design
metric glassware and weighing equipment are described in
Chap. 29. Sterilisation and sterile filtration equipment is
A set of a well-formulated User Requirements Specification
discussed in Chap. 30.
(URS), Functional specifications and Detail specifications
The publications of ISPE (see Sect. 39.5.6) are
has key importance proceeding any purchase (see Sect.
recommended for more detailed technical information on
34.15). A good URS is used in the performance qualification
equipment, for instance Water and Steam systems, Cold
and relates the actual production capacity and variety to the
chain management.
required machine qualities.
Some ISO (see Sect. 35.7.2) standards are appropriate as
With a couple of potential suppliers a limited list can be
well, such as EN 14175 Fume cupboards. PIC/S (see Sect.
drawn up of apparatus that might qualify for selection.
35.5.5) documents may be helpful such as on Isolators used
Specifications have to be listed, such as:
for aseptic processing and sterility testing (PI 014-3).
• Ease of cleaning and of sterilisation
• Ease of mounting and demounting and of exchange of
tools
28.2 General Requirements and Qualification • Hygienic design for product-contact surfaces, sealing
of Equipment rubbers and membranes
• Product loss at starting and stopping
Pharmaceutical equipment should be appropriately qualified • Ease of operating, and the extent that operating or hand-
and fit for use. That means that the device or equipment is: operated adjustments have impact on the product
• Safe for the user, but also for the environment (check, for • Safety
example, the required CE marking) • Failures should not pass unnoticed
• Easy to use in daily operational practice for its intended use At the final selection the compliance with the original URS
• Capable of being effectively cleaned, disinfected and should be warranted and from this a large number of
sterilised if applicable premises issues will ensue, such as:
28 Equipment 611
• Required capacities of utilities (electricity, water, steam, 28.3.1.1 Protection of the Operator
gases, and if applicable, IP-network connections, etc.) and Environment
• Floor load and possibilities of setting up; routing During the preparation of medicines, steam, vapour,
possibilities for transporting equipment to its final instal- aerosols, dust and fumes can be released, which may pose
lation place a health risk for the operator. It is not always possible to
• Heat release and other influences on the HVAC during change the process releasing these hazardous substances. As
operation a consequence it can be necessary to protect operators in
• Product transport in and out and accessibility: logistic preparation or quality control areas from exposure to the
aspects of personnel and product to and from the product or the active substance. This can be done by active
machine ventilation and exhaust and by filtration in order to protect
Although the manufacturer will build a chosen machine with the environment (see also Sect. 26.4.1). The appropriate
standard components, the final result will be more or less equipment may be fume cupboards, moveable exhaust ducts,
unique. The manufacturer will often only accept limited liabil- powder exhaust units, (bio)safety cabinets and isolators.
ity for the performance of the machine in a specific situation. Fumes, gas mixtures and volatiles might be absorbed by
Agreement on a so-called Factory Acceptance Test (FAT) is special filters, but in pharmacy practice only the technique
recommended and it should be executed at the site of the of exhausting and screen filtration is usually used.
manufacturer when the apparatus has reached the ready for
testing status. At this stage it is possible to solve any unfore- 28.3.1.2 Protection of the Product
seen problems that would be either impossible to solve, or only The operator might be a microbiological hazard for the
against huge costs after installing at the final destination. pharmaceutical product, because of the operator’s micro-
Agreement on a so-called Site Acceptance Test (SAT) is organisms coming from the skin, hands, nose etc. Apart
recommended as well, as is the execution immediately after from shielding the body to prevent these particles being
setting up. This is especially important when there is a discharged into the product, working in airflow directed
considerable amount of time between the time of delivery from the product may contribute to the protection of the
and the actual operation in practice as a consequence of product. The air in the production area must be of sufficient
elaborate qualification tests. Issues as the starting date for quality not to be a contamination source.
the guarantee period, the setting off of the maintenance plan Annex 1 of the EU GMP defines the quality of the air in
and the transfer of remaining ownership responsibilities the preparation of sterile products. See Sect. 27.4.2 for
should be well indicated in advance. The SAT offers a elaboration of this topic.
good opportunity to reveal issues such as transport damage,
PRODUCTION
any forgotten components or spare parts, etc. and it is also a 28.3.1.3 Types of Equipment
check of the fulfilment of understandings made during The terminology for local exhaust units is sometimes unclear
the FAT. and non-specific. E.g. the term ‘biological safety cabinet’,
which is historically derived from working with micro-
organisms, is rather confusing. Any definitions can be
found in [1].
28.3 Local Air Filtration and Exhaust Units
In this section a distinction is made between:
• Fume cupboard
In this section local air filtration and exhaust units are
• Moveable exhaust duct
discussed. Filtration being necessary for removing micro-
• Powder exhaust unit
organisms and dust from the air. Exhaust being necessary for
• LAF unit or booth
carrying away contaminated air. Dedicated HVAC
• Safety cabinet
installations for heating, venting and air conditioning of
• Isolator
clean rooms are described in Sect. 27.5.1.
Figure 28.1 shows the general (schematic) construction of
the different types of local exhaust and air filtering
equipment.
28.3.1 Functionalities For the protection of the operator and co-workers the
most basic engineering control measure to minimise inhala-
This equipment is needed for supplementary and dedicated tion exposure (see Sect. 26.4.1) is ventilation of the work
air filtration or exhaust at the site of preparation. In pharma- area. A ventilation rate of 2 h1 or 5 h1 is common for
ceutical preparation or quality control the objectives of air offices but not sufficiently efficient for preparation areas. A
filtration and exhaust may be the protection of the product or better effect will be obtained by containment of the activities
the operator and the environment or both. that releases hazardous substances. In order to prevent
a b c
exhaust
fan
HEPA filter
HEPA filter pre-filter
pre-filter
movable exhaust duct (side view)
fume cupboard (side view)
basic model powder extraction unit (side

view, without exhaust ULPA filter)
d e pre-filter f
pre-filter HEPA
cross flow exhaust
filter
fan plenum
lighting down flow
down fan
HEPA filter flow fan
plenum HEPA
HEPA filter downflow
filter
laminar cross flow unit
pre-filter
laminar down flow unit (bio)safety cabinet
g
exhaust HEPA filter
downflow
HEPA filter
isolator (front view)

downflow
HEPA filter
Fig. 28.1 Schematic construction of exhaust and air filtering equipment (¼ Fig. 28.1a–g). Source: Recepteerkunde 2009, #KNMP
contaminated air to enter the room, the exhaust is guided to Complete protection of operator and product can be
the outside of the building and discharged in the environ- achieved by an isolator (see Sect. 28.3.7). Apart from
ment or the exhausted air is filtered before re-entering the complete product and operator protection other advantages
room. Filtration of exhaust air will decrease any exposure of are: controlled disinfection procedures, lower initial
the environment outside the building and filtration is gener- investments costs of the background area and exploitation
ally expected. costs. Disadvantages are higher costs compared to a
For the protection of the product, working in a laminar LAF unit and its elaborate cleaning and maintenance.
airflow directed from the critical places or working in a Therefore, in practice the choice of type of local exhaust
complete gastight box are options used in practice. equipment is determined by a risk assessment of the
28 Equipment 613
process (taking into account the contamination of the prod- 28.3.2 Fume Cupboard
uct and of health damage of the operator), the available
investment and the local experience. Fume cupboards are meant to protect the operator from
For a systematic approach to the choice of the right local fumes, steam, volatiles and corrosive fluids.
exhaust ventilation, the allowed level of exposure is com- Fume cupboards are not effective enough for the safe
pared with the actual exposure level and the assumed effec- handling of aerosols and powders.
tiveness of the exhaust device. Reference is made to [2].
Local exhaust ventilation is generally expected to establish
a ten-fold reduction of the exposure level. Containment
28.3.2.1 Description
In pharmacy practice mainly the ducted type of flowhood is
with ‘small-scale breaches’ is considered to establish a
used, which is not recirculating the air into the room. The air
100-fold reduction. Total containment as is accomplished
in the hood, eventually mixed with the volatiles is
by using an isolator.
discharged into the open air outside the building, often by
For a general approach of preparation situations in com-
flexible special ducting. The extractor (fan) of a fume cup-
munity and hospital pharmacies (working with maximal
board does not come in contact with these volatiles. This is
100 g of substances of hazard classes 1–5) reference is
the reason why explosive or highly combustible material can
made to Sect. 26.5.2. For higher exposure levels the
be exhausted safe.
Advanced REACH Tool (see Sect. 26.5.1) offers guidance.
The direction of the flow inside a fume cupboard is
The small scale preparation in pharmacies may generally
upwards at the end, see Fig. 28.1a. Heavy volatiles concen-
require:
trate on the bottom of the fume cupboard; lighter volatiles
• A powder exhaust unit for most dust releasing operations:
can be found somewhat higher in the fume cupboard. In both
weighing, capsule filling, mixing of solids, rotor-stator
areas of the fume cupboard sufficient force of the airflow is
mixing
obligatory: 0.5 m/s for vapours and 1 m/s for dust [3]. How-
• A horizontal or vertical LAF unit for the common aseptic
ever, the speed of the inflow in a fume cupboard is not high
handling with closed containers (see Sect. 31.3.4)
enough for the exhaust of small solid particles. The material
• A safety cabinet or isolator for processing class 4 and
of the fume cupboard and the exhaust fan and duct must be
5 substances
resistant to corrosion, in order to work with corrosive or
• An isolator if capsules have to be prepared with class
caustic agents.
5 substances
In front of the fume cupboard there is a transparent safety
• A fume cupboard for processing volatile, inflammable or
sash, sliding gently up or down with a counterbalance mech-
corrosive substances
PRODUCTION
anism to reach precisely the defined and properly validated
It cannot be stated that a ‘normal’ down flow cabinet, with
working or loading position. The loading position is not safe,
open front and without sleeves to the work top (so not a
but high enough to place equipment inside. Low airflow
safety cabinet), or a down flow unit is safe for the operator
alarm control panels are common. The working position
if working with half-open or open systems. It may very
creates a safe area under the glass window to work in with
much depend on airflow patterns if any contamination with
(gloved) hands and arm covers for that part of the arm
a substance will be actively blown in the direction of the
entering the fume cupboard working area.
operator. If so, the exposure would be higher, in which case
no ventilation or exhaust is preferred.
28.3.2.2 Maintenance and Inspections
Influence of Local Devices on the Performance Fume hood maintenance involves periodical (daily, quar-
of Room HVAC terly, annual) cleaning, maintenance, calibration, qualifica-
Local safety cabinets of any type will influence the air tion and inspections. In daily inspection the fume hood area
pattern, temperature and HVAC system in the prepa- is visually inspected by the operator. Hood function
ration area. (HVAC means heating, ventilation, indicating devices (LEDs) are a part of the modern fume
air-conditioning; see Sect. 27.5.1). The influence will cupboard. Periodic inspection covers capture or face veloc-
vary. Sometimes all doors of the room must be closed ity measured with a velometer or anemometer.
in order to insure a correct function of a fume cup- Annual maintenance: Yearly the fume cupboard must be
board. Air expelled by the local safety flow systems maintained, calibrated and tested by a certified firm and
will also influence the ventilation and the pressure competent person and the results of the official tests
in the room. Local devices produce energy in the reported. Exhaust fan maintenance comprises lubrication,
form of heat and, unless exhausted, will change the belt tension, fan blade deterioration and speed of the fan.
room temperature. This can be uncomfortable for Air velocity at different points, window performance, bright-
the operator. ness of the light in the cupboard are tested in the working
situation, with all doors of the room closed. Control of the
frequency and method of cleaning the interior is also 28.3.3 Moveable Exhaust Equipment
important.
28.3.3.1 Applications
Moveable extraction equipment can be used for the local and
Validation of the velocity of the incoming air in the
small scale exhaust of fumes and vapours at the point where
area under the sash and validation of the volume of
these fumes and vapours are produced in an environment
the exhausted air is not sufficient proof of the safety
with no classic fume cupboard available. For example the
of the fume cupboard. The quality of design of a
handling of organic solvents in a laboratory, near the analy-
good fume cupboard is as important as it guarantees
sis equipment.
a stable vortex of the airstream. A good technical
An extraction duct may not be the best choice for the
design of the ventilation system is essential too, as is
extraction of powders and dust. However, by placing the
the dimensioning of the interior of the fume cupboard
hood very close to the point where the dust is produced we
itself. Last but not least: without good operating
can create a situation with high air velocity and an effective
procedures and trained operators a good technical
exhaust for dust. In that case the exhaust duct is a dust
design is useless.
remover, but eventually without a dust collector bag for the
The main goal of the operation within a fume cup-
dust. A problem is that collected dust in the duct or the hood
board is that it will not be possible for contaminated air
can fall back on (other) products. This is a serious risk for cross
to enter the area or room outside the fume cupboard.
contamination and needs a proper cleaning schedule in place.
Never start activities in a brand new fume cup-
A better solution for exhausting dust and powder is com-
board with certificate of the manufacturer only,
bining the exhaust unit with filters, see Fig. 28.1b.
because on site initial qualification and validation of
Contaminated air enters the pick-up hood and is drawn
the performance and proper training of the operators
through the hose and into the dust containment unit. The
is essential.
flexible duct with pick-up hood is easily adjusted to any
For initial validation (and periodical revalidation)
position by an externally mounted, self supported, adjustable
mostly a combination of tests is carried out:
arm. Larger, heavier particles are collected in a removable
• Validation of the velocity of the exhausted air in the
collection pan for easy maintenance. The first stage of filtra-
opening under the glass window and validation of
tion is a pleated pre-filter, designed to capture mid-sized
the volume of the exhausted air (extract volume
particles before reaching the main filter therefore extending
flow rate test).
the life of the main filter. The main filter is a high efficiency
• Containment testing - sometimes this test shows
95 % filter designed to capture fine particulate before being
initially differences between test results in the test
exhausted. Other main filter options are available including a
environment of the manufacturer (as built) and the
99.97 % efficient HEPA Filter. Clean filtered air is returned
results obtained in the pharmacy or in the labora-
to the environment.
tory of the end user (on site, as installed).
Professional dust removers are used in tableting, capsule
• The test protocol of European Standard EN 14175-
filling and closing machines and powder filling machines.
4 [4].
They are used to clean the equipment during processing or to
remove adsorbed dust and powder from the pharmaceutical
product. Dust removers are not designed to extract fumes,
because fumes pass the filter unit and are blown back in the
28.3.2.3 Operation
room.
It is important not to disturb the performance and airflow
Mobile dust removers (vacuum cleaners) with integrated
pattern of the fume cupboard. Staff standing or walking
HEPA filter are used in clean rooms, most of the time to
in front of the fume cupboard will disturb the air exhaust.
clean the floor and ceilings. Dust removers are not designed
The operator must have sufficient space in front of the
to extract fumes, because fumes pass the filter unit and are
fume cupboard to work easily and comfortable. Room
blown back in the room. The HEPA filter has to be replaced
doors that open frequently during operation in a fume cup-
periodically.
board and (strong) inflowing air from the room ventilation
system (in the direction of the fume cupboard) may have a
negative impact on the performance of the fume cupboard. 28.3.3.2 Description
Airflow visualisation with smoke is illustrative and often Extractors for industrial or laboratory environments are
necessary. available in several duct diameters (Ø 75–200 mm), duct
28 Equipment 615
materials and sizes, with various constructions for ceiling, influenced by the changing air pattern every time the door
wall and bench installations. The standard model for fume swings open or is closed.
extraction is used in most laboratory environments. The
joints are made from polypropylene and ducts from anodised
The velocity of the incoming air stream in an exhaust
aluminium, for example. Polypropylene PP is used in
unit must be between 0.25 and 0.50 m/s, with no major
environments containing high concentrations of corrosive
disturbing air pattern around or in front of the exhaust
pollutants; joints and tubes are made from polypropylene.
unit. A higher exhaust velocity causes unwanted tur-
ATEX material is used where hazardous explosive
bulence before and in the unit.
atmospheres may occur (see Sect. 26.11); joints and tubes
Weighing in an exhaust unit is possible. Dependent
are made from conductive polypropylene.
on the results of the accuracy of the weighing tests it
can be necessary to shut down the exhaust unit at the
very moment that the weighing result is recorded.
28.3.4 Powder Exhaust Units
28.3.4.1 Application
Powder exhaust units are often benches with horizontal 28.3.4.3 Operating Instructions
backward flow and final vertical HEPA filters (see • Switch on the exhaust unit just before starting the
Fig. 28.1c), suitable to protect the operator largely from activities. Clean the unit inside before and after activities.
fine powder particles in the air or from water-based aerosols • Check the velocity meter. Check the status of the filtra-
that otherwise would be released in the working area. These tion area, no damage may be seen.
exhaust units might recirculate the exhausted air and • Check the unit once a year on air velocity; a leak test for
pollutants can (also through basic filtration material) enter HEPA or ULPA filters is easy to perform by an expert.
the room. In a Wibojekt® powder exhaust units the extracted • Change all pre-filters and the HEPA filter only after
air with particles is blown towards a special slit. That air is leakage or damage.
filtered and exhausted outside the room.
The filtration efficiency depends on the type of filter but is 28.3.4.4 Replacement of the Pre-Filters
as said above generally expected to establish a ten-fold The pre-filters have to be changed when after a visual check
reduction of exposure. the pre-filter is dirty or saturated, or after a chosen time
These types of exhaust units usually don’t have a duct interval (once per 1–3 months for example).
PRODUCTION
leading to the outside of the building and therefore are not During a change of the pre-filter the operator has to wear
suitable for the extraction of gasses, fumes and volatile a protective P2- or P3 mask (see Sect. 26.4.1) for dust and
products. aerosols. The exhaust unit fan is switched on, so dust
particles are trapped in the HEPA or ULPA filter cassette.
28.3.4.2 Description Clean the filter frames and remove the old filters in a
Fine dust particles or small aerosol droplets generated in a closed bag.
powder exhaust unit must be extracted from the operators
working space horizontally in the backward direction. The
airflow is sometimes downwards into a special slit 28.3.5 Laminar Airflow Units
(Wibojekt®).
After passing a coarse pre-filter and a final ULPA filter A Laminar airflow unit, also called laminar flow -cabinet,
the exhausted air can be exhausted into the preparation -closet, -hood or -bench is a general and rather non-specific
room. It that case the unit is recirculating the air. It is term for an enclosed workbench, with a HEPA filtered
possible to discharge the air via a duct outside the building. laminar airflow inside.
As a result the room pressure will become lower. The laminar airflow is unidirectional, so not turbulent.
The efficacy of an exhaust unit depends on the air veloc- This is achieved by choosing the right design, technology,
ity in the unit. For that reason the area of the filters is not too air velocity and filter sets. This unidirectional airflow must
small. Settled dust cannot be exhausted once it has fallen not be disturbed too much by the environment or movements
down onto the horizontal work area in the unit. of the operator. So a specific working technique and
The place in the room where the exhaust unit is installed behaviour for the operator(s) is necessary. The direction of
and qualified has to be chosen carefully. A recirculating the filtered and clean laminar airflow can be horizontal (from
exhaust unit needs enough space to blow the exhausted air the left to the right or from the back of the cabinet towards
around the unit. An exhaust unit very close to a door will be the operator), or downwards: from the HEPA filter in the top
of the cabinet to the bottom (which often is a flat stainless an important part of the functional and detail specifications
steel work area). See Fig. 28.1d and e. In pharmaceutical of it.
terminology: HEPA filtered horizontal or vertical laminar
airflow (cross- or downflow) in a laminar flow bench creates
Testing of HEPA Filter Units.
an ISO 14644-1 (Class 5) / GMP Annex 1 (Class A) work
Filter efficiency, dust holding capacity and differential
area and prevents contaminated ambient air entering the
pressure changes are tested frequently.
work area. With the right working techniques, a trained
HEPA filters can be tested with different methods.
operator and the right classified background this can result
A wide range of test equipment for on-site
in good product protection.
measurements include particle counters, pressure
gauges, airflow meters, energy data loggers, corrosion
28.3.5.1 Application monitors and gas analysis equipment. One of the tests
In pharmacies a laminar flow unit is used to protect the
is the measurement of penetration of dispersed oil
product against microbiological contamination from the
particles (DOP) through the HEPA filters. DOP used
operator. With a cross flow LAF cabinet the HEPA filtered
to be the abbreviation of DiOctylPhtalate, which how-
air is directed over the working area to the operator. This type
ever has been replaced by safer products.
of LAF bench thus cannot be used for operations with haz-
By dispersing the oil aerosol towards the HEPA
ardous substances (hazardous being defined as any substance
filters in the air channel the testing operator can mea-
with a H statement, so with a hazard class higher than one, see
sure how many particles penetrate the HEPA filter and
Sect. 26.3.1). It can be used for aseptic preparation processes
can be counted at the clean part of the HEPA filter.
with closed systems, such as aseptic handling, see Chap. 31.
According to ISO 14644-3 the filter area is scanned in
For larger equipment a down flow LAF unit is common,
small well-defined sequential parts. This percentage
e.g. a HEPA plenum in a preparation area for sterile
penetrated particles can be dependent on the exact
products. A HEPA plenum with plastic curtains mounted
position on the filter where the particle counter
in and hanging from the ceiling creates a dedicated area for
measures. Inferior and good parts of the filter area
aseptic processes. A plenum can be used for example to
are detected and the position is documented. The con-
protect washed and opened glass infusion containers,
dition of the filter is expressed as percentage penetra-
moving in a filling line in the downflow of the plenum to
tion giving filter efficiency. The penetration is the
the point of aseptic filling. As said, it depends on airflow
percentage of the particles that passed; the filter effi-
patterns if any substance is actively blown in the direction of
ciency is the part that was blocked by the filter mate-
the operator. If so, the exposure may be higher than when no
rial. The efficiency for the most penetrating particle in
ventilation or exhaust takes place. This means that a down
a H14 HEPA filter can be 99,995 % and for the
flow LAF unit cannot be used for open processing
particles with a size larger than 0.3 μm the efficiency
substances with a hazard class higher than one.
can be 99,999 % or more. Small defects in the filter
can be repaired by a professional operator.
In general, the air from the production area enters the front of
the LAF cabinet in a controlled way, passes at first a set of
pre-filters in the cabinet that separates coarse dust. Some- Other important functional details of LAF cabinets are:
times more HEPA filters placed in series after the pre-filters • The light intensity in the cabinet, measured on the work
act as supplementary pre-filters (in certain types of safety spot must be sufficient to reach a minimum level of 1,000
cabinets). After pre-filtration the air is forced via a ventilator lux. The lighting unit must be built inside the cabinet and
box through a set of framed HEPA filters and finally enters the frame of it must be easily cleaned and disinfected.
the aseptic process area as sterile filtered air in a unidirec- • The speed of the ventilator must be adjustable, and auto-
tional flow. The speed of the unidirectional flow is kept matically controlled in order to reach the required quality
between limits. Finally the exhaust air re-enters the room of laminar flow and speed.
(crossflow LAF units), or can be exhausted to the outside • Detection of full speed, half speed, on and off or night
with or without extra HEPA filtration (safety cabinets). function.
With these principles in mind horizontal crossflow LAF • The speed of the unidirectional flow must be monitored
cabinets, downflow LAF cabinets, downflow safety cabinets and shown on a display to detect disturbances in the flow
or downflow LAF units with a large area (HEPA filter by a clogged filter or a defective ventilator.
plenums) are constructed. To keep the flow as unidirectional as possible a minimal
The exact positioning of pre-filters in a LAF cabinet number of extra utilities inside the working area of LAF
depends on the brand and type of the LAF cabinet and is cabinet are allowed. Extra utilities might be:
28 Equipment 617
• Nitrogen and compressed air valves, for membrane filtra- LAF cabinets that do not run 24 h a day must be switched
tion devices. on first; after 15 min operating at full speed the cabinet must
• Vacuum valve, used only in dedicated LAF units for be disinfected and can be used.
microbiological quality control: the filtration of fluids Disinfection efficacy must be proved with contact plates
for sterility testing or bioburden control. (RODAC plates, see Sect. 31.6); specifications of the results
• Electricity sockets. can be found in Annex 1 of the European GMP.
• Electronic balances. They can be used inside the LAF Validation of the aseptic process can be found in Sect.
cabinet but give disturbance of the laminar airflow and 31.6.2.
in return the LAF cabinet might disturb the weighing
result. Use only following a risk analysis.
28.3.5.4 Qualification of a LAF Unit
• Clamps outside on the front of the LAF unit, to attach
Once or twice a year (depending on the criticality of the
temporary documentation.
processes) the LAF cabinet is inspected, calibrated and
• A stainless steel rail with hooks in the LAF area to attach
qualified. Commonly a contract is signed with a specialised
infusion bottles and bags for the aseptic processing.
external firm for this.
• Computer monitor for instructions.
The following aspects are important in qualification:
• (Continuous) monitoring equipment.
• Inspection and installation of new pre-filters. Sometimes
It is advised to require silent, modern ventilators. The expected
the filters are grey or coloured, as proof of the need of
daily noise of a LAF unit in operation must be reasonable
change.
low and specified in dB. The best solution is to choose a
• Efficacy of the HEPA filters. It is not necessary to change
cabinet ventilator with enough spare capacity. In that case
the HEPA filters too often. Change of a HEPA filter is
the ventilator will not work at the maximum capacity and the
expensive and must be a result of documented defects that
noise level in dB will be reasonable or low.
cannot be repaired.
A laminar flow cabinet will continuously produce heat
• Air velocity.
from the ventilators. If the exhaust airflow from the LAF unit
• Intensity of the light.
is returned into the room (recirculation), the temperature in
the room will rise and more room ventilation and cooling is
necessary. Air exhaust to outside the room will give less
heating of the room. 28.3.6 Safety Cabinets
28.3.5.3 Operating instructions 28.3.6.1 Application
PRODUCTION
Commonly two operators are at work in a LAF cabinet. One A safety cabinet is a laminar down flow cabinet, which is
is the operator, working with the arms and hands inside the constructed specifically for protection of both the sterile
cabinet. The second person is standing aside, supporting and product and the operator. It is frequently used in (hospital)
controlling the operator, or supporting two operators work- pharmacies for aseptic preparation (when products are not
ing simultaneously in two different cabinets. fully closed) and for aseptic handling of class 4 or
These persons must move gently in the room. Opening a 5 substances (see Sects. 26.5.2 and 26.8). Laminar down
door will have some effect on the balance of the airflow in flow has the advantage compared to cross flow that the
the cabinet. So try to avoid opening clean room doors during operator does not feel the continuous flow in his direction.
aseptic processing. Other names for a safety cabinet are: biosafety cabinet,
Spillage of material must be removed as soon as possible biosafety bench, biohazard bench, biohazard cabinet,
for example with a cloth wetted with disinfectant. biological safety cabinet etc.
The interior of the LAF cabinet (horizontal bench, two In safety cabinets with a “slope” glass window the opera-
sides left and right and the back inside of the bench) is tor works with both arms under the window into the half-
disinfected with alcohol 70–80 % at the end of each working open sterile working area.
session (shift of about two hours) and at the end of the
working day. For LAF benches that keep running 24 h a 28.3.6.2 Description
daily disinfection of the horizontal working bench only The air within a safety cabinet comes from the HEPA filter
between sessions and before start of the activities the next in the top of the cabinet (see Fig. 28.1f). The flow is led into
morning might be allowed. This decision is based on a risk exit grills at the back and the front of the work bench. A
analysis, and might be allowed because the rest of the interior second airflow is drawn from the working room into the
was disinfected at the end of the past working day. In addition front grill where the elbows of the operator are. This flow
on disinfection the interior must be cleaned frequently with prevents air or aerosols from the working area escaping the
lukewarm water and a detergent, followed by a disinfection. cabinet and protects the operator from inhaling aerosols.
After being collected through the slits the air is prefiltered

through coarse disposable filter material situated under the contaminated) air from the work bench is led without
work bench in a tray. filtration to the last exhaust HEPA filter; in this way
In safety cabinets of the type partial or total exhaust, the the ventilator compartment can be contaminated after
air eventually is collected in a box on top of the bench, sustained use of this type of safety cabinet. In Class
connected via a HEPA-filter with the air in the room (see IIB cabinets an extra HEPA filtration cassette is placed
Fig. 28.1f). The box has underpressure due to the exhaust below the work bench; as a result HEPA filtrated
air velocity. In case the safety cabinet has a breakdown, the (potentially contaminated) air from the work bench
box construction prevents the ventilator of the exhaust enters the ventilator part before it passes the last
channel to continue while the down flow ventilator in the HEPA exhaust filter. The ventilator compartment
cabinet stops. Otherwise contaminated air from the room remains cleaner by this extra HEPA filtration step.
would be sucked under the sash, contaminating the clean The environment is better protected, as well as service
side of the HEPA filter in the work area of the safety personnel working inside the safety cabinet.
cabinet. Safety cabinets placed in a room with
underpressure (for the preparation of radiopharma-
ceuticals for example) must have an extra exhaust
28.3.6.3 Specifications and Classification ventilator, discharging the exhaust air outside the
The specifications of the airflow pattern in a safety cabinet building. This exhaust ventilator must be tested also
might be confusing. Following EN 12469 (Biotechnology – in daily practice and at periodical electricity break
Performance criteria for microbiological safety cabinets) [5] tests. Safety cabinets have visual and acoustic alarms
the velocity of the incoming room air under the glass panel that warn for deviations in airflow (down flow and in
must be between 0.4 and 0.7 m/s; the mean downflow flow alarms).
velocity must be between 0.25 and 0.50 m/s, with no individ-
ual measurement outside +/ 20 % of the mean. However,
in pharmacy the GMP [6] takes precedence. In Annex 1 the
down flow air velocity differs somewhat from the EN 12469.
The mean velocity for the down flow in Annex 1 (Class A)
The classification by the U.S. Centers for Disease
must be 0.45 m/s +/ 20 %. It is important to stress GMP
Control and Prevention (CDC) is to be found in
compliance during installation and initial qualification of a
Appendix C: Types of Biological Safety Cabinets
new safety cabinet in a pharmaceutical environment.
(BSC) of the draft USP monograph Hazardous drugs
The air in a safety cabinet is filtered through pre-filters
– handling in healthcare settings [7]. Terminology
and HEPA filters so the resulting workspace inside the
(biological safety) may be confusing but is historically
bench complies to GMP Class A. All safety cabinets of
determined: the first safety cabinets were developed
type II are built with a HEPA filter at the point where the
for working with dangerous microbiological materials.
used air is finally expelled through the exhaust channel. This
The classification of the cabinets is based on their
is an extra HEPA barrier, preventing aerosols contaminating
technical construction which is described in this
the HVAC system.
Appendix. The fields of application are suggested for
each class.
Classification of Safety Cabinets Class I: A BSC that protects personnel and the
Safety cabinets must comply to Class II of the environment but does not protect the product/prepara-
European Standard EN-12469. Some types comply tion. Personnel protection is provided when a mini-
moreover to the German DIN 12980. Document your mum velocity of 75 linear feet/min of unfiltered room
specifications well before purchase and be aware that air is drawn through the front opening and across the
in pharmacy practice a down flow velocity of the air in work surface. The air is then passed through a HEPA/
a safety cabinet must comply with current GMP. Com- ULPA filter either into the room or to the outside in the
munication about GMP is very important, because exhaust plenum, providing environmental protection.
these safety cabinets are used in non-GMP Class II: Class II (Types A1, A2, B1, and B2) BSCs
laboratories too. are partial barrier systems that rely on the movement
The Classification IIA and IIB is not found in the of air to provide personnel, environmental, and prod-
EN-12469 but in US-CDC guidelines (see further uct/preparation protection. Personnel and product/
down). In a Class IIA cabinet the (potentially preparation protection is provided by the combination
28 Equipment 619
of inward and downward airflow captured by the front filter without recirculation inside the cabinet or return
grid of the cabinet. Side-to-side cross-contamination to the laboratory, and have all contaminated ducts and
of products/preparations is minimised by the internal plenums under negative pressure or surrounded by
downward flow of HEPA/ULPA filtered air moving directly exhausted negative-pressure ducts and
toward the work surface and then drawn into the front plenums. These cabinets may be used with volatile
and rear exhaust grids. Environmental protection is toxic chemicals and radionucleotides.
provided when the cabinet exhaust air is passed Class III: The Class III BSC is designed for work
through a HEPA/ULPA filter. with highly infectious microbiological agents and
Type A1 (formerly, Type A): These Class II BSCs other hazardous operations. It provides maximum pro-
maintain a minimum inflow velocity of 75 ft/min, have tection for the environment and the worker. It is a
HEPA-filtered, down-flow air that is a portion of the gas-tight enclosure with a viewing window that is
mixed down-flow and inflow air from a common ple- secured with locks and/or requires the use of tools to
num, may exhaust HEPA-filtered air back into the open. Both supply and exhaust air are HEPA/ULPA
laboratory or to the environment through an exhaust filtered. Exhaust air must pass through two HEPA/
canopy, and may have positive-pressure contaminated ULPA filters in series before discharge to the outdoors.
ducts and plenums that are not surrounded by
negative-pressure plenums. They are not suitable for
use with volatile toxic chemicals and volatile
radionucleotides. 28.3.6.4 Operation Instructions
Type A2 (formerly, Type B3): These Class II BSCs The operational aspects of maintenance and calibration for
maintain a minimum inflow velocity of 100 ft/min, safety cabinets are almost the same as for cross flow laminar
have HEPA-filtered, down-flow air that is a portion airflow units (see Sect. 28.3.5). Additionally the inflow as
of the mixed down-flow and inflow air from a common protective barrier has to be measured.
exhaust plenum, may exhaust HEPA filtered air back Daily cleaning and disinfection of the interior of a safety
into the laboratory or to the environment through an cabinet is important. The tray under the work bench as well
exhaust canopy, and have all contaminated ducts and as the pre-filter contains spilled fluids. This area has to be
plenums under negative pressure or surrounded by cleaned and disinfected at least once a week wearing a P3
negative-pressure ducts and plenums. If these cabinets mask (see Sect. 26.4.1) and protective impermeable cloth-
are used for minute quantities of volatile toxic ing. The pre-filters must be changed every 3–6 months; the
PRODUCTION
chemicals and trace amounts of radionucleotides, HEPA filters must be changed only after significant failure at
they must be exhausted through properly functioning qualification tests, repair being not possible any more.
exhaust canopies.
Type B1: These Class II BSCs maintain a minimum
inflow velocity of 100 ft/min, have HEPA-filtered 28.3.6.5 Qualification
down-flow air composed largely of uncontaminated, The protection performance of a safety cabinet is given by
recirculated inflow air, exhaust most of the the so called Protection Factor, which is determined by the
contaminated down-flow air through a dedicated duct Potassium Iodide test. Potassium Iodide solution is dropped
exhausted to the atmosphere after passing it through a on a spinning drive. An aerosol inside the work area of the
HEPA filter, and have all contaminated ducts and cabinet is formed; some droplets are forced in the direction
plenums under negative pressure or surrounded by of the protecting air curtain. The number of aerosol particles
negative-pressure ducts and plenums. If these cabinets inside the bench is counted (A). Outside the cabinet (where
are used for work involving minute quantities of vola- the operator normally is sitting) the number of aerosol
tile toxic chemicals and trace amounts of particles that escaped the air curtain in front of the bench is
radionucleotides, the work must be done in the directly counted again (B). A/B is the protection factor. The protec-
exhausted portion of the cabinet. tion factor has to be at least 1.5 105.
Type B2 (total exhaust): These Class II BSCs main- A second test is a test with spores of bacteria. This is a
tain a minimum inflow velocity of 100 ft/min, have factory test for obvious reasons, see EN-12469.
HEPA-filtered down-flow air drawn from the labora- The potassium Iodide test is time-consuming. This test is
tory or the outside, exhaust all inflow and down-flow performed in OQ/PQ qualification or when possible harm
air to the atmosphere after filtration through a HEPA could have occurred, for instance when the cabinet is moved
to another place.
(continued)
28.3.7 Isolators The operator wears disposable gloves and puts the hands
and arms in the long rubber isolator gloves, which have
An isolator, as is in its name, offers physical isolation of the inflatable gaskets for tight fitting to the isolator. Half or
operator from the product. It offers complete containment full suits are also a possibility.
(see Sect. 26.7.1). Its presence in pharmacies differs consid- The isolator gives an acoustic alarm when the pressure
erably between countries. drops or with other deviations.
In industry an isolator technique is often used for critical Maintenance or repair of an isolator has to be done with
aseptic processes. Other techniques with robots and barrier gloves, a protective mask and protective clothing. Change of
system isolator technology are in use also. Isolators for HEPA filters has to be done very carefully and with qualifi-
aseptic manufacturing can be placed in class C or D clean cation after replacement. Further descriptions can be found
rooms, whereas LAF cabinets should be placed in GMP in [8].
class B.
28.3.7.2 Using an Isolator
28.3.7.1 Description After delivery of a new isolator a qualification protocol is
An isolator is according to the description of EN-12469 a followed (see Sect. 34.15). The interior of the isolator must
Class III safety cabinet, as said a complete physical barrier, comply to GMP Class A (particles and microbiological
see Fig. 28.1g. The air inside the isolator is HEPA filtered, so tests). A program to minimize the risk of loss of integrity
inside the isolator a GMP Class A air quality is maintained. of gloves, sleeves and suits should be present including
The gloves or full or half suits are the physical barrier operator practice, vigilance and the absence of sharp edges.
between the sterile product inside the isolator and the opera- The glove ports and, if applicable, the suits present particular
tor standing outside and the integrity of this barrier requires risk because they are more prone to damage and if not
very much attention. noticed will contaminate the product. Transfer of material
The main compartment of an isolator is often made of in and out should not compromise the critical zone. The
stainless steel and has two rubber gloves in the front of a transfer is especially critical if no gassing is used. In that
clear viewing panel. The HEPA filtered airflow can be case a proper disinfection procedure such as used in normal
laminar or turbulent. LAF has to be used.
The pressure inside the main compartment is higher or As the absence of micro-organisms is expected, the ques-
lower than the background area of the isolator. Containment tion of laminar versus turbulent flow and the strict applica-
isolators often employ negative internal air pressure and tion of aseptic procedures during operations might be
most isolators use positive pressure for aseptic processing. irrelevant.
A sporicidal process, usually delivered by gassing can be The isolator and gloves are tested daily for leakage.
used to aid microbiological control. A gas generator delivers Airflow velocity if applicable is measured in-line with a
the gas (e.g. peracetic acid or hydrogen peroxide) via defined calibrated instrument. The pressure inside the isolator is
ducts [8]. checked continuously. Furthermore, gas detection in case
If the isolator is only used for non-hazardous products the gaseous disinfection is used.
exhaust air can be discharged into the background area. Before working the inside of the isolator has to be cleaned
However, commonly the air is discharged outside the and disinfected. Disinfection can be done with peracetic acid
building. or hydrogen peroxide, using special disinfection devices and
Some isolators have a modular construction for many procedures. For small scale or incidental use ethanol
different kind of applications. Sometimes an extra HEPA 70–80 % may be used as an alternative.
filter is built in, underneath the working surface. An isolator
may have no, one or two hatches, constructed as a lock. The
hatches may have their own HEPA filters and have a door to 28.4 Apparatus for the Production
the main compartment and another door to the background of Pharmaceutical Water
area. The isolator has an interlock system for the hatches to
prevent loss of air pressure. As an alternative for the hatches Water is the most important pharmaceutical substance. The
special isolator transport and loading boxes can be used with requirements to be met are being discussed in Sect. 23.3.1.
a tight (screw) fitting to the main compartment The equipment for storage and distribution (loop system,
(‘mousehole’). In practice the terms ‘open’ and ‘closed’ pump and storage vessel) is considered as a built-in installa-
isolators are used. In ‘closed’ isolators all materials are tion and therefore is discussed in Sect. 27.5.2. The develop-
inside the isolator during the gaseous disinfection and the ment of biofilms is discussed in Sect. 19.3.5.
aseptic handling is done without opening hatches or Pharmaceutical water (Ph. Eur.) is produced by a multi-
mouseholes. staged process using different techniques with different
28 Equipment 621
apparatus in series [9, 10]. In this section those different hypochlorite and acts as a disinfectant. All chlorine must
apparatus producing water with a pharmaceutical quality be flushed away thoroughly after the combined regeneration
are discussed, e.g.: and disinfection process.
• Water softeners The quality of the water will be controlled by means of
• Demineralisation apparatus based on ion exchange pressure and flow meters and by a hardness tester. The
• Apparatus for reverse osmosis hardness tester consists of an automated titration apparatus.
• Apparatus for electro-deionisation The reservoir, with combined titre and indicator solution,
• Distillation apparatus should be refilled regularly.
28.4.1 Water Softeners

28.4.2 Demineralisation Apparatus Based
on Ion Exchange
The water softening process removes most calcium and
magnesium ions from tap water. By doing so a downstream
Purified water (Ph. Eur.) can be produced from tap water or
placed apparatus, such as reverse osmosis, electro-
from pre-softened tap water by demineralisation. As this
deionisation or distillation apparatus, is protected against
production method easily leads to microbiological growth
the deposit of calcium and magnesium salts (’limescale’).
the product will not always meet the microbiological
requirements. Passing through a bacteria retentive filter
may render the demi-water compliant. However this treat-
The principle of a water softener is based on ion exchange
ment should be monitored because of micro-organisms
using synthetic resins. The synthetic resin has negatively
growing through the filter. Endotoxins will not be removed
charged functional groups with sodium as a counter ion.
by filtration.
Calcium and magnesium ions from the water are exchanged
for the sodium ions of the resin. Therefore, this type of water
softeners is called cation exchangers. See Sect. 23.3.1 for the 28.4.2.2 Description
hardness degrees. The resins pearls do not retain any other Ion exchangers can be applied both as a water softener (see
contamination such as solid particles. Sect. 28.4.1) and as a demineralisation apparatus. After
softening of tap water, calcium and magnesium ions have
28.4.1.3 Operating Procedure been removed; however any other mono and bivalent ions
PRODUCTION
Water softeners must be regenerated periodically. This (cations such as potassium and sodium and anions such as
regeneration involves the immersion of the resin, being nitrate, chloride, sulphate, bicarbonate and carbonate) have
saturated with calcium and magnesium ions, in a still to be removed in order to obtain Purified Water Ph. Eur.
concentrated sodium chloride solution (brine). This brine is This process is called deionisation or demineralisation. It
prepared and kept in a separate vessel. The calcium and proceeds at room temperature. Demineralisation apparatus
magnesium ions bound to the resin will exchange with the based on ion exchange consist of columns filled with several
sodium ions in the brine. After regeneration the brine varieties of synthetic resin pearls that remove unwanted ions
containing calcium and magnesium must be flushed thor- from the water by exchanging them for hydrogen and
oughly. Often the softening apparatus is provided with fully hydroxyl ions. The general principle is that all cations are
automatic regeneration equipment. In that case regeneration being exchanged for hydrogen ions and all anions for
will occur periodically or be triggered by an in-line hardness hydroxyl ions. Finally the recombination of hydrogen and
tester. hydroxyl ions results in pure water.
Larger installations for continuous water purification usu-
ally have two automated softening apparatus mounted in a
parallel arrangement. As soon as one of them has to be An ion exchange resin is a synthetic resin with posi-
regenerated an automated control system will switch that tively and negatively charged functional groups. The
water softener off. The other one will continue delivering demineralisation process (which might proceed over
soft water in the meantime. one combined or over separate columns) exchanges
Water softeners are a good substrate for bacteria. There- cations from the water for hydrogen ions from the
fore, apart from being regenerated, the system must be cation exchange resin and anions from the water for
disinfected periodically as well. Some (automated) softeners hydroxyl ions from the anion exchange resin.
can generate chlorine gas from the brine solution during Exemplified (s ¼ solid):
regeneration. This chlorine gas dissolves in the water as
(continued)
contamination such as solid particles. They constitute a

rather good substrate for the growth of bacteria; mixed
Naþ ðaqÞ þ RHþ ðsÞ ! RNaþ ðsÞ þ Hþ ðaqÞ bed systems are even more vulnerable. The investment
costs are comparatively low in contrast to the relatively
Any bivalent anion, e.g. sulfate, exchanges for high operational costs including regeneration. If the instal-
2 hydroxyl ions in a anion exchange resin. lation must produce Purified Water Ph. Eur. the
Two different types of anion resin are used for microbiological quality has to be monitored or the bacteria
demineralisation: weak basic and strong basic filter has to be changed frequently.
exchange resins. Both types exchange anions such as
chloride, sulfate, bicarbonate and carbonate for
hydroxyl ions. However strong basic exchange resins
can additionally exchange silicic acid and silicates for 28.4.3 Apparatus for Reverse Osmosis
hydroxyl ions.
The quality of demineralised water depends on 28.4.3.1 Application
several factors, such as the quality of the feeding An apparatus for reverse osmosis removes more than 95 %
water, the type of exchange resin, the quantity of of all ions and more than 99 % of all particles, colloids and
resin and the number of resin containing tanks. dissolved organic material including endotoxins. Neverthe-
In a mixed-bed demi-tank or column, cationic less the permeate still contains too much small, univalent
resins and anionic resins are thoroughly mixed in just ions to comply with the requirements for purified water
one container. The alternating cationic – anionic resin after one filtration step. Therefore, reverse osmosis is
pearls in one column can provide water of excellent often used as a preliminary treatment, preceding distillation
quality. A mixed bed column can achieve a water or demineralisation. The available reverse osmosis systems
quality with a conductivity of less than will only be economically feasible if a rather large amount
1 microSiemens/cm. of purified water is required. As an example reverse osmo-
Dual-bed demineralisation columns consist of two sis installations are being used, in combination with other
serially arranged containers, one with cationic resin purification methods, as a preliminary treatment in the
and one with anionic resin pearls. A dual-bed weak production of Water for Injections and in the production
basic demi-column delivers water with a conductivity of purified water for haemodialysis. Sometimes purified
of approximately 20 microSiemens/cm. A dual-bed water is prepared using just a series of semi-permeable
strong basic demi-column delivers water of approxi- membranes. Reverse osmosis has the advantage compared
mately 5 microSiemens/cm. to demineralisation that few chemicals are being con-
sumed. However, as the process does not involve any
heating, a substantial risk exists of microbiological con-
An ion exchange demineraliser has to be regenerated tamination and biofouling.
periodically by flushing the resin pearls with a highly
concentrated regeneration fluid. The type of regeneration
fluid depends on the specific type of ion exchange resin. 28.4.3.2 Description
Commonly a solution of sodium hydroxide or hydrochloric Reverse osmosis utilises semi-permeable membranes. The
acid is used. Afterwards, the regeneration medium has to be name "reverse osmosis" (abbreviated as "RO") uses the fact
flushed thoroughly and the ion exchanger can be reused that the osmotic pressure building up over a semi-permeable
again. Regeneration sometimes takes place at the site of membrane has to be overcompensated. In a reverse osmosis
the user, sometimes used columns are exchanged for process the water is forced by high pressure to flow through a
regenerated ones by the supplier. semi-permeable membrane thereby eliminating any particle
or larger ion, see Fig. 28.2.
RO membranes are designed to pass water through the
28.4.2.3 Operating Procedure intersegmental space between the polymer molecules. This
The quality of the water is controlled with conductivity space is wide enough to allow individual water molecules to
meters, pressure meters and flow meters. pass, but too small for any hydrated ions. Because the system
If the feed water contains a relatively high concentration has many additional surfaces beyond the membrane, on
of dissolved substances a dual-bed system is usually which undisturbed biofilms could built up, the prevention
preferred. If the feed water contains low concentrations a of microbiological contamination in a reverse osmosis sys-
mixed bed ion exchange demineralisation will be preferred. tem is a challenge. Biofouling is effectively limited by a
As said above for water softeners, the resins pearls in smart choice of materials and by avoiding blind angles,
a demineralisation column do not retain any other however still intensive control is mandatory.
28 Equipment 623
Fig. 28.2 Principle of reverse pressure

osmosis. Source: Recepteerkunde
2009, #KNMP
concentrated pure water concentrated purified

solution solution water
natural osmosis reverse osmosis
28.4.3.3 Operating Procedure 28.4.4.2 Description

Apparatus for reverse osmosis can function for a long time Electro-deionisation (EDI), also called continuous electro-
without much maintenance. The semi-permeable membrane deionisation (CEDI), is a special type of demineralisation.
should be replaced periodically because of ageing. The aver- The apparatus using this technique is equipped with
age lifetime of a membrane is 2–3 years. mixed resin pearls and selectively permeable membranes.
During the first start-up a balance has to be found between It functions by applying an electrical current fed through
the amount of water being produced as permeate and the resin and membranes. The feeding water will be normally
amount that is flushed away as concentrate. Usually an deionised by flushing through the resin. However, the "cap-
optimal result in water quality and quantity will be achieved tured" ions subsequently do not stick to the resin, but are
when approximately 10 % of the feed water is drained away being removed under the influence of the applied potential
as concentrate. By choosing a higher percentage the quality difference and drained through the selectively permeable
of the permeate might increase. However, this will have a membranes. The potential difference also splits a part of
negative impact on the yield of the installation. A lower the pure water into H+ and OH ions that regenerate the
concentrate percentage will decrease the quality of the resin at their turn, see Fig. 28.3.
permeate. The potential difference and the pH-gradient impede the
Most attention should be paid to the microbiological growth of micro-organisms additionally, but the risk of
PRODUCTION
quality of the water. Again a well-monitored bacteria reten- growth of micro-organisms still exists.
tive filter can be significant.
28.4.4.3 Operating Procedure
A (C)EDI-installation requires relatively limited mainte-
28.4.4 Apparatus for Electro-Deionisation nance efforts. To maintain the potential gradient a pure
sodium chloride solution has to be fed behind the selective
28.4.4.1 Application permeable membrane. This sodium chloride solution is
Electro-deionisation (EDI) is used in combination with other drained away with a part of the feed water. The stock sodium
purification methods. Electro-deionisation is applied to the chloride must be refilled regularly. The product water should
production of Purified Water Ph. Eur. or Highly Purified be checked for its conductivity.
Water Ph. Eur. Highly purified water may be used in the Tap water must be softened before being used as feed
haemodialysis department for in-line production of dialysis water. This water still contains micro-organisms and
fluids for continuous dialysis. EDI in combination with particles as well as quite a lot of minerals. Therefore, the
other techniques can be used for in-line dialysis, it requires water should be filtered as well. To achieve a stable and
thorough in process controls. A distillation apparatus, suit- reliable supply of the required water quality, it is common
able for water for injection, would not comply the large peak practice to apply a softening installation, a reverse osmosis
demand at dialysis unless equipped with a very large storage installation and a (C)EDI installation in sequence.
vessel and an extremely powerful (energetically unrealistic) The application of a firm potential difference in the water
cooling system. not just causes the migration of H+ and OH ions to the ion
Sometimes hospital pharmacies use an EDI installation exchange resin pearls, but leads to the generation of small
for the preparation of water for pharmaceutical non-sterile amounts of free hydrogen and oxygen gas as well. Therefore,
stock preparations. an effective degassing of the storage vessel containing the
Fig. 28.3 Principles of electro- supply of feed water

deionisation. Source:
ASM
ASM
CSM
CSM
Na+ Na+
Na+
Na+
OH-
H+ OH- H+
Na+
Na+
OH- CI- OH- CI-

H+
H+ OH- CI- OH- CI-

H+
Na+ H+
Na+
H+ OH-
cation
exchange
resin
anion
exchange diluate concentrate diluate
resin
ASM = anionselective membrane
CSM = cationselective membrane
product water is necessary to prevent the accumulation of these vapour is then condensed. However, even this method of
gasses which otherwise might cause an explosive mixture. purification cannot yield absolute purity. Even the highest
quality distillation apparatus will not be able to remove
100 % of all ions and endotoxins. It is commonly accepted
28.4.5 Distillation that a maximum of a log 3–4 reduction in the concentration
of impurities can be achieved. For this reason it is important
28.4.5.1 Application to put requirements on the quality of the feed water for a
With distillation chemically pure and sterile water can be distillation apparatus.
produced. Provided that any carry-over of water droplets is For small scale distillation a simple (single effect design)
effectively avoided, it can be relied upon that not just chem- water distillation apparatus can be used. For a middle or
ical impurities but micro-organisms and endotoxins as well large scale distillation stainless steel built apparatus are
will be removed. Distilled water complies to the constructed in a different way, using multi stage distillation,
requirements of being pyrogen-free according to the Water steam compression or thermo compression, to yield a much
for Injections Ph. Eur. monograph. higher capacity and a better efficiency, see Fig. 28.4.
To maintain the sterility and apyrogenity of the distillate In the past stainless steel was known for its release of
it is necessary to collect and store the water in a sterile and metal ions, but that is not the case any more in presently
pyrogen-free way as well. In larger installations this is deployed steel qualities. Nevertheless it is important to make
achieved by keeping the water in a storage vessel at least inquiries of the supplier about this.
at 80 C and by pumping it around in a loop in a turbulent A simple classical water distillation apparatus consists of
flow, see Sect. 27.5.2. a boiling vessel from glass, holding a heating element made
The sterility and apyrogenity immediately after the puri- of metal or quarts and fitted to a glass condenser. To reduce
fication process constitute the most important distinction water and energy consumption the feed water is first used as
with other purification methods. a coolant in the condenser or it is pre-heated with the aid of a
heat exchanger, see Fig. 28.5. The velocity of the vapour
28.4.5.2 Description carry-over is relatively small. Consequently the risk of
For distillation the feed water is heated to boiling. On the carry-over of any water droplets is small as well. In larger
evaporation of the water any chemical and microbiological apparatus specific measures have been taken to prevent this
impurities are retained in the boiling water. The pure water carry-over.
28 Equipment 625
Fig. 28.4 Multi stage outlet non condensable gases

distillation. Source:
Recepteerkunde 2009, #KNMP external
heating
steam
feed
water
cooling
water
supply
distillate
cooling drain condensate

water drain
drain
Provided a correct design and performance, distillation is heating lamp, water bath and microwave. Table 28.1
a very reliable process. However the apparatus does not summarises the qualities of various heaters.
tolerate being fed with tap water quality because calcium, Heating is based on three different physical principles:
magnesium and silicates would precipitate in the evaporator. radiation, conduction, and convection. All principles are to a
In addition volatile components from the tap water could higher or lesser extent present in the various heaters. In an
co-distil and condensate in the product water. Examples of ultrasonic bath, convection is promoted by means of high
those volatile constituents are trihalomethanes, ammonia frequency sound waves instead of heat.
and carbon dioxide. Therefore the feed water has to be Other important characteristics of the heating equip-
pre-treated. Purified Water Ph. Eur. is suitable as feed ment are the option of keeping the temperature of the
PRODUCTION
water. The chemical and microbiological properties of this object at a constant level, the option of simultaneous
water are defined unequivocally. Other non qualified water stirring, the heating velocity and the space that the appa-
should not be accepted as feed water for a pharmaceutical ratus occupies.
distillation apparatus. The energy costs are determined by the efficiency and the
heat transfer to and into the product. In general, the more
28.4.5.3 Operating Procedure conversions, the lower the efficiency. Compared to the
A distillation apparatus usually requires little operational energy that is required for heating and lighting of the
attention. Obviously regular maintenance is mandatory and premises, the energy usage of the heaters in the pharmacy
all measurement probes for temperature, pressure and con- is however quite modest. Differences in efficiency are there-
ductivity must always be calibrated. fore only described qualitatively.
The permanent exposure of the stainless steel to steam Differences in thermal conductivity of various materials
and ultrapure hot water might provoke the development of may play a role in the choice of a heater and the choice of
rouging. This phenomenon and its prevention is further the material of a heating vessel as well. A high thermal
discussed in Sect. 27.5.2.7. conductivity coefficient means a high conductivity, see
Table 28.2.
28.5 Ultrasonic Baths and Heaters

28.5.2 Ultrasonic Baths
28.5.1 Orientation
Heaters and ultrasonic baths are mainly used to increase Ultrasonic baths are used to increase the dissolution rate of
dissolution of substances. The most generally used heaters slowly dissolving substances, especially when a substance is
are: the gas stove and gas burner, electric heating plate, not very heat resistant.
Fig. 28.5 Singular distillation

column. Source: Recepteerkunde
2009, #KNMP
clean
steam
computer
separation
column
level
control
external
heating steam
heat exchanger
separation by
gravity
condensate
drain
feed water pump
drain
28.5.2.2 Description 28.5.2.3 Procedure

An ultrasonic bath contains water and creates waves from its The same precautions about the water quality should be
walls with a frequency of more than 20,000 Hz. A container taken with an ultrasonic bath as with a water bath for heating
(usually glass) with solvent and the substance to be dissolved purposes (see Sect. 28.5.5). Although ultrasound is not audi-
is placed in the water. The sound waves amplify in the water ble to the human ear, resonance tones are created within the
and pass, via the container wall, into the solvent. The pow- audible range, which are quite annoying. Therefore, ear
erful vibrations of the liquid increase the movement of protection and placement in a separate room are advised.
dissolved molecules from the surface of the crystals into
the solvent. This increase occurs at the micro level and
does not lead automatically to a homogeneous solution. 28.5.3 Gas Stove and Gas Burner
Therefore, the bulk of the solution should be stirred from
time to time. The ultrasonic bath may include a bath that 28.5.3.1 Application
may be equilibrated at a fixed temperature by means of an Gas stoves and Bunsen burners are used for quickly bringing
electric heating source and thermostat. to the boil water or aqueous solutions. However, accurate
28 Equipment 627
Table 28.1 Qualities of various different heaters

Heater Investment Energy consumption Speed Use space Thermostating Built-in stirring
Gas stove +
Electric heating plate + +
Heating lamp
Water bath +
Microwave
+ favourable, moderate, unfavourable
Table 28.2 Thermal conductivity of some materials 28.5.4.2 Description

An electric heating plate converts an electric current largely
Material Thermal conductivity coefficient (W.m1.K1)
directed through resistance wires into heat. A cast iron,
Copper 380
stainless steel, or ceramic plate conducts this heat to the
Iron 50
Stainless steel 20
container with the mass that should be heated. Ceramic has
Glass 1 a few advantages, since it is lighter, heats faster and can be
Water 0.6 cleaned more easily compared to cast iron. Compared to
Air 0.02 stainless steel, it conducts heat better. However, heating of
the plate requires time. The container should have a flat
bottom for optimal conduction of the heat. Most heating
plates can be adjusted to various levels of heating, which
allows control of the temperature within certain limits. The
adjustment of the heat input is difficult and it is not possible
heating plate can be combined with a magnetic stirrer, but
to set the temperature. Both a gas stove and Bunsen burner
do not take up a lot of space, but a gas supply is required. The these combinations have little stirring power. A heating plate
uses little space, but requires an electricity connection.
room should be well ventilated because of the open fire, and
An immersion heater consists of resistance wires embed-
no flammable liquids, vapours or gases should be present.
ded in ceramic material and mounted in a stainless steel
spiral. The immersion heater should be placed in the liquid
to be heated and is often connected to an immersion thermo-
The gas stove or Bunsen burner mixes natural gas with air
stat. For heating of large quantities the use of a container
to an optimally burning mixture. The tips of the flame
PRODUCTION
with a heating mantle is more efficient. The resistance wires
reach temperatures of 1,500 C. The produced heat is
are embedded in the mantle, thus the mantle conducts the
directed towards the container wall using a diffuser.
heat to the product.
Through the wall, conduction to the product occurs, in
Another option is the use of a heating tape or blanket that
which the heat spreads by conduction and convection.
can be wrapped around the container.
Domestic gas stoves or a Bunsen burner usually are com-
bined with a tripod. On top of the tripod, a metal gauze is
used, sometimes with a pressed ceramic core or ceramic
plate. The latter is the easiest to clean. The container 28.5.5 Water Bath
should have a flat bottom for the proper conduction of
the heat from the gauze or plate. 28.5.5.1 Application
The most important reason to choose a water bath for heating
purposes, is the controllability of the temperature, since this
28.5.4 Electric Heating Plate, Immersion Heater cannot exceed 100 C. Using a thermostat, the temperature
and Heating Mantle can be controlled at any temperature between room temper-
ature and 100 C. With a cooling unit, lower temperatures
28.5.4.1 Application are also possible.
Electric heaters can be applied in the same way as gas
stoves or Bunsen burners. Since these heaters have no open 28.5.5.2 Description
fire, they are generally safer. A negative aspect is that they A water bath consists of a tank that is equipped with heating
operate more slowly and have a lower efficiency. In gen- spirals with resistance wires, in which electricity is
eral, electric heaters can be better controlled than gas converted into heat. The tank is filled with water. The heated
burners, which means that overheating can be prevented water conducts the heat to the container with the product,
more easily. either by direct contact or through generated steam (‘boiling
water bath’). In principle, a water bath is equipped with a thus be heated more quickly than with other methods. Its
thermostat. The welds of the tank should be of good quality, main application in pharmacies is selective heating of water
otherwise leakage may occur as a result of calcification. The or another polar solvent when heating of the other
heating spirals are best embedded in the wall of the tank for compounds or phase is undesirable, such as:
the same reason. Tanks that consist of stainless steel can be • Drying of herbs and eradication of vermin that may be
used with purified water, which eliminates the risk of calci- present
fication. Purified water is too corrosive for less resistant • Drying and hardening of coatings
metals. The shape of the container is not important, since • Drying of granulates
both water and steam can cover non-flat surfaces well. • Regeneration of saturated silica gel being part of a
container
28.5.5.3 Procedure A short heating time may be advantageous and meaningful
The water bath should be filled to approximately two thirds because of a minimal temperature burden on the product.
of the volume with water. After incidental use, the bath
should be emptied and dried after to prevent microbiological
growth. When used daily, the water bath should be brought
A microwave converts electricity into electromagnetic
to 100 C half an hour before use, and subsequently brought
waves. The altering electromagnetic field sets molecules
to the desired temperature. Moreover, the bath must be
with a dipole, such as water, in motion. During this process,
emptied and dried at least once in 2 weeks.
friction heat is produced. The electromagnetic waves have a
frequency range of 100 to 1 million MHz, which
corresponds to a wavelength of 0.03–300 cm. The efficiency
28.5.6 Heating Lamp
of the conversion of electricity into electromagnetic waves is
approximately 50 %. The energy source (microwave) is
placed in a space (oven) with walls that are made of
A heating lamp may be applied for melting fats. Its advan-
e.g. stainless steel, enamel or aluminium, which reverberate
tage compared to a water bath is that a heating lamp bears no
the waves. Most ovens contain a metal fan as well. This fan
risk of bacterial contamination and contamination with
is not only meant to move the air in the oven, but also to mix
water droplets. However, the surface of the fats is exposed
the electromagnetic fields, in order to reduce the occurrence
to intensive radiation, to which the fat should be resistant.
of nodes and antinodes. These hot spots may nevertheless
Moreover, the heat transfer is not controllable and the risk of
occur as a result of the shape of the vessel in which it is
overheating exists.
heated, especially due to curved surfaces.
A heating lamp converts electricity through a resistance 28.5.7.3 Procedure
filament into electromagnetic waves. These waves produce For justified use of this heating method, the next points
radiation heat that is absorbed by objects. The lamp is placed should be considered:
above the substance to be heated; a wide container is pre- • The material that has to be heated and the container that
ferred for optimal heat transfer. The amount of heat cannot is being used should be permeable to electromagnetic
be regulated and depends highly on the distance from the waves. Glass and many plastics are, but metal (e.g. alu-
lamp to the product. The lamp heats quickly after it is minium foil) and melamine resin are not.
switched on. • The amount of energy that is required to heat the material
depends on the polarity of the substance. Heating of less
polar materials (such as paraffins) requires more energy
28.5.7 Microwave (thus for a fixed setting of the microwave: more time)
than polar materials.
28.5.7.1 Application • Microwaves penetrate about 3 cm into an object. There-
Microwaves can be used to heat polar substances directly fore, within larger masses the heat must be spread by
without the use of a medium such as air or water vapour to conduction, which requires time.
conduct the heat. Therefore, no energy is lost to the heating The inside of the oven must be kept clean, in order for the
of the heat source itself and only little to the container with surfaces to remain reflective. To prevent leakage of radiation
substance to be heated; the latter only heats up from heat the door must be kept clean as well and the closure must be
coming from the content. Especially small quantities can checked.
28 Equipment 629
for the smallest model; for the larger sizes it can be ordered
28.6 Grinding, Mixing and Dispersing as an optional feature. The larger sizes can be tipped over to
Apparatus facilitate the emptying of the bowl.
At maximum speed the mixer produces shearing forces at
Mixing and dispersing are the most used preparation methods, such an extent that they emulsify mixtures of water and oil.
see also Sects. 29.3–29.7. Mixing is achieved by axial, tangen- Only the rotor-stator mixer generates a higher shear force in
tial or radial flow. These concepts are clarified in Fig. 28.6 and fluids. During mixing an appreciable rise in temperature will
applied in the description of the apparatus. See Table 29.4 for occur, especially at higher speeds. If a mantle is available the
the terminology of grinding, mixing and dispersing. contents of the bowl can be heated or cooled. The applica-
This section discusses subsequently the Stephan® mixer, tion of vacuum is relevant if air must be prevented from
the rotor-stator mixer, the planetary mixer, the mortar with being whipped into the mixture.
pestle, the beaker mixer/blender, the three roll mill, the The centrally mounted shaft is provided either with two
coffee grinder, the Topitec® mixer and Unguator® mixers. stainless steel knives mounted in propeller position or with a
mixing vane. The high rotation speed of the knives or the
mixing vane down in the bowl results in an intensive mixing.
28.6.1 Stephan Mixer The mixing vane provides a tangential and radial flow and
additionally turbulence, See Fig. 28.7.
28.6.1.1 Application A plastic scraper, placed inside the bowl, facilitates
The Stephan mixer is a combined mixing and dispersing scraping down the mass from the wall of the bowl, resulting
apparatus. The brand name Stephan is used because of its in even better mixing.
specific construction and qualities. The apparatus can be The Stephan mixer requires a 380 V (3 phase) socket. The
used for the preparation of ointments, creams, emulsions, vacuum is realised with a small built-in vacuum pump. For
suspensions, gels, pastes, solutions, powder mixtures and the mantle a connection with a cooling water supply (usually
granulates. The apparatus was originally developed for tap water) and a drain is required.
food processing.
The mixer is not suitable for grinding of crystalline 28.6.1.3 Operating Procedure
substances. However, lumps and not too strong, large The constituents to be mixed are being fed into the bowl with
agglomerates can be broken up. For the mixing of powders the mixing vane or the knives. When mixing fluids, the
it should be taken into account that the shearing forces are fluid with the least density is preferably fed in at the bottom.
relatively weak compared to a mortar and pestle; they fre- A fluid with a higher density, fed in on top of a fluid with low
PRODUCTION
quently fail to break up agglomerates. density will generate already a beginning of mixing as the
heavier fluid will sink through the lighter one to the bottom.
28.6.1.2 Description The mixing bowl is closed with the lid, not only to shield
The Stephan mixer is available in different sizes, varying from splashing but also to be able to pull a vacuum as well as
from 5 to 40 L for small scale preparations. The choice for to fix the scraper that is mounted in the lid. If possible and
the size will, not taking into consideration the available desirable vacuum is applied subsequently. Mixing should
space in the pharmacy, depend on the volume of the batches. start at low speed to prevent splattering of unmixed
The vacuum version with a mantle is only a standard option constituents against the inner side of the lid. Subsequently
a higher speed is applied step by step. Depending on the
consistency of the mass and the rate of filling it may be
necessary to stir the mass in between by hand with a spatula.
Be aware that insufficiently mixed mass may splatter onto
the inner side of the lid. If emulsification is the objective the
mixing vane should run at maximum speed for at least one
minute. The precise adjustment of the apparatus depends on
the nature of the preparation, the size of the batch and from
the required sequence of adding the individual constituents.
These adjustments have to be validated.
The shaft with the mixing vane should be greased regu-
larly with a little soft paraffin. Additionally it is advisable to
mount a non-return vessel between the bowl and the vacuum
pump. This non-return vessel will collect any fluid that
Fig. 28.6 Axial, tangential or radial flow. Source: Recepteerkunde inadvertently could be sucked out of the bowl, keeping the
2009, #KNMP vacuum pump dry and clean. Should, however, some fluid
Rotor-stator mixers may be suitable for the preparation of

suppositories. For conditions see Sect. 11.5.3.
The rotor-stator mixer is a mixing and dispersing apparatus
consisting of an engine with an axis on which a rotor is
mounted. The rotor comprises a series of vertically placed
knives. The rotor turns with a very small tolerance inside the
stator comprising of a cylinder with slits. The rotor, spinning
at high speed, pumps the product through the slits of the
stator, see Fig. 28.8.
The mixer causes a tangential, a radial and an axial flow.
The mixing and dispersive effect are very intensive at the
moment that the product passes the mixing head. High
shearing forces that are required for dispersing, result from
Fig. 28.7 Stephan mixer. Source: Recepteerkunde 2009, #KNMP the narrow slits of the stator, the friction among the particles
in the fluid and from the reduced space between rotor and
stator.
The high shearing forces occurring during mixing cause
enter the pump, at least the pump should run a couple of a considerable amount of heat, and thus cooling may be
minutes ’dry’ to prevent erosion. However in this case it is necessary. However this heat can also be used for improving
better to demount the pump and clean and dry all its parts. the rate of dissolution.
Cleaning of the mixer seems to be easy, however this is
must done quite meticulously. Almost all parts can be
Optimal Speed and Mixing Effect
demounted and be cleaned separately. In any case extra
Increasing the spinning rate will raise the tangential
attention is necessary for several connection points, the
flow rate and thus extending the chance at creating a
thermometer, the inner side of the pressure gauge and the
vortex. Air will be sucked into the product and part of
inner side because they are provided with a rubber ring or
the added energy is lost in establishing the vortex. At a
contain a difficult cleanable screw thread. The apparatus
lower speed the chance of insufficient dispersive
does not contain its own drain, therefore the cleaning with
action and mixing exists. So the optimal spinning
soap water and the rinsing of the inner side requires a
speed is the one where a vortex just evolves. This
considerable amount of time.
could imply that the mixing effect in the body of the
The apparatus requires relatively little maintenance. For
product might be less intensive. Therefore, the volume
periodical servicing of the engine, the bearings, the vacuum
of mass determines the size of the rotor-stator mixer.
pump and the seals of the shaft a specialised mechanic is
The supplier gives rough outlines for this. As a rule of
necessary.
thumb the rotor-stator mixer can run effectively if one
third of the shaft is submerged in the product. If the
shaft is inserted too deep into the fluid the product
28.6.2 Rotor-Stator Mixer might be too close to the upper bearing with the risk
of contamination and damage to the engine. Some
28.6.2.1 Application models are provided with an overflow opening in the
The rotor-stator mixer is used for the preparation of upper part of the shaft. The fluid should not discharge
suspensions, emulsions and solutions. The apparatus is not from this opening. Anyhow the determination of the
suitable for mixing high viscosity fluids neither for any relation between amounts of mass to produce, the size
grinding of crystalline particles. For dissolving relatively and form of the mixing vessel and the choice of a
easily soluble substances it is easier to apply a mixer with rotor-stator mixer can only be achieved by validation
a mixing vane or a magnet stirrer instead. Keeping a suspen- of the mixing procedure. Additionally it could be
sion homogeneous during filling is better achieved with a considered to place the shaft slightly slanted or eccen-
stirrer with a well-designed mixing vane than with a rotor- trically in the vessel, or to move the vessel and its
stator mixer. The rotor-stator mixer is a dispersing apparatus contents up and down under the rotor-stator mixer.
in the first place, also suitable for breaking up agglomerates.
28 Equipment 631
Fig. 28.8 Rotor-stator mixer,

lengthwise section (a) and part of
cross section (b). Source:
28.6.2.3 Operating Procedure Next, the solid substances or fluids to be dispersed can be
To control the possible noise nuisance the rotor-stator mixer added; during this process the required speed might vary.
should be placed in a separate area (’noise room’). The Dispersing or mixing should be continued as long as is
operator should bear ear protection. determined by the validation process.
Products that are difficult to disperse or to moisturise
should be moistened in advance with a small amount of
Noise levels are expressed in dB(A), an abbreviation
fluid; after dispersing the remaining fluid should be added.
for decibel-A. This sound level is adjusted for the
When the mass is dispersed homogeneously the rotor-
frequency of the sound, because the ear is more sensi-
stator mixer should be turned off. Subsequently the shaft is
tive for high than for low tones. Damage to hearing can
pulled out and held above the product to drip dry. If neces-
occur from 80 dB(A). From this level the employer is
sary the shaft is wiped with a scrap card.
required to provide hearing protection. Starting from
85 dB(A) employees are required to wear hearing
28.6.2.4 Cleaning
protection. There are five types of hearing protection
To enable adequate cleaning the stator has to be removed
equipment. In increasing degree of effectiveness, these
from the rotor. Larger rotor-stator mixers are equipped with
are: cotton wool, earplugs, earplugs, earmuffs and ear
an extra bearing near the dispersing head to prevent the long
plastics. In the pharmacy equipment can be present at
axis from swaying. A seal, e.g. a ring that cuts off any fluid
which hearing protection is mandatory: some rotor-
from penetrating past the rotating axis, protects the bearing
stator mixers and tube closing machines. In the room
against the product. Seals are made from graphite or ceramic
PRODUCTION
where this equipment is used, there should be as few as
material. Seals made of graphite are preferred in blocking
possible people present during the preparation.
fluid penetration; however, they are more vulnerable.
Ceramic seals are much more expensive. The seal is the
Large rotor-stator mixers and the accompanying vessels most critical part as any product leakage, e.g. caused by an
should be solidly mounted. impairment during the cleaning process, will affect the bear-
The rotor-stator mixer must never run dry. Without fluid, ing. Moreover, serious contamination of the product itself
overheating occurs with risk of short circuits or affecting the will occur from bearing grease, mixed with rusty product
dispersing head. The rotor-stator mixer generates a relatively remnants, entering the product mass, past the seal.
high level of aerosols. To prevent the operator from expo- Cleaning should done immediately after use by allowing
sure to those aerosols, the upper side of the vessel could be the mixer to run in warm purified water with a small amount of
covered or placed under an exhaust. detergent. Subsequently the mixer should run at least twice in
Fill the vessel with the fluid in which other fluids or solid a portion of fresh lukewarm purified water, until the rinsing
substances are to be dispersed. Place the shaft at the correct water is clear and clean. This method is preferred if the rotor
height (e.g. 1 cm above the bottom) in the vessel. Switch on axis is equipped with an extra bearing near the dispersing head.
the engine and gradually turn up the running speed. Be After each cleaning process the adequate function of the
aware that switching on immediately at full power will seal should be checked, e.g. using a piece of filter paper to
raise strong reaction forces that might destabilise the plac- test leakage on the axis past the seal. Additionally a shaft of
ing. The fluid that is pumped by the rotor through the stator this type should be demounted periodically by a qualified
will be replenished at the down side of the head by hydro- mechanic to check on any leakage traces. Parts that cannot
static pressure. Sometimes, the fluid that is sucked up can be dried thoroughly after cleaning, e.g. because it is not
carry along the vessel which then might be sucked onto the suitable to demount the dispersing head, might be flushed
dispersing head. Therefore, the vessel should be kept steady with alcohol 70 %. Finally all parts should dry in the air.
with a firm grip with the free hand. Glass vessels might Drying in a stove or warm drying cabinet is not advisable
easily break when being touched by the spinning mixer. because this will also dry the bearing grease.
There are mixers available with a mantle to heat, cool or

Depending on manufacturers instructions an operator isolate the contents of the bowl. The choice of the vane
could demount the shaft. In that case all separate parts depends on the kind of product that is prepared. Most
are cleaned with soapsuds prepared from soap and hot products will be prepared using the vane with the anchor
water. However, soap entering the parts with bearings form (also called "K-arm"). The so-called whisk vane is less
should be avoided at any cost. Subsequently the parts suitable for fluid or semisolid products as this vane will
are well rinsed with purified water and dried with easily beat in too much air. To prevent splashing product
absorption paper. from the bowl during mixing some apparatus are equipped
with a lid or splashboard that will completely or partly close
off the upper side of the bowl.
Planetary mixers are available in different sizes, from
kitchen apparatus to small industrial machines. The choice
28.6.3 Planetary Mixer for the format of the mixer will, except from available space
in the pharmacy, depend on the batch volumes. The appara-
tus can be cleaned easily, because both bowl and stirring
The planetary mixer is used for the preparation of creams,
vane can be detached from the apparatus. A maintenance
ointments, emulsions, suspensions, gels and light viscous
agreement should be concluded, especially concerning
fluids. The planetary mixer is developed primarily for the
larger mixers.
food preparation and thus not especially designed for phar-
A relative disadvantage of planetary mixers is that they
maceutical preparations. The shearing forces during mixing
cannot run under vacuum. However, a good closing lid has
are considerably less than those of the rotor-stator mixer (see
advantages because it reduces the risk of microbiological
Sect. 28.6.2) and those of the Stephan mixer (see
contamination and of evaporation of water.
Sect. 28.6.1). This mixer therefore is not suitable for grind-
ing particles or to break up agglomerates.
The stirring vane is attached to the apparatus and a part of
28.6.3.2 Description the constituents to mix are transferred into the bowl. Fluids
The eccentrically placed stirring mechanism rotates around
with the lowest density are preferably placed at the bottom
its own axis. The axis also makes a rotating movement in the
of the bowl. When another fluid with higher density is
vessel. Therefore, movement of the stirring vane is the same
placed on top, its gravity will already start the mixing
as a planet that rotates around its own axis as well as around
process. Subsequently the mixer is switched on at low
the sun, hence the name planetary mixer, see Fig. 28.9. The
speed. The speed should then gradually be increased until
mixer causes mainly a tangential and a radial flow. The
the desired one. During mixing other constituents could be
mixing is very intensive.
added. The speed never should be turned up to such a level
that air is whipped in or the mass could spill over the rim
of the bowl. This risk can be limited by placing a lid or
splashboard.
In the case of viscous products the contents should be
released from the wall with a scraper by hand, because in the
immediate vicinity of the wall hardly any mixing takes place.
The mixing bowl and the stirring vane are usually cleaned
by placing them in a washing machine.
28.6.4 Mortar with Pestle
The mortar with pestle is a hand operated milling
(pulverising), mixing and dispersing apparatus. The mortar
is used for the preparation of ointments, creams, emulsions,
suspensions, gels, pastes, solutions, triturations and
granulates up to a scale that reasonably can be processed
by hand. The brass of bronze mortar is also used for crushing
Fig. 28.9 Planetary mixer. Source: Recepteerkunde 2009, #KNMP plant materials.
28 Equipment 633
28.6.4.2 Description a rule of thumb a rough mortar is used for pulverising

A mortar with pestle is a vessel widening to the upper side pharmaceutical substances. A smooth one is more suitable
and a thick rod with a club form at the end, the pestle, see for mixing and the breaking up of agglomerates.
Fig. 28.10. A scrape card used for wiping off the mass of the A melamine resin mortar is suitable for mixing and
wall is an essential attribute. A brass or bronze mortar breaking up agglomerates, but not for pulverising. Addition-
distinguishes itself from the standard mortar in that the ally this kind of mortars should never be heated over 100 C.
vessel usually is higher. Moreover coloured substances may give rise to difficult to
By shoving the pestle against the wall of the mortar a remove smudges. A supplier suggests that stains may be
milling and dispersing effect results. Mixing takes place in removed by immersing the mortar in hot perborate solution
primarily tangential direction. In semisolid and dry mixtures at 80–90 C.
a more or less axial movement results from ladling the mass A stainless steel mortar is suitable for mixing, not for
with a scrape card. This is hardly possible in fluid mixtures. pulverising. Additionally a stainless steel mortar lends itself
Triturations should regularly be released from the wall and for melting Hard fat for suppositories and fatty substances
shovelled around with a scrape card. Additionally it is useful for ointments and creams. If necessary this mortar can with-
to tap the mortar, held a little slantwise, against the table top stand rather high temperatures. As a pestle only a melamine
to recollect the powder. resin one should be used as a porcelain pestle might scrape
off metal particles from the wall.
Material Furthermore plastic mortars and pestles are commercially
The mortar is usually made of porcelain (’stone’ mortar’), available as a sterilised set. Disinfection and sterilisation of
melamine resin (’plastic mortar’) or stainless steel (’metal these kind of materials on a small scale takes validation and
mortar’). The pestle is made of smooth or rough porcelain or thus is inefficient.
of smooth melamine resin. When a pharmaceutical sub-
stance is ground in a mortar some losses may result from
The material of the mortar has a substantial impact on
’sticking’ to the wall of the mortar and the pestle or by being
the outcome of the preparation. An example is the
electrostatically charged and subsequently being drawn
preparation of Prednisone capsules 10–75 mg. In a
away by the air of any dust suction installation. Sticking to
rough porcelain mortar more substance ’sticks’ to the
the wall is most pronounced in rough porcelain mortars.
wall (3–5 %) than in a smooth one (2 %). Moreover it
Electrostatic charging is expected to be most substantial in
has been shown that preparation in a melamine resin
melamine resin mortars.
mortar causes losses resulting from electrostatic
Traditionally, a porcelain mortar has either a smooth or a
PRODUCTION
charging [11]. Using a stainless steel mortar results
rough inner wall. A rough inner wall facilitates a more
in no charging whatsoever.
forceful rubbing, resulting in more friction; shearing forces
However, any general conclusions on the relation-
then will be larger so a rough mortar is expected to be more
ship between the material of the mortar and the attain-
suitable for pulverising than a smooth one. On the other hand
able mixing quality are not possible.
pharmaceutical substances appear to stick more effectively
to a rough wall (’into the pores’). Therefore, a general
distinction in the effect of preparation in either a rough or
a smooth mortar cannot easily be determined in practice. As
For pulverising, a rough porcelain mortar with a rough pestle
is necessary; an excess of pharmaceutical substance is
pulverised and subsequently the prescribed amount should
be weighed. Mixing usually is done with a smooth porcelain,
melamine resin or stainless steel mortar. For mixing, the
mortar should be sufficiently wide to facilitate scraping the
sides and turning around the mixture. However, if the mortar
is too wide it will result in a higher rate of loss. It is obvious
that the total amount of constituents to mix will have an
impact on the mixing time. However no suitable practical
data on this issue are available.
If low dosed pharmaceutical substances, coloured
Fig. 28.10 Mortar with pestle. Source: Recepteerkunde 2009, substances or easily electrostatically chargeable substances
#KNMP are to be mixed in a mortar it is best practice to primarily
transfer a layer of bulking substance into the mortar, put the Sometimes mixing cross and mixing beaker are one
critical substance on top of that and finally cover it with entity; in other cases the mixing cross is permanently
another layer of bulking substance: the so-called wrapping attached to the engine block. Apparatus in which the mixing
method, see Sect. 4.5.1. If a porcelain mortar is rough and cross part can be detached from the engine are preferred
has large pores, the wall can be rubbed with excipient first, to because of the more easy cleaning of the mixing cross.
block the pores. This is not necessary when a mortar with a
smooth wall is used.
Mixing is achieved by stirring around the mass with the
The mixing cross part is attached to the engine. Subse-
pestle. The stirring should be interrupted regularly to scrape
quently the beaker is screwed on top of it. The constituents
the material from the wall with a scrape card. Powder
to mix are transferred into the beaker. The beaker may only
mixtures should be shovelled around regularly and also the
be filled up to half its volume as otherwise insufficient
mortar should be tapped on the table slantwise too loosen the
mixing will result.
powder. Agglomerates are being broken up by vigorously
To prevent splashing contents from the beaker it should
rubbing by a suitable means (see Sect. 29.3). This should
always be covered with a lid. Subsequently the mixer is
always imply small amounts, because otherwise vigorous
turned on. Sometimes it may be necessary to release the
rubbing is not possible.
mass from the wall with a scraper. When the mixing beaker
is detached from the engine block it is obvious that the
mixing cross part should stay in place to prevent the contents
28.6.5 Beaker Mixer/Blender from pouring out from the bottom. When the mixing cross
part is one entity with the engine block the contents must be
The blender may be used for small scale preparation of poured out before the beaker is detached. Extra attention
emulsions, suspensions and solutions. The apparatus is not should be paid to the mixing cross and the duct and the
suitable for grinding crystalline substances. bearings of the axis during the cleaning process.
The blender is a mixing and dispersing apparatus. At the 28.6.6 Three Roll Mill
bottom of the mixing beaker a mixing cross is situated
consisting of four knives; two of them lying horizontally or 28.6.6.1 Application
are placed slantwise to the bottom; a second pair are placed A three roll mill (or ointment mill) is used to disperse solid
slantwise upwards, see Fig. 28.11. substances in a semi solid or thick fluid base. The
The mixing cross also causes a tangential and a radial constituents themselves should be mixed homogeneously
flow and turbulence. During mixing a lot of air is whipped in advance.
into the mass and after long mixing the temperature will
increase.
A three roll mill may be used:
• When the product mass is too bulky to be handled
in a mortar.
• When the raw materials have ultra fine particles,
such as zinc oxide, precipitated sulfur and
substances indicated as ’micronised’ (see Sect.
23.1.8). These powders have a strong inclination
to form agglomerates. The three roll mill disperses
those agglomerates in the semi solid base into the
primary particles. After transferring through the
three roll mill the mass should be mixed again
(by hand or in a mixer) to distribute the particles
evenly over the whole mass.
• To clear away whipped-in air. During the mixing of
semi solid masses air is usually whipped in to some
Fig. 28.11 Blender. Source: Recepteerkunde 2009, #KNMP (continued)

28 Equipment 635
depend on the duration of the process and thus from the

degree. This might result in the inability to fit the batch volume.
required mass into a tube. With the three roll mill Transferring a product through a three roll mill will cause
the whipped in air is pressed out again from losses. So if the resulting mass is an intermediary product
the mass. used in another preparation process, this loss should be taken
If the transfer of a cream through a three roll mill is into account.
considered, it should be shown that the emulsion will
not break. Description Three Roll Mill Exakt®, Type 35
Resp. 50
Shiftable guides are used to adjust the working width if
small volumes are to be processed.
28.6.6.2 Description The rollers are subsequently adjusted to their
The three roll mill has, as its names already depicts, three smallest slit width (position I). A small volume of
rollers, usually made of ceramic material, having adjustable product is then transferred between the back and the
mutual clearances, see Fig. 28.12. centre roller. If the mass is not or difficult to transport
The mutual rotation speed of the rolls is, independent of the slit width is increased until the mass appears on the
the adjustments of their position, always different. Thus scraper plate. Subsequently the slit width is narrowed
when a semi solid mass with incorporated agglomerates are again as far as possible to maintain a minimum of
transferred between the rolls and subsequently are transport. This procedure will attain the highest possi-
transported from the slower to the faster roll, shearing forces ble shearing forces. With rotating rollers the rest of the
are being exerted on the agglomerates, breaking them up into mass is transferred either with a scrape card or a
the primary particles. spatula onto the back roller by wiping off in the oppo-
The distance between the rolls can be reduced up to a site rotation direction of the roller, or the mass is
minimum of 20 μm, thus principally enabling the grinding of transferred into the loading funnel.
crystalline particles to this size. Whether this is appropriate The processed mass is collected in a mortar and
should be determined for each individual product. Com- then again meticulously mixed.
monly preparations in the pharmacy will use raw materials To check the mass for any agglomerates, a couple
with the required particle size. of samples are randomly taken from the mass, flat-
At the end of the milling process the mass is removed tened between two glass slides and then assessed by
from the last roll with the mounted scraper. The scraper
PRODUCTION
examining it against light. If agglomerates are still
(drain board) is made of stainless steel or plastic. visible the mass is transferred once more through the
three roll mill.
In case of processing creams and other products that contain
volatile substances evaporation should be considered. This
evaporation might occur in an irregular way, thus
28.6.6.4 Cleaning
necessitating final mixing. The degree of evaporation will
The apparatus should be cleaned immediately after use. The
cleaning procedure has to be validated with a well designed
procedure based on a worst case situation. If cleaning of
a specific product or substance appears to be notoriously
difficult, the product may play a role in the cleaning valida-
tion. Cleaning starts with pulling the plug from the socket.
Also the funnel (if applicable) the guides and the scraper
are removed. All parts are cleaned (using detergent and
lukewarm water) and well dried. Subsequently the rollers
are adjusted to their greatest slit width (position III). The
rollers can be rotated by hand by means of a knob at the left
side. Never run the rollers, engine-driven, during cleaning.
The main part of remaining mass is then removed using a
Fig. 28.12 Three roll mill. Source: Recepteerkunde 2009, #KNMP tissue.
The cleaning of the rollers is done with a tissue drenched considered. If mixing is aimed at, it should be assessed if
with water in case of a water-soluble mass, or with a tissue the grinding and the temperature increase are acceptable and
drenched with liquid paraffin in case of a fatty mass. The if a homogeneous blend will result.
flanks of the rollers and the places just below them must not Additionally the possibility of dust explosions should be
be forgotten. considered. This is of special concern in a mixture of high
Finally the rollers should be wiped off and dried thor- concentrations of substances with elevated explosion risk.
oughly with another tissue. Usually substances of this type in the pharmacy are being
Ether or other inflammable organic solvents should never offered as ’phlegmatised’, which means that they are
be used for cleaning; Switching on the motor may elicit a premixed with excipients that extinguish their explosion
spark and cause a fire. risk (such as benzoyl peroxide hydrated 25 % water and
After cleaning the guides, the scraper and if applicable nitroglycerin with 40 % lactose).
the funnel, are mounted again. All parts should be
completely dry. Finally the apparatus should be covered 28.6.7.4 Cleaning
with a dust cover. The apparatus should be cleaned thoroughly to prevent any
At least once a year maintenance is required. cross contamination. This procedure should be validated.
Substances which dissolve slowly may play a role. A suit-
able procedure could consist of the following steps:
28.6.7 Coffee Grinder • Wipe the empty mill (including the knives) with tissues
drenched in water.
28.6.7.1 Application • Repeat this with tissues drenched in ethanol 70–96 %.
In some instances a coffee grinder might be used in the • Then let the grinder run with microcrystalline cellulose.
pharmacy to pulverise (coated) tablets to process them into The cellulose acts in this situation as a pharmaceutical
capsules. The application is contentious because the milling inertial cleaning powder.
process cannot be controlled very well and the cleaning
process cannot be validated either. The apparatus is
discussed because nevertheless in pharmacy practice 28.6.8 Topitec and Unguator
applications for the coffee grinder do exist. The only small
scale alternative for milling and mixing of powders is the 28.6.8.1 Application
mortar, having the drawback that fragments might spill from The Unguator and the Topitec are mixing apparatus for
the mortar and the result might not be fine enough. This is semisolid preparations. Mixing is executed inside the final
especially applicable for hard (coated) tablets. The coffee container, see Fig. 28.13. The mixing process can be
grinder may be used for mixing powders as well. It has the programmed after validation. During the mixing process
advantage, over hand-operated mixing, of being fast and the operator will hardly be exposed to substances.
intensive, although also segregation is reported to evolve
sometimes. A drawback however is that mixing may cause 28.6.8.2 Description
unintentional grinding and heating. A mixing disc or propeller is mounted to a bar driven by a
If a coffee grinder is used for one of the purposes stirring engine. The bar is guided through the lid of the
described it must be validated that this way of processing container or through the movable bottom. When placed
will actually yield a product that meets all requirements. inside the mixing vessel (final container) this mixer cause,
predominantly, a radial flow. Axial and tangential flow
28.6.7.2 Description should be created by moving the vessel up and down.
In principle the coffee grinder is a beating mill. Grinding is
realised by strokes of the knives that spin with high speed 28.6.8.3 Topitec
down in the milling space. A fine powder with a narrow Three types of the Topitec are available. The most simple
particle size distribution is provided. one is the Basic. The mixing vessel should be moved up and
down by hand, which precludes standardisation of the prep-
28.6.7.3 Operating Procedure aration method.
Reproducible milling and thorough cleaning are major The vertical movement in the type Automatic is executed
points of attention. The efficacy of milling depends on the automatically. The preparation programs (rotational speed
filling rate and the duration of milling, so this should be and mixing time) are adjustable and can be stored in a
determined and documented for each individual substance. memory. With the Automatic amounts up to 1 kg can be
Variations in starting material properties, losses by atomised produced and the apparatus can be cleaned easily. The
ultra fine particles and temperature increase should be movement in the type Touch is also executed automatically.
28 Equipment 637
The DAC/NRF [12] issues following guidelines:

• Never mix any coarse or fine crystalline substances with
the cream or ointment; just very fine pulverised, prefera-
bly micronised, solids or suitable concentrates (see Sect.
29.1.8) should be used.
• Stir if necessary the active substance intensely with a
small amount of base as a premix, comparable to the
first step in geometric dilution using mortar and pestle
(see Sect. 29.3.3).
• Apply the wrapping method: first transfer half of the basis
into the container, than add the active pharmaceutical
substance and finally introduce the rest of the base.
• Remove enclosed air as far as possible before mixing.
• If heating is involved stir gently and repeatedly within the
cooling-off time.
• Don’t process heat labile preparations.
Premixing in the container may be advantageous if insuf-
ficient homogeneity is obtained, especially when processing
of low concentrations. The active substance is at first mixed
with 5–10 % of the base and subsequently the rest of the
base is introduced. Another option is mixing at different
rotational speeds: first at about 500 rpm and then at a higher
speed.
Fig. 28.13 Unguator, schematic. Source: Recepteerkunde 2009, Some creams are known to lose viscosity by mixing with
#KNMP
this type of apparatus.
28.6.8.4 Unguator 28.6.8.6 Testing and Validation

Of the Unguator three types are available: B/R; e/s and 2100. Validation has been described in [13]. The risk of inhomo-
The B/R model requires moving the mixing vessel up and geneity is most prominent with more viscous bases and with
down by hand, which precludes standardisation of the prep- low dosed active substances.
PRODUCTION
aration method. Every formulation and batch size should be related to a
The vertical movement in the type e/s is executed auto- specific rotational speed and mixing time. These should be
matically. Rotational speed and mixing time are adjustable documented and their correct application warranted.
and programmable. With this type up to 500 g can be Samples should be taken from the most critical places in
produced in one process. In the type 2100 up to 1 kg can the container: near the nozzle, at the bottom and in the centre
be prepared and numerous preparation processes can be of the mixing disc or propeller. The centre of the mass is a
stored and reproduced for repeated execution. critical place as well: the mixing effect of the mixing disc or
propeller sometimes fails at that particular place.
28.6.8.5 Preparation Method Validation is best started with a limited number of typical
The suitability of the apparatus should be validated for each preparations. With experience from the results the range of
formulation and batch size. The following points of attention products can be expanded gradually. Colouring agents may
can be given, with reference to dispersion and mixing by be used to indicate homogeneity, however it cannot replace
hand with mortar and pestle (see Sect. 28.6.4, see also Sects. the analytical assay of content regarding active substances
29.2–29.7 on the basic operations on dispersing and mixing): with a variety of particle sizes or other properties. The
• Control of the product is not possible during processing. Topitec and the Unguator are mainly used for individual
The visual control of homogeneity in the final product preparations; a small overproduction could be used for con-
(and for instance the surface of the mixing disc or propel- tinuous validation.
ler) requires more attention.
• Physical stability may be challenged because of the high 28.6.8.7 Packaging and Shelf Life
rotational speed of the mixing disc or propeller. The mixing vessel is the container in which the product is
• Heating may occur due to mixing which may increase dispensed to the patient (see Sect. 24.4.7). This container is
degradation of heat labile substances and may cause not air and light tight which has to be taken into account.
supersaturation (see Sect. 18.1.6). Substances that are vulnerable to oxygen or light may
degrade. Products containing dithranol, tretinoin or

isosorbide dinitrate, therefore should be packed in alumin-
ium tubes immediately after the mixing process.
A series of container sizes are available. For the Unguator
type containers several attachments can be supplied,
i.e. cannulas for more accurate dosing. To push or screw in
the bottom of the container requires quite some force: this
will not work for all patients. The solution is then to pack in
aluminium tubes instead.
28.7 Filling and Apportioning Apparatus
When the bulk mass is ready it has to be divided into

portions with the quantity of one dose (capsules,
suppositories or powders) or one dispensing unit (bottles or
tubes).
This section will discuss subsequently:
• Filling apparatus for fluids
• Suppository molding apparatus
• Capsule filling and closing apparatus Fig. 28.14 Dispenser. Source: Recepteerkunde 2009, #KNMP
• Tubes filling apparatus
28.7.1 Small Scale Filling Apparatus for Fluids
Devices that are used to deliver a fixed volume per container
are called dispensers or filling pumps. Apart from these,
pumps are used e.g. to transfer the product from one vessel
to the other.
Fluids that are portioned out in a pharmacy usually are
solutions for external use and oral liquids. However,
emulsions, suspensions and light viscous fluids are also
being portioned out with dispensers or filling apparatus.
Apportioning of suspensions and emulsions always should
be executed under continuous stirring.
Fig. 28.15 Peristaltic tube pump (principle). Source: Recepteerkunde

28.7.1.2 Description 2009, #KNMP
The filling apparatus in the pharmacy usually is a dispenser
or a peristaltic tube pump, see Figs. 28.14 and 28.15. For
filling very tiny batches an injection syringe may be suitable • Parts that are in direct contact with the product should be
as well. designed for easy cleaning and drying and if necessary
Requirements for a dispenser or pump are: should be autoclavable.
• The dosing must be accurate, correct and reproducible. • Appliances such as hoses should be economically effi-
• The apparatus or tubing should not discharge any foreign cient in use.
substances or particles (this should be documented for
each apparatus).
• The apparatus, tubing or the filling process should not be 28.7.1.3 Dispenser
a source of microbiological contamination. A dispenser is a semi-automatic dosing and filling apparatus,
• The material that has immediate contact with the filled allowing fixed volume dosing by hand. The apparatus
product should neither adsorb nor absorb any substance. consists of a glass cylinder, in which a piston is mounted.
28 Equipment 639
The piston is moved up and down by hand. The stroke can be practice it can be a more or less pulseless, small or medium
adjusted to the desired dosing quantity. size bench top pump. It has manual or semi-automatic con-
The choice of the size will, apart from available space, trol. It has the principle of a positive displacement pump,
depend on the quantities that should be filled per stroke and used for dispensing a variety of solutions for oral, parenteral
from the desired filling speed. or external use and of different viscosities. They are easy to
Most dispensers may be designed for laboratory use install and after training simple to operate.
which might involve that general principles of hygienic For all pharmaceutical applications a hygienic design of
design are not or insufficiently met. So all parts should be the hose pump including hosing is very important to prevent
dismounted after use and be cleaned, rinsed and dried. For microbial growth in the tubing. For parenteral use membrane
critical applications a cleaning validation is required. filtration in the filling line is recommended to prevent for-
Maintenance is usually carried out within the department. eign particles entering the parenteral finished product.
However availability of spare parts is required. The heart of a hose pump is the rolling pump head.
Dispensers are available in different dosing ranges, Usually this will be a precision multi-roller pump head for
e.g. from (small volume) 0.4–2.0 mL, increasing to (large accurate flows. The fluid is being drawn into the pump,
volume) 300 mL. The material in direct contact with the trapped between two shoes or rollers and finally being
product usually consists of inertial glass (piston, cylinder) expelled from the pump. The complete closure of the hose
and Teflon® (nozzle, suction hose). Some dispensers are which is squeezed between a shoe and the track, gives the
made suitable for the dosing of aggressive fluids by a spe- pump its positive displacement action, preventing backflow
cific choice of materials. and eliminating the need for check-valves when the pump is
The product is transferred into a pharmaceutical grade not running.
holding flask of which the screw thread fits onto the dis- The operator has to place special pump head hosing or
penser from which a Teflon suction hose stretches to the special silicone dispensing hosing under the rollers of the
bottom of the flask. pump head. The tubing to be fixed in the pump head can be
The cylinder is stripped from air bubbles by pumping the either a separate short piece of special pump head tubing or it
piston a number of times. can be the tubing hose itself (in one piece). The pump head
The empty unit to be filled is placed under the plastic section divides the tubing in a suction part and a dispensing
nozzle. Thereafter, the adjusted volume is dosed by moving part. Fixating points in the pump head prevent the tubing in
the piston up and down by hand. the pump head from sliding and moving during pump action.
The pump head itself consists of several hard hose rollers
that revolve within a C-shaped recess in which the silicon
PRODUCTION
28.7.1.4 Peristaltic Pumps pump hose tightly fits. The rollers squeeze the pump hose by
Apart from the dispenser the peristaltic tube pump is rolling over, resulting in a peristaltic pump action with a
generally used as a filling apparatus for liquids. Lower suction effect. The rolling speed can be chosen by the oper-
pressure peristaltic pumps typically have dry casings and ator. At the suction side an extension hose made of a phar-
use rollers along with non-reinforced, extruded tubing. maceutical grade rubber might be attached to the silicon
This class of pump is sometimes called a ‘tube pump’ or hose to dip into the stock vessel. This extension hose should
‘tubing pump’. Pumps that work with higher pressure and be rigid to prevent it from collapsing during suction. The
(reinforced) hosing are called hose pumps. rubber material should be compatible with the product. That
This tube pump facilitates the automation of the filling extension hose must be autoclavable as well. This hose
process. The most simple model is actuated by a foot switch. should have a stainless steel notch at its end to prevent the
In more automated filling systems the empty container is suction hose from sticking to the wall of the vessel during
placed under an electronic eye, actuating the pump, to fill the suction. At the dosing side of the pump a compatible and
required volume. autoclavable hose is mounted with, at its end, a filling needle
Peristaltic pumps have no valves, seals or glands to leak, (nozzle) made of stainless steel, to be fixed in a holder above
clog or replace. the package to be filled. The filling needle can be sterilised
The pumped fluid does not touch the pump itself – it is in or cleaned and stored dry.
contact only with a high-pressure, flexible hose or tubing, Some special hose pumps are equipped with a double
thus eliminating the risk of the pump contaminating the pump head. This is to buffer the pulsing action by
fluid, or the fluid contaminating the pump. Maintenance is synchronising both pump heads in such a way that a more
confined to a periodic hose change, which takes minutes. steady flow arises at the filling process. A drawback is that
Peristaltic pumps can run dry, reverse their direction of flow, the assembling of such a pump configuration requires a lot of
and are self-priming. A tube pump is an example of a training of the operator and a good management of the
peristaltic pump for accurate dispensing. In pharmacy (sterilised) materials as well.
Per product the specific pump (tubing) parameters and • Documenting the use of every tubing in order to remain
any other adjustable variables should be well documented, within its shelf life
for instance pump speed, pump tubing specifications, type of Cleaning tubes after use requires, in excess of these require-
pump head and specifications of extension tubings for the ments, the validation of the cleaning process, which is prac-
suction side and for the dosing side. tically unfeasible.
Needles and nozzles should be cleaned very thoroughly
28.7.1.5 Pump Tubing regarding their tiny apertures. The effectiveness of the
Both the inner diameter and the wall thickness of the pump cleaning should be validated.
tubing are of great importance. The manufacturer supplies
obligatory guidelines. The supplier should deliver the tubing
in a well labelled box, with a clear description about 28.7.2 Suppository Molding Apparatus
diameters and application purpose. Per pump model a set
of tubing formats should be introduced, varying from large 28.7.2.1 Application
to small. The large ones dose more fluid per unit of time than Suppository molding apparatus are used to produce compar-
the small ones. atively larger batches of suppositories. In the pharmacy this
Only qualified silicone pump tubings should be used. Any will usually amount to 250–1,000 suppositories per batch.
tubing, not specifically designed for tubing pumps might The apparatus is denoted as hand-operated if the apparatus is
have a poor chemical and physical material quality soon just designed to keep a relatively large amount of supposi-
resulting in internal abrasion. This could lead to contamina- tory mass homogeneous and at the right temperature during
tion of the product and to inaccurate dosing. For the dosing molding. The actual dosing and placing of suppository
of parenterals some producers recommend the ‘platinum molds below the dosing point is hand-operated, in that
cured’ tubing. This rubber quality has a relatively low wear- case. If the dosing is executed automatically the apparatus
ing off of extractable components. is denoted as half-automatic. With a fully automated appara-
The tubings when mounted on the pump, should be tus also the transport of molds below the dosing point is
pre-rinsed with the product to be filled. This is to prevent automated.
dilution of the product by retained condensation water after
sterilisation and to saturate any possible adsorption sites. 28.7.2.2 Description
Pump tubings may easily adsorb substances, which could A Suppository molding apparatus (see Fig. 28.16) consists of
cause cross contamination or staining of the tubings. This the following components:
problem may be approached differently: • A double-walled metal or glass vessel in which the sup-
• By single use tubings pository mass is contained
• By using dedicated tubings • A water reservoir in the casing of the vessel which is kept
• By cleaning the tubings after use at the desired temperature by a heating coil and a
The single use of tubings seems to be quite expensive. thermostat
However it may be an acceptable option when put in the • A stirrer placed inside the vessel to keep the mass homo-
perspective of the efforts coming with both other options. geneous during molding
Using dedicated tubings requires: • A dosing point, equipped with a tap or an automatic
• Cleaning, rinsing and drying after use (or sterilising as a dosing mechanism, heated or not
more reliable process than rinsing and drying). Drying • A number of holders for strips of plastic suppository
may occur in drying hot air cabinets. The assessment of molds, optionally with an automated transport mecha-
the correct drying time however is not easy; as a conse- nism and a foot switch
quence tubings might stay too long inside the hot drying The calibration of the temperature probe and the accuracy of
cabinet. For sterilisation the best practise may be to let the the temperature adjustment of the suppository mass are
tubing drip dry after the last rinsing phase, as far as critical for the process. Additionally the cooling rate near
possible, subsequently wrapping it into a special the dosing point is critical as the mass might solidify
sterilisation-laminate pouch and finally steam-sterilise prematurely.
it. The steam will, by means of the vacuum pulses pre- The water reservoir is at an ideal temperature for micro-
ceding the sterilisation process, penetrate the tubing fully organisms to grow. Therefore effective measures should be
and sterilise it externally and internally. Verify the taken to prevent microbiological contamination. The
sterilisation temperature recommended by the producer indications in Sect. 28.5 apply.
of the tubing. This should be at least 121 C. The (half) automated apparatus, in principle, facilitate a
• Storage of a large pile of laminate pouches with packed, more reproducible method of working than hand operated
sterilised tubings and filling needles apparatus.
28 Equipment 641
Fig. 28.16 Suppository molding

and pouring apparatus. Source:
PRODUCTION
28.7.2.3 Operating Procedure 11.5. Dispersion of larger quantities of active substance is

Either suspension suppositories or suppositories with best performed by using a rotor-stator mixer, which cannot
dissolved active substances can be molded with the supposi- be executed within the suppository molding apparatus. An
tory molding apparatus. Preparation of suspension alternative way of dispersing is triturating the powder with
suppositories is the most common, however it is also the molten base in a mortar and add it to the rest of the molten
most critical process, as is discussed elaborately in Sect. mass in the apparatus vessel. The blade stirrer of the molding
apparatus is only suitable to keep the pre-dispersed supposi- Large scale capsule filling machines are not commonly
tory mass homogeneously during the phase of molding; no used in pharmacies. They may require a different design of
dispersion can be achieved. the powder mixture because the way of operating requires a
The mass should be mixed continuously during molding. better flowability.
A rotor-stator dispersing apparatus is not suitable for this If large batches of oral dosage forms are necessary, usu-
purpose as it whips air into the mass and its mixing is ally the production of tablets is considered. Tableting
insufficient. machines for relative small batches are commercially avail-
The shape of the stirring blade, the position of the stirrer able, e.g. Korsch XP1, Manesty B4, Optima 3000, Riva-
in the vessel and the stirring speed all have decisive impact Piccola.
on the efficacy of the mixing process. The stirring blade
should be placed as close above the molding drain as possi- 28.7.3.2 Description
ble. The stirrer should be pre-adjusted, and re-adjusted dur- A hand-operated capsule opening, filling and closing appa-
ing the molding, at such a speed that no air is whipped into ratus consists of a rectangular metal frame with below and
the mass [14–16]. above four horizontal plates, see Fig. 28.17.
A suppository molding apparatus should be subjected to The lower plate can be moved up and down relative
initial and periodical qualification and the molding process to the frame. The upper plate is mounted with a hinged
to validation. The precise method to execute the PQ depends transparent cover that can be fixed. The upper plate,
on the formulation and batch size. A worst case scenario as well as the middle plates, is perforated with 50–100
should always be defined and test processes should be holes for the capsules. Apparatus brands that are used fre-
executed with a suitable formulation. The test product quently are Capsunorm® (plastic type), Feton® (plastic
should be mainly examined on content uniformity, weight type), Loeco® (polycarbonate), Loetschert® (aluminium),
uniformity, and appearance. Optima® (aluminium) and Profill® (aluminium). The over-
all width of the holes depends on the capsule size. Each
apparatus is dedicated to a fixed capsule size. The holes
28.7.3 Capsule Filling and Closing Apparatus in the upper plate are tapered to the underside, so only
the lower halves of the capsules fall through, see also
28.7.3.1 Application Fig. 28.18.
The small scale preparation of capsules (see also Sect. 4.6.3) The holes in the two middle plates are smaller and have
is performed with hand operated capsule opening, filling and the same size as the smaller lower halves of the capsules.
closing apparatus for small batches. The lower middle plate can be moved slightly in horizontal
Per single batch a portion of 50, 60 or 100 capsules can be direction relative to the upper middle plate resulting in
prepared; larger batches can be made by reiterating the slightly displaced holes relative to each other. The lower
filling of the single batches. The production capacity per middle plate can be fixed in its shifted position by means of
hour is at maximum about 1,000 capsules. two clamp screws, thus fixing the lower halves of the
Fig. 28.17 Hand-operated

capsule filling and closing
apparatus. Source:
28 Equipment 643
1 2 3
a a
b b b
c c c
4 5 6
e
b b
c c
a
b
d d c
7 d
e a = upper plate
b = upper intermediate plate
a c = lower intermediate plate
b
c d = lower plate
e = cover
d
Fig. 28.18 Filling of hard gelatine capsules. Source: Recepteerkunde 2009, #KNMP
capsules and facilitating the separation of the upper halves 28.7.3.3 Operating Procedure
all at once. The preparation of hard gelatine capsules covers four steps:
The upper middle plate is equipped with an edge that insertion, opening, filling and closing, see Fig. 28.18.
contains the powder during its spreading over the plate. If less than the apparatus capacity of 50 or 100 capsules is
After filling of the lower half of the capsules the upper half being prepared, the unused openings of the apparatus should
is placed and the capsules are closed. be covered, for instance with tape.
If the insertion of loose capsules is done by hand, gloves
PRODUCTION
(unsterile) should be worn to avoid any contamination of the
Issues to consider at the purchase of a capsule filling
capsules. Wearing gloves is recommended anyway to avoid
and closing apparatus are, ease of use and
exposure of the skin with hazardous substances (see Sect.
sustainability. However apart from this there are addi-
26.4.3).
tional issues:
Insertion by means of a capsule sorting apparatus is
• Material of the plate sets; the plate sets are made of
executed, in principle, quicker and more hygienic, although
aluminium or plastic; plastic plates are not resistant
the apparatus does not always function flawlessly. Capsules
to hot water cleaning; the plates might warp easily.
arrayed on a card can be inserted quickly, hygienically
The process, cleaning instructions and the periodi-
and faultlessly. The card is placed, with or without an
cal assessment should be adjusted appropriately.
adapter, and using a little bar the capsules are pressed out
• The option of using capsules arrayed on card; the
off the card into the holes of the apparatus. A card may have
efficiency of these cards may outweigh its extra
the disadvantage that the choice of the capsule type itself is
costs.
limited.
• The option of the use of a capsule sorting apparatus;
this is an empty capsule “orienter” to drive the
capsules in the right position. 28.7.3.4 Cleaning
• A tamper, powder spreader or disposable plastic After use the apparatus must be cleaned thoroughly to pre-
powder spreading card might be practical for pow- vent cross contamination. The upper plate and both middle
der distribution and filling in some cases; however plates are removed from the frame. The plates should be
be careful: the use of these and other devices must cleaned with a soap solution. Plastic type plates may not be
always be standardised and validated. Otherwise resistant to hot water as is the case with the Capsunorm and
the process might not be reproducible enough. Feton apparatus: the water temperature should not exceed
40 C.
All parts are rinsed with clean water subsequently; if the

hardness of the water could result in scaling, purified water is When examining the test results the outcome not
to be preferred. Drying should be done using a clean, only depends on the quality of the apparatus but also
non-fluffing cloth or piece of tissue paper. on the experience of the operator.
The apparatus should dry further in the air, possibly near It is also possible to document the operator qualifi-
a heater or in a stove. The Capsunorm and the Feton appara- cation for the preparation of capsules using a
tus may only dry in air. pre-approved apparatus.
The apparatus support is cleaned by means of a moist
cloth.
Frequent maintenance is very important for the prepara-
tion of good quality capsules. By the frequent tapping of the
apparatus onto the worktop or by a too rough (warm) way of
28.7.4 Tube Filling Apparatus
cleaning, the apparatus can easily be dislocated or the plates
The filling of tubes can be executed by hand, with simple
could warp. As a consequence the upper rim of the lower
tools and with larger apparatus. The following tools and
halves of the capsules might not align everywhere with the
apparatus are described:
upside of the upper middle plate. This can be detected by
• Polypropylene film or paraffined weighing paper plus
careful visual inspection.
spatula (filling by hand);
• Piston-cylinder apparatus, simple (for a few dozens of
A regular test to assess whether the capsules apparatus tubes);
still works correctly is described below: • Piston-cylinder apparatus with hand wheel (dozens to
• Insert empty capsules in the apparatus and remove hundreds of tubes);
the upper halves; • Apparatus with a pumping mechanism (larger batches;
• Check if the upper rims of the lower halves level not discussed in this Chapter).
exactly on or at the most a fraction of a millimetre
below the upside of the upper middle plate; 28.7.4.1 Polypropylene Film or Weighing Paper
• If the alignment is not levelled, e.g. by the frequent Application
tapping of the apparatus onto the worktop, the Propylene film or weighing paper is used to fill an amount of
lower plate should be adjusted. At the Capsunorm ointment or cream into a tube by hand by pushing the
and the Loetschert-apparatus this is done by means substance with a spatula into the tube.
of setscrews at the legs, using a small key or not.
For the Feton-apparatus the legs have to be Operating Procedure
unscrewed followed by placing extra rings at the The chosen amount of ointment or cream is put onto the film
hexagonal parts of the legs; like a sausage. The film is rolled around the ’sausage’ sub-
• After adjusting, the apparatus is assessed for its func- sequently and the whole is slid into the tube. After flattening
tioning by the preparation of a batch of 60, respec- the open end of the tube firmly with a spatula the film is
tively 100 capsules with, for instance, pulled out of the tube again. Film is preferred over weighing
microcrystalline cellulose. Subsequently the relative paper with creams and water containing ointments, as paper
standard deviation and the mean of weights of the could attract too much water. For closing the tube neatly a
content of the capsules is determined. If the relative pair of tube squeezing pincers should be used.
standard deviation exceeds 1.5 %, or the deviation of
the mean of weights from the theoretical weight Operating Procedure for Aseptic Preparation
exceeds 1.5 %, the functioning of the apparatus Filling of e.g. eye creams should be carried out aseptically.
should be investigated. The variation of weights of See Sect. 12.7.3 for the preparation method including
the empty capsules should be taken into account; filling of tubes with a syringe. If the filling has to be done
• Results should be logged on a maintenance card, a by hand the polypropylene film is preferred as this can be
logbook or in a journal. steam sterilised. The drawback of this filling method is the
If the apparatus is dislocated, capsules will be filled relatively large risk of direct or indirect contact of the product
irregularly and a too large a variation of weights is the with the hands of the operator. Additionally at the filling of
result. In that case the position of the lower plate more than one tube each portion must be weighed onto the
should be re-adjusted. Subsequently the test should film. This requires the placement of an electronic balance in
be re-executed. the LAF-workbench, with special attention to aseptic working
with this in the laminar airstream (see Sect. 28.3.5).
(continued)
28 Equipment 645
the cylinder. For this reason the apparatus is less suitable for
transferring small quantities (<50 g) into a tube.
For several tube sizes adapters and screw joints are avail-
able, however the cannula of an eye cream tube is too narrow
to press the cream into the tube. This problem can be solved
by mounting a (metal) filling pipe onto the cylinder over
which the rear side of the eye cream tube fits. Consequently
the tube will be filled from the open end. This kind of filling
pipe is available. To monitor how far the eye cream tube can
be filled, a mark should be applied.
28.7.4.3 Piston-Cylinder Apparatus with Hand

Wheel
Application
Fig. 28.19 Schematic drawing of a piston-cylinder apparatus The piston-cylinder apparatus with hand wheel is suitable for
some dozens to hundreds of tubes per batch, see Fig. 28.20.
28.7.4.2 Piston-Cylinder Apparatus, Simple

Application Description
The piston-cylinder apparatus is suitable for the filling of The piston-cylinder apparatus is made of stainless steel. It is
some dozens of tubes, see Fig. 28.19. available in sizes/volumes of 1–3 L, with tube filling pipes
for several tube-opening sizes, see Fig. 28.20.
Description
The piston pushes the mass through the threaded opening of Operation Procedure
the cylinder into the empty tube screwed on top of that. The The cream or ointment is transferred into the cylinder-
synthetic material is resistant against almost all ointment shaped vessel. By bringing down the piston using the hand
ingredients, though not against long-lasting contact with wheel the cream or ointment is pressed into the tube which
most organic solvents. Phenols, tar preparations, alcohol has been slid over the outflow opening. At the filling pipes
PRODUCTION
and acetone do not affect the material. The apparatus can ring marks are applied to provide equal filling of the tubes,
be steam-sterilised (15 min at 121 C). see Fig. 28.20.
During cleaning the bleeding valve in the piston should
always be demounted as well.
Operation Procedure
Using this apparatus requires less operator experience and
skill than the hand operated method with film or paper,
however cleaning requires much attention.
First the right amount of product must be brought into the
cylinder. Especially with the handling of thick masses atten-
tion should be paid to avoid the introduction of air bubbles
during filling, as in that case insufficient ointment will be semi solid product
filled into the tube. This can be achieved by tamping down
the cylinder with the mass several times during the filling.
While handling masses with a thin consistency, a closing cap
should be placed on the cylinder opening during the filling tube
process to prevent leakage. When the consistency is too
thick it can be an awkward task to push the mass through
the neck of the tube.
The loss remaining after one filling procedure depends on
the used amount and the type of mass and usually ranges from
3 to 7 %. During stock preparation this should be taken into Fig. 28.20 Schematic drawing of a piston-cylinder apparatus with
account by weighing in some 5 % excess at the first filling of hand wheel. Source: Recepteerkunde 2009, #KNMP
program and the nature and quantities of detergents and, if

28.8 Cleaning Apparatus (Dishwasher) applicable, neutralising products, should be documented in
advance to guarantee a clean product.
28.8.1 Application Validation of the cleaning process has to be done before
operating. As difficult to clean objects utensils contaminated
A washing-up machine is used to clean all utensils with zinc oxide paste (if desired with 3 % brown iron oxide)
(implements and parts of preparation apparatus) which have can be recommended. The validation should be repeated
such a form and dimension that they fit into the washing-up periodically, e.g. yearly, or at any time utensils are not
machine and can be placed in such a way that all surfaces will clean after washing up or when new utensils are introduced.
be reached by the detergent solution during the washing Results should be documented.
process. Additionally the utensils must be resistant to the For adequate cleaning an alkaline detergent is necessary,
treatment, the cleaning temperature and the used detergents. preferably designed for laboratory use. Household agents
will not always clean sufficiently [17]. The detergent must
be dosed in accordance with the initial validation tests.
28.8.2 Description Prior to use, the sieves must be checked on possible
residues of the proceeding run. Utensils must be placed in
A professional washing-up machine will achieve the such a way that water from the spray nozzles will effectively
following: hit the dirty parts. In general, this means that the most
• Mechanical removal (along with destructive effect of heat) contaminated part should be directed downward.
of micro-organisms, however this is not a sterilising cycle Utensils with hollows or cavities should be placed in a
• Removal of nutrients for micro-organisms slanted position otherwise water cannot drip off. High and
• Removal of remainders of any products narrow utensils should be placed directly over the spray.
In general mechanically cleaning and rinsing is the pre- Loading procedures are necessary to put utensils in the
ferred method because it is easier to be standardised. Visible machine that either have difficult to access places or aren’t
product residues are best removed by hand using absorbing resistant to the temperatures or chemicals in the machine.
paper. Vulnerable utensils should not be placed against
The machine washing-up cycle consists of pre-rinsing, other ones.
cleaning, post-rinsing (several runs, the last of them prefera- To guarantee an adequate cleaning the machine should
bly using purified water) and drying. A professional not be overloaded. Neither objects should contain any caked
washing-up machine should have a built-in dryer. Further- dirt, which should be removed by pre-cleaning any residues
more the water temperature of the main program should be directly with absorbing paper and by enforcing the
65 C or higher. pre-cleaning hold time. This pre-cleaning also prevents the
Some professional washing-up machines log the cleaning sieves of the machine from clogging.
and rinsing process parameters. The correct operation (program choice, dosing of
detergents and neutralising agents, logging of runs) should
be incorporated in an operating instruction. This should
28.8.3 Operating Procedure include the instruction that after every run each utensil is
checked for its cleanliness and dryness. The washing-up
The removal of visible product residues should preferably be machine should preferably not be started at the end of a
done immediately after the preparation process and the Friday afternoon because in that case any water residue
mechanical cleaning should be done within one day. This will remain in place for a couple of days, increasing the
so-called ‘pre-cleaning hold time’ should be assessed in risk for microbial contamination.
advance and be warranted in practice. After all, residues
that are left during a longer time might be hard to remove
effectively by a standard cleaning process. Additionally 28.9 Apparatus for Cooled Storage
micro-organisms may grow.
A load scheme should be available in order to clean the 28.9.1 Application
utensils in a standard way. So called rinsing shadows must
be prevented: surfaces which aren’t reached during the Cooled storage (refrigerators, cold stores and freezers) is
cleaning process because they are covered by other objects. necessary in every pharmacy. For some medicines,
The load scheme should also prevent placing objects in such e.g. certain vaccines, a common refrigerator is not suffi-
a way that upward situated cavities collect rinsing water that ciently specified. The pharmacy refrigerator for licensed
will remain. The load scheme, the chosen washing-up products is part of the so-called cold chain, see also Sects.
28 Equipment 647
36.9 and 37.3. The producer or wholesaler usually will store All measurements can be executed in two different ways:
medicines that should be kept ’cool’ in large cold stores with • Using minimal two calibrated minimum/maximum
a temperature control. The cold chain should warrant that thermometers or
storage conditions will be maintained during transport and • Using a calibrated temperature-data logger.
temporarily storage. The use of calibrated electronic temperature-data loggers
have many advantages over the use of minimum/maximum
thermometers as the course of the temperature over time can
28.9.2 Description be measured and recorded.
Some data loggers are able to indicate whether the tem-
A pharmacy refrigerator should maintain a temperature of perature fall below 2 C or rises over 8 C by a light signal.
2–8 C. A freezer has a temperature of 18 C as maximum.
No standard applies for a minimum temperature. However it
The refrigerator can be used after the correct function-
might be useful to define some minimum temperature,
ing has been established.
e.g. 30 C, because a lower temperature can indicate a
Criteria for approval are:
malfunction.
• All measured temperatures have to be between 2 C
A refrigerator without internal freezing compartment will
and 8 C, both in the empty and in the three-quarter
best meet the temperature requirement of 2–8 C; next to a
filled refrigerator;
freezing compartment a temperature zone below 0 C might
• Minimum and maximum temperatures, measured at
arise. Automated thawing is undesirable as well if the refrig-
one location, should not vary more than 6 C;
erator has only one evaporator, because this will raise the
• The measured mean minimal temperature should
temperature every now and then to have frozen moisture
not differ more than 6 C from the measured mean
thawed and drained away. A good refrigerator is provided
maximum temperature.
with forced air circulation to achieve an even temperature
If these criteria are not met, arrangements should
and with a thermostat to control the temperature at 4 C.
be made and subsequently the measurements of
Some refrigerators are equipped with specific provisions for
temperatures and temperature-differences should be
monitoring. Other have an external temperature display or a
repeated.
logging function.
The thermostat adjustment to achieve the correct
If there are several refrigerators placed together in one
functioning should be documented.
room it is advised to connect them to different electricity
groups to diminish the consequences of any failures.
PRODUCTION
If the stock of cooled products requires considerable
space it should be decided whether several refrigerators or
28.9.3.2 Use
one cold store is preferred. Several refrigerators usually
Relevant points in the use are:
are energetically less favourable then a cold store. How-
• The control of cooling provisions need continuously
ever in case of a failure of one refrigerator it might be an
attention. Household provisions are not sufficient.
advantage to have spare capacity in the others. In a cold
• Current interruptions or a failure in the closing of the door
store the risk of failure might be abated by installing a
might cause unacceptable deviations of the temperature.
redundant pair of compressors. A cold store should be
• The refrigerator should never be filled for more than three
installed, validated and controlled in a similar way as a
quarter of its capacity. This filling rate leaves sufficient
refrigerator.
space for an adequate air circulation, providing a homo-
geneous temperature distribution.
• Product should not be placed against the back wall; this
28.9.3 Operating Procedure
disturbs the air circulation and, in case of an automatic
thawing refrigerator, ice might built up against the
28.9.3.1 Installation
back wall.
The instructions of the manufacturer should be followed
carefully. Usually this means that a stabilisation time should
be observed of 24 h after initial installation or after a removal. 28.9.3.3 Cleaning
Then, after switching on, the temperature and the mutual For cleaning no scouring agents or alkaline detergents
temperature differences should be measured at a sufficient should be used as the plastic parts might be affected. By
number of different places in the empty refrigerator. cleaning each shelf individually it is possible to keep the
Subsequently these measurements are to be repeated in a contents of each shelf or drawer cool during cleaning. The
three-quarter filled refrigerator, again at a number of places contents can be stored temporarily on a different shelf or in
according to a comparable scheme. another drawer.
Another possibility is the use of a cool box; in that case

direct contact of the product with the freezer packs should be Several causes of failure can be discerned:
avoided to prevent any local freezing. The freezer packs • The door does not close very well or has been left
belong in the upper part of the box, preferably inside the open for a prolonged time (the most common inter-
lid, because otherwise the temperature inside the box will ruption of the cold chain in community pharmacies
not fall below 15 C. seems to be caused by an open door).
• The thermostat is not adjusted correctly.
• A power failure has occurred.
28.9.3.4 Thawing (for Non Automatic Fridges) • The refrigerator does not function well: e.g. a spe-
The timing and frequency of thawing of the refrigerator is cific part has broken down (thermostat switch, ven-
determined by the thickness of the ice built-up onto the cooling tilator, automatic thawing mechanism or
elements. With a thick ice sheet it takes considerably more compressor failure).
energy to cool. However thawing and cooling costs energy as A temperature calibration should be executed each
well. A rule of thumb for thawing is to do it when the ice sheet time any doubt has risen about the temperature.
has grown to 1–2 cm. Another possibility is thawing with a The consequences of a failure to the product are
closed door. In that case the contents are kept in the refrigerator. based on the maximum temperature and the duration
Leaking meltwater should be collected in such a way that the of the failure. The duration of a power failure can be
products remain dry. A drawback is that cleaning cannot take retrieved from the energy company. Producers of
place at the same time. Finally it can be considered to remove licensed medicines usually have specific information
all products from the refrigerator and stack them in a cool place to assess the gravity of the interruption of the cold
wrapped in isolating material such as a woollen cloth. The low chain.
temperature can be retained for some time in this way. It is suggested to investigate the increase of the
temperature in some situations in order to have an
indication of the possible damage when disturbances
28.9.3.5 Monitoring
have occurred:
The required temperature should be verified continuously.
• A power interruption of at least 12 h.
The temperature can be recorded continuously using two
• A defective thermostat while the ventilator keeps
temperature sensors. One of these has to be placed in the
running.
coldest place and the other in the least cold place, which are
• Leave the door ajar 1 cm for at least 12 h.
determined during validation. The use of only one moveable
Measurements best be executed in a closed, empty
temperature sensor can be justified if the temperature
refrigerator as a worst case in relation to the rate of
differences in the refrigerator are almost negligible at the
temperature increase.
several measurement places.
The temperature sensor used to control and monitor or
both is preferably placed in a holder, e.g. in a little cardboard
box or better in a vial filled with glycerol. By this method the As a preventive measure the purchase of an emergency
reaction of the sensor to the opening of the door can be buff- power supply might be considered. This could consist of an
ered. Electronic data loggers can provide continuous recording. apparatus with a back-up time of e.g. 8 h, producing 230 V
Pharmacy employees have to check the temperature every from closed gel batteries, built-in into the refrigerator or
time they open the fridge and proceed in accordance with alert installed outside of it.
and action levels of the temperature. By this procedure any
failure during operating hours can be detected easily. How-
ever the connection of a cooling system to a building control References
system raising an alarm any time the temperature fails to stay
within its prescribed boundaries is to be preferred. 1. Health and Safety Executive (2011) Controlling airborne
contaminants at work. A guide to local exhaust ventilation, 2nd
edn. http://www.hse.gov.uk/lev/index.htm
Procedure in Case of Failure 2. Health and Safety Executive (2009) The technical basis for COSHH
Failures can arise by any break down of the refrigera- essentials: easy steps to control chemicals. www.coshh-essentials.
tor (e.g. power failure). A failure is defined if the org.uk/assets/live/CETB.pdf
3. Health and Safety Executive (2003) COSHH Fume cupboard, engi-
temperature rises (has risen) over 10 C or fall (has neering control, sheet 201. http://www.coshh-essentials.org.uk/
fallen) below 2 C. assets/live/g201.pdf
4. EN 14175-4 Fume cupboards on site test methods
(continued)
28 Equipment 649
5. EN 12469 Biotechnology – performance criteria for Neues Rezeptur-Formularium (NRF). Govi-Verlag Pharmazeutischer
microbiological safety cabinets Verlag GmbH Eschborn. Deutscher Apotheker-Verlag, Stuttgart
6. Eudralex. Volume 4. Guide to good manufacturing practices for 13. Wagenaar HWG, Dessing WS, Joosten AAM (2008)
medicinal products. http://ec.europa.eu/health/documents/ Mengapparaten Topitec en Unguator vergeleken met handmatige
eudralex/vol-4/index_en.htm bereiding van dermatica met hydrocortisonacetaat. PW
7. General Chapter <800> Hazardous drugs – handling in healthcare Wetenschappelijk Platform 2(8):170–174
settings. (draft). 2014. http://www.usp.org/usp-nf/notices/ 14. Cox HLM, De Kind LAP, Vink-Stephan JJ (1979) Onderzoek naar
compounding-notice gelijkmatigheid van de verdeling van het geneesmiddel over
8. Midcalf B, Mitchell PW, Neiger JS, Coles TJ (ed) (2004) Pharma- zetpillen bij gebruik van een zetpillengietapparaat IV. Het ROWA
ceutical Isolators a guide to their application, design and control. zetpillengietapparaat. Pharm Weekbl 114:811–815
Pharmaceutical Press, London 15. Cox HLM, De Kind LAP (1978) Onderzoek naar gelijkmatigheid
9. Collentro WV (2007) Pharmaceutical water, system design, opera- van de verdeling van het geneesmiddel over zetpillen bij gebruik
tion and validation. Informa Healthcare, Richmond van een zetpillengietapparaat I. Pharm Weekbl 113:364–368
10. ISPE Water and steam systems Baseline guide. ISPE, 2011 16. Cox HLM, Holthuis JJM, De Kind LAP (1981) Onderzoek naar
11. van de Poll MAPC, Jelsma RBH, Lukkien M, Boeke AW (1992) gelijkmatigheid van de verdeling van het geneesmiddel over
Mortier dichtwrijven, een mythe? Pharm Weekbl 127:258–259 zetpillen bij gebruik van een zetpillengietapparaat V. Het GPI
12. I.6. Dermatika – Zubereitungen zur kutanen Anwendung. I.6.3.2.1. type H250 zetpillengietapparaat. Pharm Weekbl 116:1101–1104
Alternative Herstellungstechniken. Halb- und vollautomatische 17. Cabaleiro J (2004) Automatic dishwashers and detergents in the
Rührsysteme. Fassung 2014/1. Deutscher Arzneimittel-Codex/ pharmacy: the basics. Int J Comp 8:200–202
PRODUCTION
Basic Operations
29
Herman Woerdenbag, Małgorzata Sznitowska,
and Yvonne Bouwman-Boer
Contents 29.7 Dispersing in Liquids and Semisolids . . . . . . . . . . . . . . . . . 673

29.7.1 Dispersing a Solid into a Liquid . . . . . . . . . . . . . . . . . . . . . . . . . 674
29.1 Weighing and Volume Measuring . . . . . . . . . . . . . . . . . . . . . 652 29.7.2 Dispersion of a Solid into a Semisolid Substance . . . . . . . 674
29.1.1 Required Accuracy and Precision . . . . . . . . . . . . . . . . . . . . . . . . 652 29.7.3 Dispersion of a Liquid into a Non-Miscible Liquid . . . . . 675
29.1.2 Weighing versus Volume Measuring . . . . . . . . . . . . . . . . . . . . 653
29.1.3 Physical Principles of Weighing . . . . . . . . . . . . . . . . . . . . . . . . . 655 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
29.1.4 Selection of an Electronic Balance . . . . . . . . . . . . . . . . . . . . . . 657
29.1.5 Installation and Minimum Weight . . . . . . . . . . . . . . . . . . . . . . . 659
29.1.6 Operation and Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
29.1.7 Volume Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
29.1.8 Non-Directly Weighable Quantities . . . . . . . . . . . . . . . . . . . . . 663
29.2 Particle Size Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
29.2.1 The Purpose of Particle Size Reduction . . . . . . . . . . . . . . . . . 664
29.2.2 Grinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665 Abstract
29.2.3 Physico-chemical Particle Size Reduction . . . . . . . . . . . . . . . 665
Weighing, volume measuring, particle size reduction,
29.3 Dispersing Agglomerates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667 dispersing, dissolving and mixing, including checking
29.3.1 Orientation and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
each step, are key issues in all pharmaceutical preparation
29.3.2 Selection of the Medium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
29.3.3 Dispersion Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 processes. Accuracy, precision and measurement uncer-
tainty are essential concepts in performing these basic
29.4 Mixing of Solid Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
29.4.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 operations. In this chapter the background to basic
29.4.2 Random Mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669 operations in pharmacy preparations is provided, good
29.4.3 Ordered Mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 practices are discussed and examples from practice are
29.4.4 Mixing Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 given as illustrations. The concept of Minimum weight
29.5 Dissolving Solid Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672 and metrological control are discussed. It is shown how to
29.6 Mixing of Liquids, Semisolid Substances and Molten choose the proper method for optimal performance in
Solid Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 practice. As equipment and utensils for weighing and
measuring are closely linked to the operations they are
also discussed. They encompass balances, receivers for
Based upon the chapter ‘Wegen, meten en mengen’ by Herman weighing, devices for volume measuring, mortars and
Woerdenbag, Yvonne Bouwman-Boer and Erik Frijlink in the 2009
edition of Recepteerkunde.
mixers. Particle size reduction and de-agglomeration are
discussed in relation to mixing and dispersing. A proper
H.J. Woerdenbag (*)
understanding of these techniques significantly influences
University of Groningen, Antonius Deusinglaan 1, the quality of a pharmacy preparation and thus the
9713 AV Groningen, The Netherlands required pharmacotherapeutic outcome.
M. Sznitowska Keywords
Department of Pharmaceutical Technology, Medical University of Dispersing Dissolving Mixing Particle size
Gdansk, Hallera 107, 80-416 Gdansk, Poland
reduction Volume measurement Weighing
Agglomerates
Y. Bouwman-Boer

652 H.J. Woerdenbag et al.
preparations are dealt with, in a concise, though justified,

29.1 Weighing and Volume Measuring way. For more profound scientific information the afore-
mentioned GUM [4] is highly recommended.
Weighing is determining the mass of an object or of a
quantity of substance. In pharmaceutical preparation pro-
cesses it is usually the accurate weighing out of a set amount 29.1.1.1 Concepts of Accuracy and Precision
of a substance. A weighing instrument is a measuring instru- Accuracy and precision are essential concepts for weighing
ment to determine the mass of an object by using the action and volume measuring in pharmaceutical preparation pro-
of gravity on that object [1]. Analogously, volume measure- cesses. Accuracy represents the degree of the closeness of a
ment in pharmaceutical preparations is the accurate mea- measurement to the actual or true value (the standard or
surement of a given volume of a required material, which is reference). Precision (also called reproducibility or repeat-
usually a liquid. But also the powder mixture for capsules is ability) is defined as the degree to which repeated
prepared by volume. Historical information on weighing and measurements under the same conditions yield the same
volume measuring in pharmaceutical practice as well as results. It is the refinement in a measurement, calculation
pharmaceutical calculations can be found in general or specification, represented by the number of decimal
textbooks [2, 3]. figures given. Accuracy and precision are visualised in
The basic good performance of weighing and volume Fig. 29.1. See also Sect. 20.2.2. For the sum of inaccuracy
measuring depends on choosing the right equipment, using and imprecision the terminology ‘measurement uncertainty’
it in a careful and correct manner and maintaining it in good is used, e.g. by the Joint Committee for Guides in Metrology
order. (JCGM) [5, 6].
29.1.1.2 Required Accuracy and Precision

29.1.1 Required Accuracy and Precision In relation to preparation in the pharmacy, weighing is used
in the preparation process and in Quality Control. Firstly
Describing measuring means caring about measurement measurement uncertainty is dealt with in relation to Quality
uncertainty, which is a universal concept. The universal Control.
and very useful document on measurement uncertainty is For Quality Control purposes the required measurement
the Guide to the Expression of Uncertainty in Measurement uncertainty is set by the Official Medicines Control
(GUM) [4]. In this chapter the concepts of measurement Laboratories (OMCL) Network of the Council of Europe.
needed for preparation and manufacturing of pharmaceutical The measurement uncertainty for analytical weighing is
a b c d
High accuracy and High accuracy and Low accuracy and Low accuracy and
high precision low precision high precision low precision
Fig. 29.1 Schematic representation of accuracy and precision. (c) Low accuracy and high precision, good balance in repeatability;
(a) High accuracy and high precision, good balance in repeatability; (d) Low accuracy and low precision, measured values are wide-spread.
(b) High accuracy and low precision, measured values are wide-spread; From Radwag [7] with permission
29 Basic Operations 653
considered to be satisfactory if three times the standard A maximum deviation of 5 % from the mean content
deviation of not less than ten replicate weight measurements, would lead to a maximum allowed weighing uncertainty of
divided by the amount weighed (at approximately 50 % of 0.018, expressed as most probable standard deviation. To
the maximum capacity of the balance), does not exceed obtain this value all four components contributing to uncer-
0.001 [8]. For comparison: USP gives a requirement for tainty (see next section) are taken into account. This requires
weighing tolerance (based on the requirement for repeatabil- specific mathematics and reasoning, which are explained in
ity as the most determining uncertainty at small weights) for [10]. The value of 0.018 results from a recalculation with a
“materials that must be accurately weighed” [9] which is 5 % deviation of the mean content instead of the original
0.1 % for two times the relative standard deviation of 7 % allowed. To leave some room for other processes, to be
10 times weighing a test weight. memorable and to give a clear comparison to analytical
For the preparation process, no official requirement is weighing a true standard deviation σ of 0.01 could be pro-
known to the authors, so it has to be derived. Most prepara- posed. As said, OMCL requires 0.001 for analytical
tion processes start with accurately weighing the required weighing. For comparison with the requirements for the
amount of active substance(s) and excipients or with mea- mean content it should be realised that this standard devia-
suring them by volume. Several process steps, such as trans- tion (sd) corresponds with a relative standard deviation (rsd)
ferring or mixing, may cause loss of active substance or of 1 % at the minimum amount to be weight Mmin. This
excipients due to spillage, exhausting, adsorption. Usually standard deviation of 1 % corresponds subsequently to most
this leads to a deviation of the actual content from the measurements being within 2–3 times that sd from the mean,
required content. It depends on the type of processing and so to a maximum deviation of 2–3 %. This deviation rapidly
the properties of the involved active substances and decreases with weighing larger quantities: to 1–1.5 % at
excipients, whether the resulting mean content will be weighing of two times the Mmin and so on. How to assess
lower or higher than 100 %. Especially in small-scale prep- the Minimum weight in practice is further derived in Sect.
aration any small process imperfection may lead to a notice- 29.1.3.3.
able deviation in content, which is acknowledged by the Maximal measurement uncertainty at volume measure-
somewhat less rigid requirements to mean content of phar- ments could be calculated as well. However volume mea-
macy preparations compared to licensed medicines. Taking surements are generally only performed as second choice if
this into account, one may argue that weighing and volume weighing would pose too many drawbacks for the reliability
measuring should negligibly contribute to these deviations of the preparation process (see Sect. 29.1.2). Therefore, the
because it is relatively easy, especially for weighing, to acceptable measurement uncertainty for volume measuring
perform these process steps accurately and precisely. Due depends strongly on the nature of the process in question.
PRODUCTION
to the small obtainable uncertainty in weighing and measur- Usually only inaccuracy is taken into consideration. It is
ing, other processes can use up the ‘uncertainty budget’ limited by requiring a minimum filling of the device to be
[9]. It immediately follows however that they should not used, as is explained in Sect. 29.1.7. More exact calculations
be executed so accurately and precisely that it hampers an would be irrelevant.
efficient performance of the preparation process.
Although uncertainty in weighing and measuring can be
small, it is worth knowing ‘how small’ for purposes of: 29.1.2 Weighing versus Volume Measuring
• Using the right balance and the right volume measuring
device; The measurement uncertainty of weighing will usually lead
• Knowing the minimum weight (Mmin) that can be to a deviation due to inaccuracy and imprecision of not more
weighed on that balance and the minimum amount to be than 1 % [10]. Volume measurements however, may show a
measured with the volume measuring device. deviation of 1.5 % under the most favourable conditions.
Mean content of pharmacy preparations is required to be Under less favourable conditions this can easily rise to 3 %
between 90 % and 110 % (see Sect. 32.6). If one would or more (see Sect. 29.1.7).
reckon with instability during storage and the need to have Weighing has three advantages over volume measuring:
a feasible shelf life, further narrowing this to 95–105 % for • Greater accuracy and precision to be achieved so smaller
the mean content immediately after preparation is reason- quantities can be handled.
able (see Sect. 22.4.1). This can be interpreted as there being • The read-out of a weight is less subjective than of a
an uncertainty range of maximal 5 % for weighing and volume.
measuring. However it may be more reasonable to leave • The use of an electronic balance offers the possibility to
some room for other processes contributing to the deviation record the result of a weighing objectively, by connecting
of the mean content. to a printer or a computer programme (in-process control).
Viscous liquids can be accurately weighed but are equipped with load cells (transducers that convert
difficult to be measured on a volume basis. Consider, force into an electrical signal) so that weighing can
for example, Chlorhexidine Digluconate Solution be performed.
(Ph. Eur.), which is a rather viscous solution. In an The nurse who prepares parenterals prior to admin-
investigation of chlorhexidine containing istration to a patient sometimes only needs a small part
preparations, prepared in Dutch pharmacies, it was of an injection solution from an ampoule or has to take
shown that chlorhexidine solution measured by vol- the appropriate amount from the ampoule for further
ume often resulted in too low concentrations of this dilution to achieve the appropriate dose. She will take
ingredient. This was caused by the adherence of the out the desired volume from the ampoule with a
solution onto the measuring device. For instance, the syringe and probably use other syringes for further
average content of a chlorhexidine mouth wash dilution (see also Sect. 29.1.7).
(Table 29.1) in samples prepared by volume measur-
ing was 3 % lower than in those prepared by weighing.
In pharmacy preparation, volume and weight of liquids
This formula of Chlorhexidine mouth wash was then
sometimes have to be converted into each other through the
redesigned so as to give the weight of the required
relative density.
amount of chlorhexidine solution instead of the
volume.
Syrups do not contain active ingredients. They are not
Table 29.1 Chlorhexidine Digluconate Mouth Wash 0.2 % [11]
administered as such but serve as a vehicle because of
FNA their flavouring and sweetening properties. Since the
Chlorhexidine digluconate solution 10.65 g
density of syrups is high, the volume in mL will not
Ethanol (96 % V/V) 70 g
equal the weight in grams. Syrup BP contains 667 g
Peppermint oil 3 dr
sucrose and purified water to produce 1,000 g. The
Sorbitol liquid, crystallising 535 g
density is 1.315–1.333 g/mL, yielding a sucrose con-
centration of about 64.6 %.
Total 1109 g (¼ 1000 mL) Benzalkonium chloride is available as
Benzalkonium Chloride Solution (Ph. Eur.) which
contains a mixture of alkylbenzyldimethylammonium
For some steps of the preparation processes, however,
chlorides in water at a concentration of 500 g/L
weighing is not or hardly possible or volume measurement
(50 % w/v). If the final concentration of benzalkonium
has advantages for reasons that outweigh inaccuracy.
chloride in a product has to be 0.01 % (either w/v or
Examples include: the adjustment to volume of large
w/w), for 1,000 mL of the preparation 100 mg of
amounts of solutions, working in a laminar flow cabinet,
benzalkonium chloride is required. Volume measuring
and preparing parenterals prior to administration on
would require 0.2 mL of the Benzalkonium Chloride
the ward.
Solution (50 % w/v) to be taken which cannot be
performed with adequate accuracy because of its
high viscosity. For weighing instead, the density of
If a preparation is carried out in a small working
the solution has to be known. Density may be taken
space with conditioned airflow (laminar flow cabinet,
from the product certificate issued by the manufacturer
safety cabinet, isolator), a balance cannot be too big
or it has to be measured. If the density would be
and must be protected to weigh free from draft. Those
0.9805 g/mL (as measured) one should weigh
balances are suitable to weigh ingredients but not to
196 mg of the 50 % Benzalkonium Chloride Solution
determine the final weight of a preparation, for
for 1,000 mL of the solution to be prepared.
instance a measuring cylinder with eye drop solution.
The final step will therefore be filling up to volume and
not to weight. If minor amounts are to be used of an excipient, such as
If a large vessel (e.g. 50–100 L) is used for a an essence or an essential oil in liquid oral preparations, the
preparation process, this may be carried out on a required weight should be known as well, regardless of the
volume basis. In that case the volume is determined fact that a limited variation in quantity has no essential
using a calibrated vessel with volume marks or by influence on product quality. A pharmacist can convert the
using a calibrated rod. Newly bought vessels are weight into droplets if such small quantities of the product
are prepared that weighing is not practical. In such cases the
(continued)
required quantity on a preparation worksheet can be stated in

droplets instead of weight. handling, although using a sterile stock solution with
Other examples from practice are the preservation of eye accurately weighted substances is definitely to be pre-
drops and the addition of a vitamin solution. ferred. For active ingredients such as vitamin A, for
which a content of 90–110 % is required, it may result
in the final product not meeting the requirements.
The combination of benzalkonium chloride and
betaphenylethanol in final concentrations of 0.05 g/L
and 4 g/L, respectively, is sometimes used to preserve
eye drops (but with care and restrictions as betapheny-
lethanol often causes irritation). In that case, for the
29.1.3 Physical Principles of Weighing
preparation of 10 mL of 0.5 % Atropine sulfate eye
drops, 0.5 mg of benzalkonium chloride and 40 mg of
For weighing in the pharmacy a balance is used. Two types
betaphenylethanol are required. The preservatives can
of balances exist: electronic (principle: comparison of force)
be added to the prepared solution by droplets as
and mechanical (principle: comparison of mass). Most
follows: the amount of 40 mg of betaphenylethanol
balances in European pharmacies are electronic balances.
corresponds to two drops of this liquid preservative;
benzalkonium chloride is used as a 0.5 % stock solu-
tion: five drops (100 mg of the stock solution) are 29.1.3.1 Electronic Balance
needed. The principle of an electronic balance is electromagnetic
An oily concentrate of vitamin A contains force compensation: the force of the mass to be weighed is
1,000,000 IU/g of the active substance, corresponding compared with an electromagnetic force. The electronic
to 34,500 IU in one drop. If 25 g of an ointment should balance has a magnet, a coil and a load carrier that is
contain 120,000 IU, it means that four drops of the mechanically connected to the coil. Under the influence of
concentrate should be added. If better precision is load on the load carrier the coil drops into the magnet and the
required the concentrate should be diluted with an current through the coil must be amplified to reach the
appropriate oil and added to the ointment by weight. starting position (equilibrium) again (see Fig. 29.2).
In the case of the preservation of eye drops this may Two types of electronic balances exist. For the first, the
be an acceptable approach especially because it may difference in current between the loaded and unloaded state
decrease the number of process steps in aseptic is a measure for the weight, the working of the second is
PRODUCTION
based on electrical resistance.
(continued)
Fig. 29.2 Principle of a balance 6

with electromagnetic force 1
compensation. The structure is 4
based on a lever. Typically, the
weighing pan with the item to be 3
weighed is attached to one end of
the lever. A coil that generates an 2
5
electromagnetic force is attached
to the other end of the lever. 3
Source: Recepteerkunde 2009, 7
A/D
#KNMP 9 8
000.00 g μP
1 weighing pan 6 precision resistance

2 parallel pair of levers 7 A/D converter
3 fulcrum 8 microprocessor
4 coil 9 digital read-out
5 permanent magnet
Most electronic balances are provided with an adjustable 29.1.3.3 Weighing Uncertainty at Preparation
integration time and stability indicator (that releases the To obtain the allowed weighing uncertainty the contribution
weighing result). These functions decrease the influence of of all components that are related to the weighing at prepa-
draft and vibrations on the weighing result. The integration ration have to be summed up. Four components are
time is the duration of the measurement cycle of the balance, contributing to weighing uncertainty [10]:
and the result of the measurement is read out when the 1. Intrinsic inaccuracy and imprecision of the balance
balance indicates ’standstill’. This is indicated by means of 2. Imprecision due to the imperfect placement of the bal-
a signal lamp or the passing on of the read-out result to a ance in practice
printer. A longer integration time may occur if the weighing 3. A difference between the value at which the weighing is
is disturbed by draft and vibrations. read out and the quantity to be weighed according to the
preparation worksheet
29.1.3.2 Mechanical Beam (Equal Arm) Balance 4. Reading out before the balance has stabilised sufficiently
The principle of a mechanical balance is based on compari- The intrinsic inaccuracy and imprecision of an electronic
son of mass. The mechanical beam balance may be present balance will be given by the manufacturer’s balance
in the pharmacy as a back-up. The equal arm balance is specifications, see further Sect. 29.1.4.
three-knife yoke balance (see Fig. 29.3). The object to be To keep inaccuracy and imprecision of a balance to their
weighed is placed on one scale and it is brought into balance intrinsic (or ideal) values, a balance should be placed
with different calibrated weights on the other scale. completely free from disturbances. However in pharmacy
Before use, levelling and zero position should be preparation imperfect placing is the rule. By using a stability
checked. Levelling can be set using the adjusting screws. If indicator the additional imprecision due to imperfect place-
the scales are clean but the pointer does not indicate zero in ment can be restricted but it is generally acknowledged that
the unloaded state, the balance should undergo service. Such the additional imprecision due to imperfect placement has to
deviation should never be abrogated with the adjusting be monitored (see Sect. 29.1.6).
screws or by pieces of paper put on the weighing scales. The third deviation is caused by the fact that the weighed
After use, the weighing scales should be cleaned when out quantity never exactly equals the quantity that should be
necessary. Maintenance consists of cleaning the knives, the weighed according to the preparation worksheet. It is there-
pans and the loose weights and checking whether parts that fore important to determine what deviation is allowable. For
are worn by the (mechanical) use should be replaced. The set instance, weighing out to meet exactly the target amount will
of weights, when used regularly, should be recalibrated take a lot of time. With a maximum deviation of 1 % from
regularly, depending on applicable national laws. If the the target amount, weighing in small-scale preparation can
balance is used for emergencies only, it is recommended be executed conveniently. Setting this deviation is also nec-
that the weights be sealed after recalibration and stored essary for programming the stability control for accepting
under dry conditions to avoid corrosion occurring. the weighing result and releasing it for the printer.
When using a beam balance the extent of any deviation is The fourth deviation is usually an operator’s deviation;
not known. At the end of the weighing the pointer should be impatience may lead to reading out before the balance has
positioned exactly in the middle of the scale. If this is not the stabilised sufficiently. If the balance is connected to a
case, the extent of the deviation is unclear. printer, this impatience will be to no effect as the printer
will only accept results between 1 % (or any other set
value). If impatience occurs the reason for it should be
checked as it may be due to technical problems (see also
Sect. 29.1.5). If the balance is not connected to a printer the
operator has to calculate the maximum allowed deviation of
the result from the target amount. It is safer, however, to
express it in the number of decimal figures in the amount on
the preparation worksheet. If, for instance, the amount to be
weighed is specified as 7.0 g, the weighing can be stopped
when the weighing result lies between 6.95 and 7.05 g.
Within that range the deviation from the quantity to be
weighed will be less than 1 %. If a deviation of less than
Fig. 29.3 Principle of a mechanical beam balance. Source: 0.5 % is desirable, the target amount in the protocol should
Recepteerkunde 2009, #KNMP be specified as: 7.00 g. For example, ‘1.00 kg’ implicates
Fig. 29.4 Properties of weighing

instruments: The dashed line with
the associated grey area
represents the sensitivity offset of
the instrument, superimposed is
the nonlinearity (blue area,
indicating the deviation of the
characteristic curve from the
straight line). The red circles
represent the measurement values
caused by eccentric loading, and
the yellow circles represent the
distribution of the measurement
values due to repeatability, from
Mettler-Toledo [13] with
permission
that a larger deviation is permitted than for ‘1,000 g’ (5 g and imprecision. The intrinsic inaccuracy of an electronic bal-
0.5 g respectively). Thus, the number of decimals places has ance is caused by deviations from sensitivity, linearity and
a practical meaning [12]. eccentricity. Sensitivity is defined as the change in weighing
value divided by the change in load, usually measured
between zero and the capacity of a balance. Linearity is the
The BP describes the accuracy requirements as ability of a balance to follow the linear relationship between
follows: Quantities are weighed or measured with an a load and the indicated weighing value. Eccentricity is the
accuracy commensurate with the indicated degree of deviation in the measurement value caused by eccentric
PRODUCTION
precision. For weighings, the precision corresponds to loading (asymmetrical placement of the load). Figure 29.4
plus or minus 5 units after the last figure stated (for illustrates these uncertainties.
example, 0.25 g is to be interpreted as 0.245 g to Intrinsic imprecision is also called repeatability and is
0.255 g). For the measurement of volumes, if the usually determined included in total repeatability. Intrinsic
figure after the decimal point is a zero or ends in a measurement inaccuracy is checked by calibration.
zero (for example, 10.0 mL or 0.50 mL). For analytical balances and microbalances the contribu-
tion of the components to measurement uncertainty are
very different. For the lower weighing range, repeatability
To find out if the total influence of these deviations on the is by far the most important. For precision balances and
mean content is still within the set amount of 5 %, all industrial scales, this is less prominent. But testing
deviations have to be accumulated. Weighing deviations frequencies (see Sect. 29.1.6) are, via risk assessment, for
may compensate for each other so straightforward totalling these balances are largely determined by checking repeat-
limit values will reflect an extremely worst case. Combining ability and sensitivity.
deviations that have a different mathematical type is essen-
tially an addition of quadratic standard deviations
(variances), but only after limit values have been turned 29.1.4 Selection of an Electronic Balance
into standard deviations according to their specific statistical
distribution. This propagation (or accumulation) of 29.1.4.1 General Selection Criteria
uncertainties is elaborated in Sect. 5 and Annex E.4 of [4] The relevant classes of balances for pharmaceutical purposes
and applied to small-scale preparation in [10]. are: semi-micro-balances, analytical balances, precision
Intrinsic measurement uncertainty, as has been said balances and platform or industrial balances [14]. They are
(Sect. 29.1.1), can be differentiated in inaccuracy and categorised by their capacity and readability (Table 29.2):
Table 29.2 Categorisation of balances for pharmaceutical purposes

Type (typical) Capacity (typical) Readability Remarks
Semi-micro 30 g 0.001 mg or 0.002 mg With an enclosed draft shield
For quantitative analysis in the laboratory only
Analytical 500 g 0.1 mg or 0.01 mg With an enclosed draft shield
For small-scale preparation and for quantitative analysis
Precision (or top pan) 20 kg 0.001 g or greater For production, and for general weighing in the laboratory
Platform 1,000 kg 0.1 g or greater For industrial production
The selection of a balance may be determined by: Measuring instruments subject to metrological control
• Weighing range undergo metrological inspections by the competent
• Required precision and accuracy authorities: a notified body. The specific requirements have
• Metrological approval of the model been entered in the regulations.
• The shape and area of the weighing pan The EU directive distinguishes four accuracy classes for
• The area and height of the weighing chamber, e.g. are balances: I (special), II (high), III (medium) and IIII (ordi-
containers to be weighed on the balance nary). The balances used in pharmacies’ practice usually
• The power supply required, e.g. 115 V, 240 V or battery belong to the accuracy classes I and II. In the pharmaceutical
powered industry (for large-scale preparations) also technical
All balance types for pharmacy preparation preferably have balances (platform balances) of class III may be used [1].
an automatic internal calibration option and can operate The accuracy classes are characterised by their
in connection with software functions, e.g. for in-process corresponding measurement uncertainties, expressed in spe-
control. The balance should be equipped with a stability cific parameters:
indicator so that the weight is only registered or printed • The verification scale interval “e”, representing the oper-
after stabilisation of the balance. Draft shields are important, ational deviation limit in the lower parts of the weighing
especially for weighing in controlled (ventilated!) environ- range.
ments. Special functions such as piece counting (for • The actual scale interval “d” (readability, the smallest
counting tablets or capsules; the so-called ‘pill counter’) digit that can be read out from the display).
may be advantageous. • The minimum capacity “Min”, the metrological lower
limit of the weighing range.
• The maximum weighing capacity “Max”, being the upper
29.1.4.2 Metrological Approval limit of the weighing range. Weighing of a quantity
For pharmacies (as opposed to industries) it is legally exceeding the maximum weighing capacity may damage
required [1] to use balances under metrological control of the balance.
the model. So when buying a balance, it should be verified if A typical e-value for an analytical balance (accuracy class I)
the model can be supplied under metrological control. is 0.001 g, indicating an operational inaccuracy limit of
0.001 g in the lower part of the weighing range. For less
The manufacturer produces the instrument in accor- sensitive precision balance (accuracy class II) a typical
dance with the product specification. The CE marking e-value is 0.1 g.
and the supplementary metrology marking are affixed The measurement uncertainty these parameters are apply-
by, or under the responsibility of, the manufacturer ing to is the ‘intrinsic’ one: based on an ideal, disturbance-
onto the instrument during the fabrication process as free placement of the balance. Ideal placement may be
proof of conformity with the EU directives. The man- attained in a laboratory situation but usually not in a phar-
ufacturer must have had such a metrological control macy production environment. For selection of the appropri-
carried out by one of the competent authorities of the ate balance these parameters may be helpful, although there
Member States of the European Union, called a is not much advantage above the usual categorisation as is
notified body. Details are described in [1, 15]. Balances reflected in Table 29.2.
used in pharmacies are defined as ‘non-automatic But measurement uncertainty in practice has to be
weighing instruments’ according to the European checked by investigating the actual repeatability leading to
law, meaning that they require the intervention of an a Minimum weight Mmin in practical circumstances, as
operator during weighing [1, 15]. opposed to the metrological minimum capacity ‘Min’ (see
Sect. 29.1.5).
29.1.5 Installation and Minimum Weight Using 0.10 % as the weighing tolerance for materials that
have to be accurately weighed (see Sect. 29.1.1) the equation
29.1.5.1 Installation amounts to: Mmin ¼ 2,000 s. Note that repeatability is
In order to work under optimal conditions a balance should taken as the measure for uncertainty. This is allowed at
stand stable, preferably in a weighing room or on a weighing low loads as repeatability is dominating the contributions
bench, on a solid, level, nonmagnetic surface that minimises of non-linearity, sensitivity or eccentricity [9].
the transmission of vibration. A balance should be shielded For preparation processes, the required weighing uncer-
from big changes in airflow or draft (laminar flow, air tainty was derived in Sect. 29.1.1 and expressed as a maxi-
exhaust, radiator, open door or window, passage area) and mum standard deviation γw of 0.018. Via γw ¼ σw/Mmin
temperature (direct sunlight, radiator). Humidity must be and σw ¼ 1.59sw (n ¼ 10) this leads to a Mmin of about
constant, preferably between 40 and 60 % RH. A low 100 s; s being the standard deviation of 10 replicate
humidity will increase the effect of static electricity. The measurements of a practical and relevant load. For an
positioning should be free from electromagnetic fields, static approach that leaves more room for other processes
electricity (due other equipment) and vibrations, e.g. by contributing to deviation from the mean content, as said
construction work or traffic passing [9, 16]. (Sect. 29.1.1), γw of 0.01 could be used. This would result
Prior to installation and release for use, it is in a Mmin of about 150 s.
recommended to check all the requirements set during the As a conclusion, Mmin for preparation purposes is to be
selection of the instrument. Secondly a full calibration determined by performing 10 replicate weighings of a prac-
(involving sensitivity, linearity, eccentricity and repeatabil- tical, relevant object such as usual receivers: a mortar,
ity over the entire operation range of the balance) should be a flask, a paper with a large surface. After calculating
performed before putting into service. This is done at the the standard deviation s10, multiplication by a factor
location where the balance is used [9]. 100 150 will lead to the Mmin
A balance should be adjusted for each location where it is
used. Weight varies slightly according to latitude, altitude, Mmin ¼ 100 150 s10
temperature and pressure. A measuring instrument must
therefore be adjusted for the particular part of the country
(gravitational area) where it will be used. In a small country
like the Netherlands, eight gravitational areas are distin- However, theoretically Mmin should never be less
guished. When moving to another part of the country or than about 80 d, d being the scale interval, see
the world, a balance may enter into a different gravitational Sect. 29.1.1. Due to rounding of the digital indication,
PRODUCTION
area and requires re-adjustment. By using an internal cali- the lower limit smin of the standard deviation of a
bration this adjustment is not necessary. weighing is calculated as being 0.41 d for technical
Finally, the minimum weight in practical circumstances reasons [13]). This fact of a lower limit of s, is also
Mmin should be assessed. taken into account in [17]. It will lead in the case of
preparation to a minimal Mmin of about 80 d.
29.1.5.2 Concept of Minimum Weight
The Minimum weight Mmin describes the lower limit of the
balance below which the required weighing tolerance (accu- An alternative approach could be that the Mmin is deter-
racy) is not adhered to [9]. Or put differently: one has to mined by an experienced operator and multiplied by a safety
weigh at least this amount of material in order to meet a limit factor of 2 (or even a higher number) to account for all future
of uncertainty that satisfies the weighing accuracy variations [13].
requirements specific to the process involved [12]. The Min-
imum weight Mmin is specific for the process for which the
weighing is used. Mmin is to be distinguished from the 29.1.6 Operation and Maintenance
metrological Min ¼ Minimum capacity (see Sect. 29.1.4),
which is a technical specification of the balance itself. 29.1.6.1 Operation of a Balance for Pharmacy
With regard to Quality Control the Mmin can be derived from Preparation
the allowed measurement uncertainty given by OMCL or USP. A clean balance that is in a completely level position should
USP uses the following equation for the minimum be used. In all cases the balance chosen should be appropri-
weight [9]: ate for the quantity to be weighed and for the accuracy
Mmin ¼ (k s)/required weighing tolerance; k being a needed.
‘coverage factor’ and s being the standard deviation of The first step is to switch on a balance. Depending on the
10 weighings. type of balance a warming-up period should be taken into
account. The balance should reach thermal equilibrium after as a measure that is easy and good practice for all materials,
being connected with the power supply. If the balance is in but especially for the toxic ones (see Sect. 26.4.3). Because
the standby mode (which is generally recommended when a usually powdered substances are weighed, decreasing the
balance is used regularly) the electronics are still energised exposure by inhalation is relevant. The use of an exhaust at
and no warming-up period is necessary. the back of the balance is preferred, but expensive. The use
It should be checked to see if the balance is levelled. If of a safety cabinet or isolator could even be necessary. As an
this is not the case, the balance should be aligned using the alternative in specific situations qualified nose-mouth masks
adjustable feet while monitoring the level indicator. It or respirators can be worn. The best measure to decrease
should be checked that the balance displays exactly zero at exposure is to use fluid or semisolid triturations of the active
the start of each weighing (stability indicator, substance instead of the powder form (see Sect. 29.5).
Sect. 29.1.3.1). The balance can then be tared.
The allowed difference between the quantity to be 29.1.6.2 Utensils for Weighing
weighed and the actual weighed quantity, for instance 1 % For weighing out ingredients, a range of paper sheets,
(see Sect. 29.1.3.3), can be incorporated into a weighing vessels and containers, spatulas and spoons are available.
programme. It may also be indicated in the worksheet by All receivers must be clean, dry and inert. The total weight
the number of decimals of the quantity to be weighed (see of the receiver plus the substance to be weighed must not
Sect. 29.1.3.3). exceed the maximum capacity of the balance. If the repeat-
Strong (electro) magnetic fields and static electricity may ability and hence the Mmin has been determined (see
disrupt the operation of an electronic balance. For example, Sect. 29.1.5.2) with the usual, probably large, receivers
Plexiglas draft shields, protective plastic covers or plastic (as is recommended), small quantities can be weighed from
weighing trays can be charged to such an extent that it Mmin, if necessary also in those receivers.
influences the weighing result. In that case there is a large The choice of the receiver is mostly determined by the
fluctuation of the figures that indicate the weighing result, ease for the preparation process concerned. Solids are often
especially when moving the charged object above the weighed on (paraffin) paper or in the processing vessel itself.
weighing scale. Avoid weighing vessels made of plastic Weighing polystyrene boats, antistatic weighing canoes or
when atmospheric humidity is below 30–40 %. The risk of greaseproof paper are used as receivers as well. After trans-
electrostatic charges is greater under these conditions. This ferring the solid from a weighing paper, hardly visible
leads to inaccurate weighing results. residues may still remain. By re-weighing the receiver and
A deviation may be caused by the presence of a stir bar in residuals the loss can be controlled to an acceptable level.
the vessel into which the weighing is done. Therefore, a stir The actual quantity added can also be determined through
bar should preferably be removed from the vessel before weighing the original container before and after the extrac-
weighing. If any deviation is remaining despite sensible tion. By weighing directly into the preparation vessel no loss
actions, consultation of the supplier is necessary to be able occurs through transfer. Small amounts of powder can even-
to undertake the proper corrective action. tually be weighed on filler substance, but this harbours the
Temperature is one of the most important factors of a risk that an excess cannot be removed in the case that too
weighing process. For balances equipped with an automatic much of the substance is weighed. It is a matter of skills and
adjustment system, the balance precision restoring process is experience.
carried out automatically, with consideration of temperature Semisolids are weighed on greaseproof paper or cello-
as time changes. However, this concerns only temperature of phane. To prevent loss, a small amount of a substance can be
the environment. One must not weigh hot or very cold weighed on a bit of the ointment base into which it will be
objects on the balance. Hot objects will give erroneously incorporated (see above).
low readings due to buoyancy of hot air, while cold objects Compatibility with the receiver should be checked espe-
will give high readings. Therefore, after removing the cially with fluids. Spatulas and spoons made of stainless
weighing vessel from a drying oven or dishwasher, allow steel may interact with substances such as chloral hydrate
time to cool before placing it on the balance. Analogously or iodine. But for the short contact time involved in the
products taken out of the refrigerator should adjust to room weighing procedure these interactions don’t appear to be
temperature before they can be properly weighed. relevant. Plastic spatulas may cause a problem with electro-
A beaker taken from a water bath should be dried on the static charge. Also with some substances discolouration of
bottom before it can be placed on a balance scale. the plastic occurs so disposable spoons are
Weighing vessels must be put in the centre of the increasingly used.
weighing pan to prevent influence of eccentricity. For liquids that are best weighed droplet-wise, vials with
Finally, health and safety precautions at weighing a drop dispenser (dropper) are suitable. By varying the
procedures generally brings with it the wearing of gloves position of the vial, the droplet size can be easily adjusted.
An accurate weighing of volatile solvents or solutions graduated. During pharmacy preparation processes all
(alcohol, ether, methylene chloride) is still an unsolved observed volumes are recorded on the batch preparation
problem. Evaporation occurs and the readings change con- record as in-process controls.
stantly showing decreasing weight. The read-out of the As explained in Sect. 29.1.2 for preparation processes
weight should be performed only if the vial is closed. weighing is generally preferred to volume measurements,
because a better accuracy and precision can be obtained.
29.1.6.3 Maintenance When measuring a volume the following deviations (see
Balances should be protected from damage, cleaned with also Sect. 29.1.1) are distinguished:
great care and checked periodically. The weighing chamber • Inaccuracy of the measurement devices
and weighing pan should be kept clean (using conventional • Inaccuracy due to a temperature other than 20 C
window-cleaning fluids, lint-free cloths), only clean • Imprecision of the read-out
weighing vessels should be used, contaminants should not For the accuracy of volumetric measurement devices, ISO
be brushed into potential openings and all removable parts standards apply which are mentioned at the description in
should be removed before cleaning. the next subsections.
All balances should be regularly calibrated and monitored Under ‘room temperature’ conditions, the temperature
for their performance. The applicable frequency of such tests only has a small influence: 5 C deviation of the calibration
should be based on risk assessment: the higher the impact of temperature of 20 C results in a deviation of 0.1 % in the
deviations, the more often testing should take place. Cali- volume, based on the relative density of water. Warm or hot
bration is to be performed by the user either manually (with liquids cannot be measured accurately.
an external calibration weight) or using the internal The imprecision of the read-out can be made as small as
calibration. possible by choosing a graduated pipette, syringe or measur-
Calibration of a balance by an automatic internal calibra- ing cylinder with a nominal capacity as near to the volume to
tion weight can be easily and regularly performed. Although be measured as possible. For example: a volume of 0.5 mL
it only indicates intrinsic accuracy and precision, which is should be measured by a 0.5 mL automatic pipette or with a
not expected to change easily, it will indicate gross 1.0 mL traditional graduated pipette. A volume of 21 mL
deviations as well, also those of the most important contrib- should preferably be measured with a 25 mL graduated
utor to uncertainty: repeatability [13]. Repeatability and thus pipette or a measuring cylinder of a nominal volume of
Mmin depends also on environmental circumstances that may 25 mL.
differ. Change of location, levelling the balance, major
changes in temperature, humidity or air pressure make cali- 29.1.7.2 Graduated Pipettes
PRODUCTION
bration and determination of Mmin particularly important. Graduated pipettes must only be used for liquids that behave
When large deviations are noticed, the manufacturer has to like water. They are calibrated on dispensing water, so that
adjust the balance. rinsing afterwards is not necessary. Graduated pipettes must
So, calibration is to be performed daily and repeatability meet ISO standards (International Organization for
(leading to Mmin, see Sect. 29.1.5.2) should be determined Standardization) [18]. The inaccuracy is limited in this
regularly as well, for instance weekly. For repeatability way. The volume is read at eye level, at the bottom of the
also the alternative approach as described in Sect. 29.1.5.2. liquid surface (meniscus). The pipette is held vertically with
can be used. All other specific checks can be better the tip against the sloped wall of the receiving container and
performed at a technical service. allowed to flow out vertically. Liquids should never be
Balances that are broken or not qualified should be aspirated by mouth. Aspiration devices such as rubber balls
removed from the pharmacy or clearly marked. are used in practice for sucking up fluids to be pipetted.
Automatic pipettes, however, are by far to be preferred for
this purpose.
29.1.7 Volume Measurement When using graduated pipettes for more viscous liquids,
an additional inaccuracy must be taken into account. Vis-
29.1.7.1 Accuracy and Precision cous fluids are therefore preferably weighed (see
Volume measuring means the exact determination of a Sect. 29.1.2).
defined volume of a liquid (or of a powder mixture in the
case of preparing capsules). Devices for measuring of 29.1.7.3 Syringes
volumes for pharmacy preparations include: graduated In the framework of pharmacy preparations syringes are
pipettes (traditional or automatic), syringes and graduated mainly used for measuring non-aqueous fluids and to make
cylinders. Beakers, Erlenmeyer flasks and medicine bottles dilutions for parenteral administration on the ward. Espe-
are not fit for volume measurement, even if they are cially for the latter application it is important to take the
attainable accuracy into account, according to ISO standards

for syringes [19]. The size of a syringe for measuring a six syringes being identical, the standard deviation of
required volume should be carefully chosen 0.025 g reflects the repeatability (imprecision due to
handling). A single volume measurement may be
affected in a worst case (imprecision having the same
To make parenterals ready to administer, sometimes
sign as the inaccuracy) with an inaccuracy of 0.03 mL
dilutions are to be made (see also Chap. 13). The
as well as an additional deviation of about 2 times
deviation of the volume to be measured decreases
the standard deviation 0.025 g ¼ 0.08 mL. This
with the increasing degree of filling of the syringe
correspondences with a worst case relative deviation
used. From the viewpoint of the pharmaceutical prep-
of about 13 %; which will be quite acceptable com-
aration a deviation of no more than 5–10 % is
pared to clinical risk.
recommended (see Sect. 29.1.1). This recommenda-
tion, however, may require an additional dilution step
to be performed. This increases the risk of When a syringe is used to deliver a given volume, the
microbiological contamination and calculation errors. liquid is expelled quantitatively with the piston. Depending
Therefore risk assessment is necessary to decide which on the type of operation performed, the dead volume of the
measurement accuracy is accepted in practice. syringe and the needle (if used) should be taken into account.
The dose to be administered should also be This is for instance the case when a volume of a liquid is
measured. Also for this purpose the volume of the measured in a syringe, after which it is diluted by aspiring a
syringe to be used should be as close as possible to volume of another liquid into the same syringe [20, 21]. To
the required dose (volume). To achieve this, the injec- minimise dead volume deviations, smaller volumes are bet-
tion fluid can be diluted, but when administered to ter aspired with a separate syringe and added to another
neonates this is not common practice because fluid syringe which contains the diluent. The dead volume can
restriction in this patient group is more important be calculated from the difference in weight of a syringe (with
than ultimate dose accuracy. In practice for example, needle) before use and after the liquid has been expelled.
a 1 mL syringe is preferably used for the administra- The dead volume is, of course, not applicable if only a
tion of 0.6 mL (or even less), but a 2 mL syringe is fraction of a liquid present in the syringe is measured (for
taken if a 1 mL is unavailable. example, if from a syringe filled up to 10 mL only 5 mL is
As an illustration the following clinical case may be expelled) or even when a measured volume is fully expelled.
considered. For the preparation of a parenteral infu- Accuracy and precision is best if syringes are used with a
sion solution at the neonatal ward, an antibiotic capacity as near as possible to the quantity to be measured.
injectable solution for adults has to be diluted. It was Filling a syringe that is meeting the appropriate ISO norm
calculated that 0.6 mL of the ‘adult’ solution should be (7886-1) [22] to more than 50 % of its capacity will result in
diluted to 10 mL with 0.9 % NaCl infusion solution. an inaccuracy not exceeding 5 %. If the filling degree is
The dilution should preferably be prepared in a 10 mL around 20 % the inaccuracy will rise to 10 % and filling to
syringe that subsequently could be installed in a not more than 10 % may lead to an inaccuracy of about
syringe infusion pump. However, 0.6 mL of the 20 %. Imprecision depends very much on individual
concentrated antibiotic solution cannot be accurately handling, but will be smallest when the capacity is nearest
measured with a 10 mL syringe, which does not even to the quantity to be measured.
bears markings with 0.1 increments. A 1 mL syringe What is considered acceptable depends on the purpose or
was used to sample 0.6 mL of the concentrated antibi- application. A risk assessment should reveal whether a lower
otic solution and to transfer it to a 10 mL syringe. This deviation obtained by stepwise dilutions offsets the higher
process was checked for accuracy and repeatability. risk of bacterial contamination introduced by the higher
With six 1 mL syringes, each syringe used six times, number of handlings, see also Sect. 31.3.2).
‘0.6 mL’ water was sampled and weighed. The aver-
age weight was 0.63 g and the standard deviation
(n ¼ 36) was 0.025 g. So the inaccuracy (deviation 29.1.7.4 Measuring Cylinders
from the nominal volume as a property of this batch of The measuring cylinders that are used in pharmaceutical
syringes) was 0.63–0.6 ¼ 0.03 g ¼ 0.03 mL which preparation processes have to comply to international
corresponds to a relative inaccuracy of 5 %. This is standards for graduated measuring cylinders (ISO norm
within the ISO norm (see further down). Assuming the 4788) [23]. A measuring cylinder is calibrated either to
contain or to deliver (marked ‘TC’ (to contain) (or ‘IN’) or
(continued)
‘TD’ (to deliver) (or ‘EX’) accordingly). For preparation Mmin (see Sect. 29.1.5) of the most sensitive balance avail-
purposes a cylinder to deliver the liquid may be most appro- able: a non-directly weighable quantity. The best procedure
priate. The volume is read out at eye level. For measuring is to prepare a larger batch of the preparation than necessary
viscous liquids, the measuring cylinder has to be rinsed and to reject what will not be dispensed. However, this may
afterwards with another fluid (such as water) used in the not be economically feasible, in which case there are two
preparation process because the nominal volume is related (less good) alternatives: trituration/dilution, or starting from
to the volume that is contained in it. If there is no liquid in another preparation or licensed medicine with a low concen-
the preparation to rinse a measuring cylinder with, it should tration of the active substance required.
not be used. Instead a syringe can be used. If rinsing is
impossible because of too high the viscosity, the liquid
should be weighed (see also Sect. 29.1.2). 29.1.8.1 Triturations and Dilutions
The inaccuracy of measuring cylinders have to meet ISO A trituration of a powdered active substance is obtained by
requirements as well. The inaccuracy is limited to 5 % when mixing (see also Sect. 29.4.3) with an excipient (for instance
using at least 40 % of the nominal capacity of cylinders lactose) in a ratio that is easy for calculation when creating a
50 mL, and at least 20 % of the nominal capacity of batch preparation worksheet (1:10; 1:100). The excipient
100–2,000 mL cylinders. For preparation purposes there can also be a semisolid substance such as white paraffin,
will be hardly any reasons for not aiming at a maximum with which simultaneously a deagglomeration can be
inaccuracy of 5 %, realising the requirements for the mean accomplished.
content (see also Sect. 29.1.1).
Salicylic Acid Trituration 50 % DAC [24] is an
29.1.7.5 Preparation Vessels example of a trituration with semisolid excipients.
Medicine bottles are often provided with a graduated mark. The composition is given in Table 29.3.
It is intended, and accurate enough, to measure a quantity to
Table 29.3 Salicylic Acid Trituration 50 %
be dispensed to the patient. To adjust the volume during a
preparation process it is too inaccurate. This may also apply Salicylic acid 50 g
to the reconstitution of an antibiotic oral mixture in a bottle
Paraffin, white or yellow soft 40 g
provided by the manufacturer. In this case it is also relevant
that the meniscus cannot be accurately read due to foaming Total 100 g
of the mixture. Separate measuring or weighing of the
PRODUCTION
required quantity of water is the right approach. The preparation method consists of three subsequent
In very large preparation containers a calibrated rod or steps: (1) grinding of salicylic acid, (2) triturating sali-
mark indicates the volume (as an alternative to load cells). In cylic acid with liquid paraffin, (3) mixing the salicylic
a calibrated rod a dash can be accurately notched. acid – paraffin mixture with white or yellow soft
paraffin.
With a calibrated rod that is suspended centrally
above the liquid in a preparation container, the level In case of a dilution, the active substance is dissolved in a
is readable at 1 mm. In a container with a capacity of suitable liquid to obtain a concentration that is easy for
100 L and a diameter of 50 cm, a difference of 1 mm in calculation when creating a batch preparation worksheet.
height corresponds to 0.2 % of the volume. If a The risk of calculation errors, inhomogeneity and insta-
calibrated rod would be used along the side of the bility with preparing triturations and dilutions is probable
container, the mistracking may be 3 mm (by ’creep’ and therefore, an analytical control is advised.
of water against the wall). This corresponds to a devi- The content of active substance in a dilution or a tritura-
ation of 0.6 % of the volume. tion must be low enough, to ensure that a volume can be
measured with sufficient accuracy from a dilution, and a
quantity can be weighed with sufficient accuracy from a
trituration. For the sake of homogeneity, the content of the
trituration should however be as high as possible.
29.1.8 Non-Directly Weighable Quantities When designing dilutions, the solubility of the active
substance should be known and stability and preservation
Especially in the case of extemporaneous preparations, it should be taken care of if the dilution is stored. When
may happen that the quantity of an active substance or designing triturations, similar aspects as in the preparation
excipient to be processed lies below the minimum weight of a powder mixture for capsules must be examined:
adsorption to fillers, physico-chemical changes due to tritu- agglomerates). In this section the importance of particle
ration, homogeneity. The same aspects apply to semisolid size for the quality of the medicine is discussed and two
triturations. Chemical and physical stability (demixing, methods of reducing primary particles are highlighted:
evaporation) and interactions have to be investigated if the mechanically (by grinding or milling) and by using
trituration is stored. If a trituration is kept in stock, appropri- physico-chemical methods: the solution method (solvent
ate measures must be taken to avoid mistaking the trituration deposition method, see Sect. 29.2.3) and the precipitation
for the pure active substance. method. Dispersion of agglomerates is discussed in
For each specific dilution or trituration a batch prepara- Sect. 29.3. See Table 23.3 for the terminology of the degree
tion worksheet (see Sect. 32.4) must be designed. The of fineness of raw materials and Sect. 23.1.8 for measure-
in-process controls are the same as for the mixing of ment of particle size.
substances.
As a conclusion, chose a 10- or 100-fold trituration
respectively, a 10-, 100- or 1,000-fold dilution, so that the
29.2.1 The Purpose of Particle Size Reduction
quantity to be weighed or the volume to be measured lies
above the minimum weighable or measurable quantity. An
For pharmaceutical or biopharmaceutical reasons, or both,
excipient has to be used that does not affect the therapeutic
requirements for the particle size are set for many active
and biopharmaceutical properties of the preparation, nor its
substances and excipients. See Sects. 16.1.2 and 23.1.8.
stability. An excipient, already used in the preparation,
Particle size reduction may be advantageous:
might be a good choice. The trituration is made by grinding
• For the uniformity of content and dose accuracy. Particle
(in case of a solid) or trituration (in case of a semisolid) and
size reduction increases the number of particles per unit
mixing of the powder substances. A dilution is made by
of weight and thereby the homogeneity of the mixture.
dissolution.
• For the stability of a suspension. Smaller particles have a
lower sedimentation rate.
29.1.8.2 Starting from Pharmaceutical • To prevent demixing. By striving for a particle size that is
Preparations approximately equal for all components, demixing is
Weighing a (ground) pharmaceutical preparation instead of prevented.
the pure raw material may be necessary if a very small • To enhance the dissolution rate of poorly soluble
amount of active substance – below the minimum weight substances. Poorly soluble substances dissolve faster as
Mmin – is needed. Tablets or capsules may be used, in which the particles are smaller (see Sects. 18.1 and 16.1.4).
the active substance is contained in a low concentration, and • To prevent irritation upon contact of the particles with the
ground. Counting substitutes weighing and mixing becomes skin, eye or mucous membranes.
easier because of the larger bulk volume and may lead to less • For a smooth appearance (in ointments).
exposure (see Sect. 26.5). Caution should be exercised, • To avoid high local concentrations (in ointments and
however, as the content of active substance in the few tablets suppositories).
or capsule that are ground may differ, sometimes consider- Particle size reduction may also have drawbacks:
ably, from 100 %. Also to be borne in mind is the presence • Increasing the particle surface increases access by water
of excipients in the preparation which can affect the release vapour or oxygen which may accelerate degradation.
rate when used in a new formulation (e.g. a tablet that is used • The flowability of the substance is deteriorated.
in preparing low dose suppositories). The feasibility of • If only the particles of the active substance are reduced
tablets and capsules for this procedure is further discussed and the excipient particles remain larger, demixing will
in Sect. 4.10.7. The use of tablets or capsules as starting be favoured.
material is discussed in Sect. 4.5.1. • Wetting becomes more difficult, making a substance
harder to dissolve or more difficult to bring into
suspension.
29.2 Particle Size Reduction • Tendency to uncontrolled agglomeration.
• Electrostatic properties increase.
Single crystalline or amorphous particles are called primary • Inhalation of particles in dust.
particles, agglomerates are secondary particles. Particle size When designing a formulation, the requirements for the
can be reduced by reducing primary particles, or by splitting particle size may be conflicting. In practice, one must often
secondary particles into primary particles (dispersion of be satisfied with a compromise.
Tetracycline hydrochloride comes in two different On an industrial scale, micronisation of substances is

grades: ’micronisatum’ (microcrystalline) and often achieved with a jet mill. The strong air current in
’ponderosum’ (the pressed form). Microcrystalline tet- this device results in electrostatic charging of the
racycline is finer, easy to disperse in a cream or particles, making them more difficult to be moistened.
ointment base but less stable because of its larger This can also lead to agglomerate formation. This
surface in contact with water. Preparations containing phenomenon is called tribo-electrification. During the
the microcrystalline form have a relatively short grinding of very hard materials, such as borates,
shelf-life. The pressed quality has a considerably particles (plastic or metal) of the grinding equipment
better flowability and is more stable, but when may contaminate the powder. These are visible as an
processing it into a cream or ointment base much impurity when the substance is dissolved and may
more attention should be paid to get a homogeneous even hinder wetting. In contrast to other mills, con-
distribution. tamination with metal particles in the jet mill is
In the preparation of Paracetamol-codeine very rare.
suppositories FNA (Table 11.5), paracetamol (45) is
used as small particles because they provide a faster
Grinding in the presence of a liquid or semi-liquid (wet
release rate [25]. In addition, the small particles sedi-
grinding) can be as effective as dry grinding and may have
ment less rapidly during the preparation of the
the advantage of preventing electrostatic charging that may
suppositories. Particles with this degree of fineness,
cause agglomeration, stickiness or ‘jumpy’ behaviour.
however, establish a poor flow and have a high bulk
volume. This makes them unsuitable for processing
into capsules. For this purpose the paracetamol quality When metronidazole (crystals 500–600 μm) for the
(90–500) is used. For sieve ranges in relation to parti- preparation of a fat-based eye ointment is made into a
cle size see Table 23.3. paste in a mortar with a few drops of paraffin, the
particles are 20–70 μm in size after 1 min of mixing.
After 15 min of mixing, a powder is achieved with
particles less than 10 μm in size. To obtain such a
particle size reduction without the paraffin is difficult
29.2.2 Grinding since the powder escapes from the mortar due to its
strong electrostatic properties. If a hydrophilic oint-
PRODUCTION
Many raw materials are available in a quality that is suffi- ment base is used, glycerol may be considered to
ciently fine for pharmaceutical preparation. If mechanical triturate the metronidazole with.
particle size reduction is still needed, this is done manually
by grinding in a rough stone or porcelain mortar, using a
stone pestle. However, this is only useful for substances with
primary particles larger than about 100 μm. For finer
materials there is a considerable risk of agglomerates being 29.2.3 Physico-chemical Particle Size Reduction
formed. By grinding in a mortar often no particles smaller
than about 50 μm are obtained. Using small impact mills, for Physico-chemical methods for particle size reduction com-
example a beating mill (coffee grinder, see Sect. 28.6.7), prise methods wherein the substance is first dissolved and
finer powders with a narrow particle size distribution can be then precipitated in a finer form during further processing.
obtained. This has the advantage that it is independent of the fineness
If the primary particle size is >180 μm (or in case of of the starting material and that the formation of small
doubt) first an excess is ground in a rough stone mortar to agglomerating particles is largely prevented. Two methods
obtain the correct particle size (see Sect. 28.6.4). Excess are distinguished: the solution method and the precipitation
material (usually depending on a size of mortar) is used, method.
the required quantity weighed and the remainder is thrown The names ’solution method’ and ’precipitation method’
away (not put back into the container), in order to avoid are actually not very well chosen. Indeed, in the precipitation
possible contamination. Tablets can be ground in the method the active substance is first dissolved, while in the
same way. solution method the substance is also precipitated, but onto
a solid substance as a carrier. For the latter, the term ’solvent

deposition’ is applied as well [26]. powder mixture on which the active substance is
precipitated can be moistened. The active substance
is dissolved in the solvent in a mortar with a smooth
29.2.3.1 Solution Method or Solvent Deposition
wall. Half of the filler is added and the powder is
Method
mixed until dry and the smell of the solvent no longer
In the solution method or solvent deposition method, the
detectable. The powder mixture is then taken from the
active substance is dissolved in a volatile solvent. The solu-
mortar. Because the active substance can deposit and /
tion is triturated dry on a powder (carrier material) that is
or crystallise on the mortar wall, mortar and pestle are
insoluble in the solvent. After evaporation of the solvent, the
subsequently wetted with the solvent and the other half
substance is evenly and finely divided over the surface of the
of the filler is mixed therewith. Once the smell is gone,
carrier, in a non-agglomerated form.
both portions of powder mixture are mixed and the
The solution method is, for example, suitable for the
capsules filled.
preparation of capsules with a low dose of active substance.
The solution method can also be used for the
But the method can only be applied if:
achievement of a homogeneous mixture in the mixing
• The active substance is sufficiently soluble in a quantity
of solids with a poor mixing ratio. Also for colouring a
of non-toxic volatile solvent that can be evaporated
powder, this method is very suitable. Much less dye is
within a reasonable time (most often ethanol is used).
necessary: if the colouring agent (see Sect. 23.11) is
• The active substance is stable in solution.
homogeneously dispersed on a carrier, the colour will
• There is sufficient carrier material in proportion to the
be much more intense than when the dye particles are
amount of active substance that is divided, as otherwise
distributed between other particles.
agglomerates of the active substance may occur.
Triamcinolone acetonide in dermal preparations is
• The crystal form of the active substance is changed by
processed as a trituration with rice starch (1:10). Here,
dissolving and precipitation, but the stability and the
the particles of triamcinolone acetonide are reduced in
dissolution behaviour may not be altered.
size firstly by dissolving the substance in a volatile
Furthermore, it must be ensured during the preparation pro-
solvent, after which this solution is rubbed until dry
cess that:
with rice starch. The resulting particles of triamcino-
• The dissolved active substance does not remain on the
lone acetonide of about 5 μm are in this way mixed
wall of the mortar and pestle.
with and held apart by the starch particles. By
• There is no (toxic) solvent residue remaining in the
pulverising triamcinolone acetonide as such in a
mixture.
mortar such fineness of particles is not achieved.
• The solvent is properly exhausted because most suitable
Moreover, agglomerates will be created. Also rubbing
solvents are flammable and explosive and toxic to the
the solution until dry without rice starch does not yield
compounder.
a good result. Not only agglomerates will be recreated,
This method is known as ‘solvent method’ for the prepara-
but part of the triamcinolone acetonide will crystallise
tion of low dose capsules, and is further described in Sect.
in a coarser form.
4.5.1. The method brings about not only particle size reduc-
tion and deagglomeration but is also used for the preparation
of triturations of low-dose active substances (see also
Sect. 29.1.8).
29.2.3.2 Precipitation Method
The precipitation method may be used when an active sub-
The solution method proved to be useful for capsules stance with too large particles has to be processed in a
with a low dose (5 mg per capsule) of colchicine, suspension. In this method the active substance is first
diazepam or ethinylestradiol. Colchicine and diaze- dissolved, and then after changing the medium into the
pam are sufficiently soluble in dichloromethane, after final composition, the active substance will precipitate, in a
which it is precipitated on microcrystalline cellulose, more finely divided form.
which also serves as a filler for the capsules. To (temporarily) dissolve an active substance for the
Ethinylestradiol is soluble in acetone and is precipitation method, the following methods are applicable:
precipitated on lactose, which is used as a filler here. • Temperature rise
In all cases, an amount of solvent is taken in which the • pH shift
active substance dissolves and by which half of the • Dissolution in only one of the components of the final
medium
(continued)
If out of habit or ‘to take out lumps’ a very fine active

Two examples, concerning the processing of active substance is rubbed in a mortar while not adding a suitable
substances in an oral suspension. medium, agglomeration may be increased. As a result, it
If sulfonamides have too large particles, first the takes much more effort to disperse them in a medium
corresponding soluble sodium salt is prepared in aque- afterwards. The right approach to get rid of visible
ous medium with sodium hydroxide. Then, by adding lumps is to press them gently by hand (between two
citric acid solution the sulfonamide finely precipitates. papers, e.g. for sulfur), with a plastic pestle or with a
Tetracycline hydrochloride dissolves partially in brush and sieve.
water and then degrades quickly. Moreover, the pH The term trituration is used if a solid substance is firstly
of such a solution is very low (about 2) which is too mixed with just enough of the liquid (or of the semisolid) in a
low for an oral liquid. By adding sodium citrate the pH formulation and subsequently gradually mixed with the rest.
is increased to about 6. Tetracycline precipitates finely This is usually done in a mortar with pestle. With trituration
divided and the dissolved fraction is as small as possi- agglomerates can be properly dispersed.
ble. This method can be used as well to prepare a Table 29.4 summarises the terminology used on particle
cream containing tetracycline. size reduction, mixing and de-agglomeration.
In Polish pharmacies the most popular method to
obtain very small particle sizes is a combination of the
precipitation method with grinding: the substance is
dissolved in a porcelain mortar in a very small amount 29.3.2 Selection of the Medium
of ethanol or even ether and rubbed with a pestle until
the solvent evaporates. When the solvent evaporates, The medium used to disperse agglomerates must be
precipitation occurs and the crystals are immediately selected so that no re-agglomeration occurs. The choice
pulverised. Not using a carrier however increases the of medium also depends on the pharmaceutical dosage
risk of agglomeration of the fine particles (see form that is prepared. Agglomerates can be dispersed in
Sect. 29.3.2). another solid, in a liquid or semisolid. Examples of
solid medium are lactose for de-agglomerating morphine
hydrochloride processed in suppositories, and rice starch
for triamcinolone acetonide (processed in dermal
preparations). Examples of a liquid medium are propylene
29.3 Dispersing Agglomerates glycol in the processing of miconazole nitrate or hydro-
PRODUCTION
cortisone acetate as an addition to dermatological bases, or
29.3.1 Orientation and Definitions a mixture of propylene glycol and water for the processing
of carbomer in the preparation of a gel. Miglyol 812 ®
Primary particles may form agglomerates under the influ- (Triglycerida saturata media), a mixture of medium chain
ence of moisture, electrostatic or Van der Waals forces. The triglycerides, is a low viscous lipophilic substance that is
tendency to form agglomerates increases with decreasing very suitable to de-agglomerate solids. Semisolid
particle size, as is seen in many micronised active substances and preparations that can be used as a medium
substances. Lipophilic substances exhibit a stronger ten- include molten suppository base (the standard method for
dency to agglomerate than hydrophilic substances. Agglom- the preparation of suspension suppositories) and cream
erate formation is often the cause of poor flow of a powder bases.
mixture. The dispersion of agglomerates improves the
flowability. For further reading see [27].
When processing agglomerating substances, agglome- The uniformity of content of suppositories with mor-
rates must be dispersed and re-agglomeration prevented. phine hydrochloride 20 mg in a fat base is consider-
For the dispersion (shear) forces are needed, but the medium ably improved by triturating the morphine
in which the agglomerates are dispersed should ensure that hydrochloride first with 100 mg of lactose or mannitol
dispersed primary particles remain separate. For that pur- [28]. It is likely that the agglomerates of morphine
pose interactions have to be offered that replace the hydrochloride are ‘ground’ between the crystals of
interactions that lead to agglomerate formation. If dispersing lactose or mannitol into smaller primary particles.
of agglomerates occurs by trituration and dispersing into a Zinc oxide is better wetted by oil than by paraffin.
medium, the cohesive interaction between the particles of Therefore, it is relatively easy to disperse Zinc oxide in
active ingredient is replaced by adhesive interaction between oil, and more difficult in liquid paraffin [29].
active ingredient and excipient.
Table 29.4 Overview of the terminology used in relation to particle size reduction, mixing and de-agglomeration
Topic Term Description
Particles Primary particles Particles that consist of a single crystal
Secondary particles Particles are agglomerates
Particle size Milling Particle size reduction by (different) forces
reduction Grinding Milling a substance by hand
Wet grinding Grinding with an amount of liquid as small as possible for reasons of: preventing agglomeration,
augmenting milling efficiency (grease effect) or for occupational safety and health reasons
(to prevent the creation of dust particles)
Pulverising Smashing a material into a powder
Comminuting Reducing to powder (US)
Mixing and Dispersing Distributing primary particles in a medium; may simultaneously lead to the breaking up of
de-agglomeration agglomerates (de-agglomeration)
Geometrically dilution Mixing using the ratio 1:1 repeatedly
(Triturating)
Mixing (¼ blending) Putting substances together to get a homogeneous distribution
Rubbing Intensely mixing (triturated) powders with a semisolid or liquid on a surface to obtain a smooth
mixture
Making into a (thick) paste
Levigating (US)
Triturating Mixing a solid with a solid, semisolid or liquid substance in such a ratio and intensity that
agglomerates are dispersed (de-agglomeration); de-agglomeration may take place if the right
medium is chosen
29.3.3 Dispersion Methods • A raw material having very small particles with a high
tendency for agglomeration points to the use of an oint-
Agglomeration might be the cause of poor flowability, for ment mill if a semisolid can be used.
instance of a powder mixture for filling of capsules or tablet • If the percentage of solids in ointments is more than about
dies. The addition of anhydrous colloidal silica (Aerosil 10 % or if the batch size exceeds 200 g the use of an
200V) may be effective for the dispersion of agglomerates. ointment mill is preferred.
Silica is added to 0.5–1 % (w/w) of the total weight of active • A rotor-stator mixer requires a sufficiently large volume
substance and excipients. and is unsuitable for viscous and foaming media.
Flowability can be measured (quantitated) by determin- The choice of the mixing tool which is able to reduce particle
ing the angle of repose, flow through an orifice or tapped and size and to eliminate agglomerates depends of the physical
bulk density [30]. characteristics of the preparation. The most suitable ones are:
For dispersion of agglomerates amid another substance • For powders: mortar, mechanical mill, blender.
usually a (non-rough) pestle and mortar, an three roll mill • For liquid suspensions: rotor-stator, Stephan mixer, other
(ointment mill, see Sect. 28.6.6) or a rotor-stator mixer (see mixers (e.g. Unguator®).
Sect. 28.6.2) are used as a tool. Sometimes a beaker mixer/ • For suspension-type semisolids: mortar, mixer, ointment
blender (Sect. 28.6.5) or the Stephan® mixer (Sect. 28.6.1) mill, spatula.
is used). Trituration of an active substance with eye ointment • For emulsions: rotor-stator mixer, high pressure
base is done in a stone mortar with a stone pestle because a homogeniser, ointment mill.
lot of force is needed. Sometimes it is possible to disperse
agglomerates on an ointment tile with a spatula, but a draw-
back is that no great force can be exerted. For the dispersion
of a solid substance amid other solids, a plastic or metal 29.4 Mixing of Solid Substances
mortar can be used.
To choose the most appropriate method for dispersing 29.4.1 Orientation
agglomerates some basic rules are given:
• For small quantities, it is first investigated whether tritu- A characteristic feature in mixing solid substances is that
ration with the medium in a mortar yields the required temporary expansion is necessary. After mixing, demixing
dispersion. may occur when the mixture is brought into motion.
Mixing of solids takes place in the pharmacy in the The best attainable mixing in that case is a statistically
preparation of capsules, single-dose powders and multidose random mixture (see Fig. 29.5). A fully homogeneous and
powders. But also in the preparation of suppositories and regular mixture (Fig. 29.6) is impossible to obtain in
dermal preparations solids may first be mixed together practice.
before they are combined with the base. A common reason In a random mixture the probability that a sample
for this is that mixing solids may give an opportunity to: contains a certain amount of active substance is equal
• Disperse agglomerates (morphine hydrochloride with throughout the entire mixture. This probability is propor-
lactose) tional to the fraction of active substance present in the
• Making carbomer hydrophilic (‘hydrophilise’) with mixture. Theoretically, this applies only if the particles of
disodium edetate and trometamol) the substances in the mixture have the same shape, size and
• Improve handling (paracetamol (45) with anhydrous density, and if there are minimal surface forces in action
colloidal silica) such as moisture, electrostatic charge, or, for small particles,
In the next sections two types of mixing of solids are Van der Waals forces.
discussed: random mixing and ordered mixing. In practice, The variation of the fraction of component (an active
the mixing process mostly consists of a combination of the substance) in a random mixture can be calculated using the
two. Dispersion of agglomerates may precede the mixing of formula: [27]
solids or it may take place simultaneously [26].
The actual mixing (geometrically dilution method and rsd ¼ ð pð1 pÞ=nÞ½ 100 % ð29:1Þ
wrapping method) is discussed thereafter. The best mixing
quality is obtained when the mixing ratio of two solids is 1 to where rsd ¼ relative standard deviation, p ¼ the fraction of
1 (geometrical dilution), and the particle size is equal. A large active substance of the mixture and n ¼ the total number of
mixing ratio, and a large difference in particle size, will lead particles per sample.
to a long mixing time to obtain a homogeneous mixture [2]. With this formula the influence of the number of particles
and the mixing ratio on the theoretically achievable homo-
geneity can be demonstrated. If the number of particles (n) in
29.4.2 Random Mixing the mixture increases, the relative standard deviation will
decrease. With an equal number of particles in a sample, the
The term random mixing is used when the particles to be rsd strongly increases as the fraction of active substance
mixed show no cohesive or adhesive forces to each other. (p) in the mixture decreases.
PRODUCTION
Fig. 29.5 Statistically random mixture (from Twitchell [27], with Fig. 29.6 Fully homogeneous and regular mixture (from Twitchell
permission) [27], with permission)
• Convective mixing: portions of the powder mixture move

Suppose that the rsd for mixing must not exceed in relation to each other
5.0 % to meet the requirements for content uniformity. • Mixing under the influence of shear forces
If an active substance is mixed with an equal number (see also Sect. 28.6)
of particles of another substance (p ¼ 0.5), a total of at
least 400 particles per dose unit will be present at the
Shear forces are especially important when disper-
best attainable mixing. To a mixture of 1 % of active
sion has to be achieved during mixing. The shear
substance (p ¼ 0.01), the number of particles per dose
forces in low shear mixing equipment (mixing cube,
unit has to be 40,000 or more to meet the same
Turbula® mixer, Stephan mixer) are weak and are
requirement. From this calculation it appears that in
sometimes insufficient to disperse agglomerates. In a
case of an unfavourable mixing ratio (p is small) more
mortar with pestle and in medium shear mixers
particles in the sample (i.e. smaller particles) are
(e.g. Nauta® mixer) or high shear mixers (e.g. IKA®
needed.
mill) the shear forces are often big enough. In excep-
tional cases joint grinding of materials (co-milling) is
necessary to reach adequate mixing.
29.4.3 Ordered Mixing For good mixing, preferential directions must be

avoided. This can be achieved by combining the three
When a substance consisting of very small particles is mixed above mentioned modes in a mixing process. A preparation
with a substance consisting of larger particles, adhesion forces worksheet should give sufficient details on the mixing
between the small and large particles may start to play a role. The procedure:
smaller particles will be distributed onto the larger ones, which • Degree of filling, respectively the size of the mortar: in a
act as a carrier. The mechanism for this may be incorporation of mixing device there must be sufficient space for expan-
the particles in irregularities on the surface of the carrier or, for sion of the powder mixture and therefore it may not be
larger quantities of the active substance, formation of a film of filled to more than two-thirds
small particles on the carrier material. Both electrostatic and • Order of adding substances
mechanical forces take part in this distribution [27]. • Quantities to be added for each mixing step
This phenomenon is designated as ordered mixing, although • Mixing speed (if the process is automatic)
random distribution plays a role here as well. When ordered • Mixing time: as a consequence of mixing too long, sepa-
mixing can be used a very good mixing quality is obtained, with ration of the mixture can occur [30].
less chance of demixing compared to random mixtures. For information on mixing equipment, see Sect. 28.6.
But with ordered mixing demixing is possible as well:
• If there are insufficient sites for adhesion at the carrier.
• If the particles of the carrier largely differ in size; the 29.4.4.1 Geometrical Mixing and Wrapping
carrier particles will demix and because carrier particles Method
of various sizes adsorb different amounts of active sub- The mixing of powders in a pharmacy is typically done in
stance, this demixing may result in a considerable varia- equal parts using a mortar and pestle together with a spatula
tion of the amount of active substance per unit weight. (geometrical dilution technique) [2]. It can be considered as
• If another substance is added to the mixture that competes a combination of convective mixing and mixing under the
with the adsorbed active substance particles: a fraction of influence of shear forces. Firstly, the substance available in
the active substance can be released if there are insuffi- the smallest amount is mixed in the mortar with (as a rule) an
cient interaction sites on the carrier particles for both. equal amount of the substance available in the second
For some capsule preparations in pharmacies ordered mixing smallest quantity. Subsequently as much substance as is
may be the case. Mixing as the result of the solvent method already present in the mortar is added, etcetera, until all
may be considered as such (Sect. 4.5.1). ingredients are well mixed. If only one active substance is
processed, it must first be mixed with an equally large
amount of filler. By applying this method of mixing, diffu-
29.4.4 Mixing Methods sive and convective mixing alternate. It provides the best
mixing quality. Moreover, in this way, the small fraction is
Three methods of mixing of solids are distinguished: maximally involved in the mixing process. Sometimes this
• Diffusive mixing: the particles roll on top of each other method of mixing (in a mortar) is applied as a first step
under the influence of the gravity (pre-mixing), preceding mixing with mechanical mixers.
Using a Turbula® mixer mixing starts with shear forces, 29.4.4.2 Demixing
followed by a combination of (low) shear forces and diffu- Demixing counteracts the achievement of a homogeneous mix-
sive mixing. ture. The extent to which and the ease with which separation can
Many modern active substances show strong agglomer- occur is dependent on material properties, the mixing method
ation, the powder is electrostatic and jumpy. When mixing, applied and external influences during storage and transport.
the agglomerates must be dispersed simultaneously. How- External influences that may cause demixing are
ever, before such substances have been mixed with other gravity, movement, fall and vibrations. When a powder
substances they already adhere to the wall of the mortar or mixture is stocked, e.g. a trituration, it must be
the pestle or disappear from the mortar with the airflow in examined whether demixing occurs. This also applies to
the dust exhaust hood. Without precautions loss of these a possible transport thereof. Cutaneous powders may
active substances occurs during mixing in the mortar and in demix as a result of the shaking movements applied
other open vessels. The loss can be prevented by wrapping during use.
the active substance between two layers of filler first, prior Substance properties are an issue in the following ways of
to mixing and the dispersion of agglomerates. This is called demixing:
the wrapping method. Subsequently the principle of geo- • Differences in particle size lead to separation in poorly
metrically mixing is applied. When a stainless steel cube flowing mixtures.
mixer is used, there is no essential difference between • Differences in density lead to separation in well flowing
mixing with and without wrapping packing the active mixtures.
substance. • Differences in the shape of the particles and in electro-
In extemporaneous preparation, the mixing time in a static charge can lead to demixing.
mortar is frequently determined by visual assessment of the The mixing method may cause demixing in the following
mixture after the procedure has been validated. Usually a ways:
mixing time of powders in a mortar should not be shorter • The occurrence of preferred movements in the mixing
than 3–4 min. For larger scale preparations the required process itself. When mixing in a mortar and pestle, for
mixing times have to be assessed by analysis and validated. example, it is necessary to alternate horizontal (diffusive)
Mixing times may differ quite a lot, depending on material mixing by alternate (convective) mixing with a spatula.
properties, such as particle size, mixing ratio and volume of Good mixers are so designed that preferred movements
the powders. do not occur. The mixing process should be abruptly
PRODUCTION
An example of the effect of mixing time for size was reduced to an average of 26 μm (range
Benzocaine (as a model substance) is illustrated with 10–40 μm) (middle). Continuing pulverisation for
microphotographs (Fig. 29.7). Benzocaine (crystalline 10 and 15 min reduced the particle size to an average
particles in a range of 50–250 μm) (left) was of 5 μm (range 2–8 μm) and 2.5 μm (range
pulverised in a porcelain mortar for 1 min. The particle 1.5–3.5 μm) respectively (right picture).
Fig. 29.7 Particle size reduction of benzocaine in relation to mixing time. Left picture: no pulverisation; middle picture: 1 min
pulverisation in mortar; right picture: 10–15 min pulverisation in mortar. # Department of Pharmaceutical Technology GUMed Gdansk.
(continued)
Table 29.5 Basis for Cutaneous Powder [31]

Zinc oxide 10 g Viscosity enhancers easily form lumps, after which
Talc 90 g they do not dissolve. To avoid this during a preparation,
Total 100 g
they must first be finely divided by trituration, by dis-
persing with a rotor-stator mixer or by sprinkling them
Preparation: Mix zinc oxide and talc and pass through sieve no. 90. Mix slowly on the surface of the vigorously mixed water.
again
The way of processing cellulose derivatives
depends on the type. Some should be moistened with
ended. Slowly reducing the forces in one of the directions hot water, in which they do not dissolve, and thicken
can lead to demixing. only upon cooling. See Sect. 23.7.
• Also good flowability can lead to demixing. Particles If carbomer would be suspended in a mortar with
flow too easily past each other, making them demix by water, it would result in a lumpy mixture. In the prepara-
difference in density or particle size or both. tion of carbomer gel the carbomer is therefore processed
• When sieving a mixture (sieve sizes in Sect. 23.1.8), the in a different way. It is finely distributed with a rotor-
particles of various substances may pass the sieve openings stator mixer, or first (dry) mixed with the readily water
with different speed, mainly because of differences in size soluble substances disodium edetate and trometamol
and shape. As this may cause demixing, remixing is needed (hydrophylisation). If this mixture is subsequently
after sieving, As an example Basis for cutaneous powder triturated with water, no lumps will occur. Alternatively,
FNA is mentioned (see Table 29.5), in which preparation a carbomer gel may be prepared by adding carbomer in
talc and zinc oxide are mixed, sieved and mixed again. portions to vigorously stirred water or an aqueous solution
followed by adding the alkaline solution. It is an advan-
tage of carbomer, as opposed to cellulose derivatives, that
it is easy to use for the preparation of a gel.
29.5 Dissolving Solid Substances
Dissolution in aqueous environment is a prerequisite for the In pharmacy preparations, various methods are used to
absorption of any active substance. Furthermore, the solubil- dissolve a solid substance in a liquid:
ity behaviour of an active substance may influence the • Swirling in an Erlenmeyer flask
choice of a pharmaceutical formulation. • Shaking or swinging in a closed vessel
Dissolution of a solid into a liquid can, in principle, occur • Stirring with a glass rod or spoon in a beaker or with a
spontaneously by diffusion, but that may take quite some magnetic or mechanical stirrer
time. Once dissolved, a molecular distribution of the • Using an ultrasonic bath (sometimes)
substances in one another exists (solution) and no separation If there are semisolid ingredients they can be dissolved in a
will occur. Diffusion becomes progressively slower as the metal mortar or in a porcelain dish while warming on a water
saturation concentration (solubility) is reached (Noyes- bath. Inhomogeneity of solutions may look like trails or
Whitney equation, see Eq. 18.1). The diffusion can be strings.
accelerated in a pharmacy preparation by shaking, swirling, Heating has to be applied if saturated or supersaturated
stirring and eventually heating. Semisolid substances, such solutions are prepared (see Sect. 18.1.6). To create a nearly
as fats and macrogols, nearly always have to be dissolved saturated solution, another approach starts with a medium in
under heating (via melting). which the necessary concentration for supersaturation can be
The dissolution rate of a solid substance in a liquid can be easily dissolved: using cosolvents or a different pH. In the
increased in three different ways: first case, a small amount of solvent is used in which the
1. By first squeezing any lumps. substance is very soluble, after which it is filled up to volume
2. By using a quality with finer particles. This is only with the desired solvent. In the second case, a pH is chosen at
necessary when the substance dissolves extremely which a substance dissolves easily and then the solution is
slowly. adjusted to the desired pH with acid or base.
3. By dry premixing (trituration) with a substance that is Volatile substances should be added at the end of a prepa-
easily wetted by water. This means that the powder is ration in order to limit the time they may evaporate. If we heat
temporarily hydrophilised. (gently) during the preparation process, the mixing vessel
Mixing with a well wettable substance is needed for poorly must be covered. This is required, for example, when sorbic
wettable substances that otherwise in contact with water will acid, which is volatile with water vapour, is dissolved in
form lumps with a water inaccessible core. water under boiling. Fragrances are added to a cold mass.
Sorbic acid is a preservative at a concentration of 29.6 Mixing of Liquids, Semisolid

0.1–0.2 % in, for example, creams. In order to obtain Substances and Molten Solid
this concentration, sorbic acid should be present as a Substances
nearly saturated solution in the water phase. In prepa-
ration, sorbic acid thus must be dissolved in water As with dissolving of solid substances, the mixing of liquids
under boiling. An alternative method is to start with that dissolve in each other, occurs spontaneously by diffu-
the good water-soluble potassium sorbate followed by sion. This process is slower with semisolids and molten
acidifying the cream, yielding a pH at which sorbic substances. If the mixture is homogeneous, no separation
acid is present in its acid form. A third way is to will occur. Diffusion can be accelerated by shaking,
dissolve sorbic acid initially in a small amount of swirling, stirring and heating.
ethanol, followed by mixing with the cream. In pharmacy preparations the same methods are being
In manufacturing, parabens are often added as used as for dissolving substances. Mixing of fluids becomes
solutions in ethanol. more difficult with increasing viscosity and with increasing
differences in density.
The addition of a solid substance in solution to an intermedi-

Vitamin K oral solution is prepared by mixing the
ate or to another medium is applicable only if it is fully soluble
viscous raw material phytomenadione with refined
in the complete product at its storage temperature. A substance
arachis oil. It appears to be difficult to obtain a homoge-
for which this does not apply will crystallise in the product, and
neous mixture with swirling small quantities in a bottle.
this can lead to an uneven distribution of the active substance.
The right approach is firstly getting phytomenadione,
Such substances should be processed like insoluble substances.
kept in the refrigerator, to room temperature, to decrease
its viscosity. Mixing is best performed in a transparent
In the preparation of Triamcinolone Ointment 0.1 % vessel (e.g., a conical flask) which enables the homoge-
FNA (Table 29.6) triamcinolone acetonide is neity to be checked by the naked eye. If not homoge-
dissolved in propylene glycol, 100 mg per 10 g. neous yet, the liquid may show trails or strings.
Upon addition of other ingredients (wool fat and
white soft paraffin) triamcinolone acetonide remains Semisolid or solid fatty substances are mixed by melting
dissolved. In the preparation of Triamcinolone them together in a metal vessel on a water bath, or under a
PRODUCTION
acetonide Cream 0.1 % FNA (Table 29.7), the same heating lamp. The use of a microwave oven is not a good
method, however, would lead to crystallisation of tri- option, since the process is not easily controlled. Liquid and
amcinolone acetonide coming from propylene glycol semisolid substances can be mixed without heating when the
in a propylene glycol-water mixture in which it is semisolid is not too tough. After melting, the mass is stirred
considerably less soluble. In this preparation, triam- until cool to obtain a homogeneous mixture. Inclusion of air
cinolone acetonide as a powder must therefore be must be avoided as much as possible in order to prevent
triturated with the cream base. oxidation of the fats. The Unguator and the Stephan mixer
Table 29.6 Triamcinolone Acetonide Ointment [32] (with vacuum) are suitable devices for this purpose (see
Triamcinolonacetonide 0.1 g Sects. 28.6.8 and 28.6.1).
Propylene glycol 10 g During intensive mixing, particularly when surfactants
Wool fat 10 g are present, substantial aeration and foaming may occur. If
Paraffin, white soft 79.9 g the preparation is viscous or semisolid it will take a long
Total 100 g
time to remove the enclosed air. Leaving the product under
vacuum or applying vacuum during the mixing process may
be necessary to avoid oxidation of the active substance due
Table 29.7 Triamcinolonacetonide Cream [33] to air present in the preparation.
Triamcinolonacetonide, micronised 0.1 g
Sorbic acid 0.2 g
Cetomacrogol emulsifying wax 15 g
29.7 Dispersing in Liquids and Semisolids
Decyloleate 20 g
Sorbitol liquid crystallising 49 g
In this section the preparation of disperse systems or
dispersions is discussed. Dispersions are mixtures consisting
Total 100 g
of a (liquid or solid) substance that is finely divided into
another (liquid or semisolid, see Sect. 29.7.1) substance.
Liquid and semisolid disperse systems are distinguished. substance, the particles will hinder each other in their move-
The act of preparing a dispersion is called ‘to disperse’. The ment. As a result, the viscosity of the preparation increases
term dispersing is used to indicate that a solid or liquid and the risk of sedimentation decreases.
substance is mixed with a liquid or a semisolid substance Also at the end of the manufacturing process, e.g. at the
to obtain a two-phase system, an emulsion or a suspension phase of filling in the package, separation by sedimentation
(see Sect. 18.4). is a crucial point. Then, keeping a suspension homogeneous
In pharmacy preparations several different types of dis- by stirring is most critical since sedimentation quickly leads
perse systems are found. Liquid dispersions are dispersions to differences in content. Inhomogeneity can be avoided by
in which a solid substance is dispersed into a liquid sub- continuous mixing during the filling process or by mixing
stance, such as suspensions for cutaneous applications and each time before, e.g. the next bottle or suppository, is filled.
oral suspensions, and dispersions in which a liquid is dis- In the preparation of suppositories mixing in a mortar
persed in a non-miscible liquid, such as emulsions and (mainly consisting of horizontal movements) with the mol-
solubilisations. ten suppository base is not sufficiently effective for this
Suppositories are semisolid dispersions in which a solid purpose. Sedimentation, and thus deviations in the content
substance is dispersed in a (melted) semisolid base at the of suppositories, is not prevented in that case.
time of preparation. In the following paragraphs the disper- The method of preparation applied for a suspension
sion of a solid into a liquid and a semisolid substance as well depends on the formulation. Therefore it is referred to the
as the dispersion of a liquid into a non-miscible liquid will be following relevant Sects.: 11.5.3 for suppositories, 5.5.4 for
discussed. suspensions for oral use, 12.6.2 for cutaneous preparations
and 13.5.7 for suspensions for parenteral use.
29.7.1 Dispersing a Solid into a Liquid

29.7.2 Dispersion of a Solid into a Semisolid
Dispersing a solid into a liquid may be done by trituration in a Substance
mortar (see Sect. 29.3). The first step in the preparation is
usually the dispersion of agglomerates and wetting of the Mixing solid substances with semisolid substances in which
particles. Then the active substance should be homogeneously they do not dissolve is mainly seen in creams and ointments.
distributed into the entire preparation. Dispersion can also be The first preparation step usually consists of the dispersion
done by vigorous mixing with a rotor-stator mixer. This of agglomerates by triturating in a mortar (see Sect. 23.3).
method is mainly used if the solid is added at once or in Then a homogeneous distribution of the active substance in
parts, to all of the liquid (or all of the semisolid). the semisolid base is gained by geometrically dilution and
The dispersion of a solid into a liquid can be found in triturating. Characteristic for this mixing process is that
dosage forms such as mixtures, dermatologic preparations, energy is needed to obtain a homogeneous mixture.
suppositories, enemas, and eye drops. Characteristic for this In pharmacy preparations, a mortar with pestle or
process is the requirement of energy to obtain a homoge- mechanical mixing equipment is used for the dispersion of
neous mixture; furthermore, often separation occurs upon a solid into a semisolid. A mortar with pestle is normally not
storage. This does not apply for suppositories, ointments or suitable for mixing quantities exceeding 500 g especially if
creams, which during the preparation are a dispersion of a the consistency is relatively tough. When mixing in a mortar,
solid into a liquid, but, once solidified, form a semisolid as a rule of thumb portions of the semisolid base are added
dispersion. to the solid while continuously mixing. When using an
A liquid suspension is an unstable system and as a dosage ointment mill to disperse agglomerates, mixing occurs
form, it should not sediment (settle) too fast. By simply locally, whereas in the entire preparation separation may
shaking, a homogeneous preparation should be produced occur. For this reason the preparation should always undergo
that remains homogeneous sufficiently long to assure that a second mixing following the use of an ointment mill.
the right dosage can be measured. The factors causing sedi-
mentation in suspensions can be derived from Stokes’ law
(see Eq. 18.11 in Sect. 18.4.2.1). Too large particles of active A fine homogeneous concentrate of 50 % salicylic
substance and too low viscosity of the medium are the most acid in soft paraffin can be made using an ointment
important factors causing fast sedimentation of the particles. mill. With this concentrate lower concentrations of
To obtain a stable suspension, the particles should be salicylic acid in soft paraffin can be prepared effi-
reduced in size or agglomerates should be dispersed as ciently without using an ointment mill. See Table 29.2
much as possible, or both. The viscosity of the medium can (Sect. 29.1.8).
be increased if necessary. At a high concentration of active
29.7.3 Dispersion of a Liquid into The method of preparation applied for an emulsion or a
a Non-Miscible Liquid solubilisation depends on the composition of the prepara-
tion. Therefore it is referred to the following relevant Sects.:
The dispersion of a liquid into another liquid with which it is 5.5.5 for emulsions for oral use, 5.5.6 for solubilisations for
immiscible to obtain a sufficiently physically stable product oral use, 12.6.1 for cutaneous preparations, and 13.5.7 and
is only possible by emulsifying or solubilising, using 13.9.2 (emulsions for parenteral use).
surface-active substances (tensides, surfactants). This pro-
cess is applied in the preparation of creams and
solubilisations. In oral emulsions surface-active substances
References
are not used, but instead viscosity enhancers that possess
little surface activity. Below the preparation of emulsions 1. Directive 2009/23/EC of the European Parliament and of the Coun-
and solubilisations is briefly discussed. cil of 23 April 2009 on non-automatic weighing instruments. Offi-
The factors that have an impact on the physical stability cial Journal of the European Union, 16 May 2009; L122/6-27.
http://europa.eu
of emulsions, can be derived from Stokes’ Law. It shows that
2. Marriott JF, Wilson KA, Langley CA, Belcher D (2012) Pharma-
the following methods are, in principle, useful for problems ceutical compounding and dispensing, 2nd edn. Pharmaceutical
with creaming or sedimentation (see Sects. 18.4.2 and Press, London
18.4.3): 3. Schnaare RL, Prince SJ (2012) Metrology and pharmaceutical
calculations. In: Felton LA (ed) Remington essentials of
• Finer distribution of the dispersed phase
pharmaceutics. Pharmaceutical Press, London, pp 101–132
• Increase the viscosity of the medium 4. Working Group 1 of the Joint Committee for Guides in Metrology
• Reduction of the difference in density between the two (JCGM/WG1) (2008) Guide to the expression of uncertainty in
phases measurement. Evaluation of measurement data. Sèvres Cedex (F);
Bureau International des Poids et Mesures (BIPM)/Joint Committee
In the practice of pharmacy preparations, it is usual to try to
for Guides in Metrology (JCGM); 100. www.bipm.org
distribute the dispersed phase more finely with a rotor-stator 5. Working Group 2 of the Joint Committee for Guides in Metrology
mixer or a simple mechanical (paddle) mixer (pourable (JCGM/WG2) (2012) International vocabulary of metrology –
emulsions), or, for semisolid emulsions, with a mortar and basic and general concepts and associated terms (VIM). Sèvres
Cedex (F); Bureau International des Poids et Mesures (BIPM)/
pestle or a mixing device. Magnetic stirrers are unsuitable.
Joint Committee for Guides in Metrology (JCGM); 200. www.
Impaction of air should be avoided because the liberation of bipm.org
air bubbles can accelerate the creaming process (in case 6. ISO 5725-1 (1994) Accuracy (trueness and precision) of measure-
of pourable emulsions) and promote possible oxidation ment methods and results. Part 1: General principles and
definitions. International Organization for Standization (ISO),
of the lipid base or of an active substance. A Stephan
PRODUCTION
Geneva. www.iso.org
mixer with vacuum (see Sect. 28.6.1) is a suitable device 7. Radwag (2010) Good weighing practice in pharmaceutical indus-
for the preparation of emulsions without inclusion of air. try. Pharmacy risk assessment for mass measurement processes.
Emulsions for oral use cannot be prepared with a surfac- Radwag Wagi Elektroniczne, Radom. www.radwag.com
8. OMCL Network of the Council of Europe (2013) Qualification of
tant, because at high doses these substances are harmful for
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Emulsions for oral use are stabilised with viscosity 9. Anonymus (2014) The United States pharmacopeia USP 37/The
enhancers. Such emulsions are less stable than emulsions National Formulary NF 32. The United States Pharmacopeial Con-
vention, Rockville. (2015) <41> Balances. Page 52
prepared using surface active excipients and can quickly
10. Boer Y (1985) Gehalte-eisen en weegonnauwkeurigheid. Pharm
show creaming. Creaming is a reversible process, while Weekbl 120:958–969
coalescence leads to large droplet sizes of the internal 11. Chloorhexidinedigluconaatmondspoeling 0,2% FNA (2013)
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Nederlandse Maatschappij ter bevordering der Pharmacie
phase to float on top. (Intensive) shaking may restore a
(KNMP), Den Haag
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Mettler-Toledo AG, Greifensee (Switzerland). www.mt.com
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Sterilisation Methods
30
Marco Prins and Mattias Paulsson
Contents Abstract
This chapter discusses sterilisation methods and equip-
30.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
ment for the sterilisation of medicinal products, medical
30.2 The Death of Micro-Organisms . . . . . . . . . . . . . . . . . . . . . . . . 678 devices and utensils. Sterilisation is an active, validated
30.3 Sterilisation Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679 process in order to kill micro-organisms. It is the most
30.4 Initial Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680 critical step in the preparation of sterile products. The
achievement of the absolute state of sterility cannot be
30.5 Terminal Sterilisation Methods . . . . . . . . . . . . . . . . . . . . . . . . 680
30.5.1 Steam (and Hot Water) Sterilisation . . . . . . . . . . . . . . . . . . . . . 681 demonstrated, sterility can be defined only in terms of
30.5.2 Dry Heat Sterilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684 probability.
30.5.3 Ionising Radiation Sterilisation . . . . . . . . . . . . . . . . . . . . . . . . . . 685 Classical sterilisation techniques using an autoclave and
30.5.4 Gas Sterilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685 saturated steam under pressure, hot water or dry heat are
30.6 Filtration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687 practical and reliable. Other reliable sterilisation methods
30.6.1 Sterilisation by Membrane Filtration . . . . . . . . . . . . . . . . . . . . 687 include membrane filtration, ionising radiation sterilisation
30.6.2 Theory of Membrane Filtration . . . . . . . . . . . . . . . . . . . . . . . . . . 687
(gamma and electron-beam radiation) and gas sterilisation
30.6.3 Retention Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
30.6.4 Application of Membrane Filters . . . . . . . . . . . . . . . . . . . . . . . . 688 (ethylene oxide, formaldehyde). Sterilisation equipment
30.6.5 Integrity Testing of Membrane Filters . . . . . . . . . . . . . . . . . . . 689 (autoclaves, membrane filters, and other sterilisers) is
30.7 Heating at 100 C over Boiling Water . . . . . . . . . . . . . . . . 692 often used in industrial manufacturing, in preparation in
pharmacies, and in other healthcare establishments. Stan-
30.8 Choosing the Best Sterilisation Method for Medicinal
Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
dard sterilisation processes are described in the Ph. Eur., in
other current Pharmacopoeias, in ISO standards and
30.9 Sterility Testing and Parametric Release . . . . . . . . . . . . . 692 National guidelines.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 The efficacy of any sterilisation process depends on
the nature of the product and container, the extent and
type of any contamination before sterilisation, the pro-
duction and sterilisation conditions. Pre-cleaning of
materials and pre-filtration by membrane filtration
result in a low bioburden. Process validation, quality
assurance and quality control are necessary to secure
sterility.
Keywords
Based upon the chapter ‘Sterilisatiemethoden’ by Frits Boom, Ewoudt Sterilisation Autoclave Sterile products Saturated
van de Garde and Philip de Vries in the 2009 edition of steam Hot air Dry heat Radiation Ethylene oxide
Recepteerkunde.
Hydrogen peroxide Plasma Membrane filtration Gas
A.M.A. Prins (*) sterilisation
Jeroen Bosch Ziekenhuis, s-Hertogenbosch, The Netherlands
M. Paulsson
Uppsala University Hospital, Uppsala, Sweden

678 A.M.A. Prins and M. Paulsson
30.1 Introduction 103
number of surviving
micro-organisms
Sterility is the absence of viable micro-organisms 100
[1]. Sterilisation is an active, validated process in order to D= D
10 =6 D=
kill micro-organisms. It is the most critical step in the prep- ,7 10
aration of sterile medicinal products, sterile medical 10-3
instruments and sterile pharmaceutical utensils. These
methods are used to obtain sterile medicines, active
substances, medical devices or devices used in pharmaceuti- 10-6
cal production equipment. Sterilisation of healthcare 0 10 20 30 40 50 60
products makes use of many specific terminology; this may sterilisation time (min)
be found in ISO [2] as well in the EU-GMP Annex 1 [3].
Fig. 30.1 Elimination curves of two types of micro-organisms with
different D-values resp. micro-organisms with
the same D-value but
different initial contamination level at 100 C heating temperature.
30.2 The Death of Micro-Organisms Source: Recepteerkunde 2009, #KNMP
The death of micro-organisms during sterilisation processes SAL also describes the killing efficacy of a sterilisation
usually follows first-order kinetics when the population is process. A very effective sterilisation process has a very low
homogeneous, which means that during every unit of time SAL. A SAL of 106 corresponds to the probability of not
the same fraction of micro-organisms is being killed. This more than one micro-organism present in 106 (one million)
kinetics can be described by the following equations: sterilised units of the product.
As for pharmacokinetics and reaction kinetics, rate
dN=dt ¼ kN ð30:1Þ parameters can be defined for sterilisation processes, such
as the first-order reaction rate constant (k) with the dimen-
or after integration sion reciprocal time and the half-life (t1/2). However, more
commonly the term decimal reduction time or D-value is
Nt ¼ N0 ekt ð30:2Þ used. The D-value is the time required to inactivate 90 % of
the present micro-organisms.
or The D-value, half-life, and k are related as follows:
logðNt =N0 Þ ¼ kt=2:3 ¼ t=D ð30:3Þ D ¼ 2:3=k ¼ 3:323 t1=2 ð30:4Þ
In these equations N is the number of living micro- The D-value is thus, like k and t1/2, a measure for the resis-
organisms at time 0 and time t respectively, k is the first- tance of the micro-organism to the sterilisation process that is
order reaction constant, and D is the decimal reduction time. applied. D is influenced by environmental factors and the state
When the logarithm of the number of surviving the micro-organism is in, especially the hydration state.
organisms is plotted against sterilisation time in a semi- The D-value is always defined for a certain temperature
logarithmic graphic, a straight line is obtained (see and for a defined process. Table 30.1 presents a number of
Fig. 30.1). D-values for micro-organisms. Spores of Bacillus and Clos-
When the number of surviving micro-organisms is plot- tridium strains have the highest heat resistance.
ted directly (not logarithmic) against time, a curve is Micro-organisms are killed faster at high temperature
obtained which approaches the X-axis asymptotically with than at low temperature. In order to quantify the change in
time. This means that theoretically the zero value is never resistance of a micro-organism in response to a change in
reached. In time, the chance of a residual contamination with temperature, the Z-value has been introduced. The Z-value is
micro-organisms becomes smaller and smaller. Therefore, the number of degrees of temperature increase required to
sterility, if defined as the absolute absence of micro- decrease the D-value by a factor 10.
organisms, can never be guaranteed nor proved. The descrip-
tion sterility assurance level (SAL) is used instead [1]. It is Z ¼ ðT2 T1 Þ=ðlogD1 logD2 Þ ð30:5Þ
the probability of a single unit being non-sterile after it has
been subjected to sterilisation. It is important to note that In practice, the Z-value of a bacterial strain is calculated
when stating “1 container in 106 may not be sterile” this does from the D-value at different temperatures (see Fig. 30.2).
not mean that it is acceptable for 1 container to be unsterile. These D values are not absolute but depend on the method of
30 Sterilisation Methods 679
Table 30.1 Thermo-resistant micro-organisms; T ¼ temperature of Ph.Eur. is 121 oC for 15 min and complies with this require-
D-value, D-value see text [4] ment. The overkill method is used when the product can
Micro-organism Medium T ( C) D-value (min) withstand excessive heat treatment such as an Fo 12 with-
Geobacillus stearothermophilusa Water 121 2 out adverse effects. Bioburden and resistance data are not
Bacillus subtilisa Air 160 5–10 required to determine the required ‘Fo’ values.
Bacillus subtilisa Water 100 11.3 The bioburden process is based on the initial contamina-
Clostridium sporogenesa Water 121 0.8–1.4 tion before sterilisation, and thus it is a tailored sterilisation
Clostridium botulinuma Water 121 0.2 process. Bioburden based sterilisation cycles are not com-
Non-spore-forming bacteria Water 65.5 0.5–1 monly used in Europe. Prerequisite is that the number and
a
spores of them thermo-resistance of the micro-organisms in the product are
documented, based on which the customised sterilisation
time can be calculated. An example can be found for paren-
log D
5
teral solutions (for injection, for infusion) in reference [4]. In
4 this example, N0 is 1 (rounded up) and the D-value at 100 C
of the most resistant micro-organism is approximately
3 2 min. Using equation 30.3, it can be calculated that a SAL
of 106 will be obtained after 12 min.
2 There are basically two possibilities for determination of
the sterilisation time of the overkill procedure:
1 • The autoclave computer software waits for the tempera-
ture in the Pt-100 in the product on the coldest spot
0 having reached the set maximum process temperature
z temperature (°C)
(for example 121 oC) and keeps the load at this tempera-
-1
ture for a specified duration (15 min); after that the
cooling phase starts.
-2
• The autoclave computer software takes into account the
elimination of micro-organisms during the heating and
Fig. 30.2 Calculation of the Z-value from the relationship between the cooling phases and adds the time that the product is kept
decimal reduction time D and the temperature. Source: Recepteerkunde at the maximum process temperature. The total lethality
2009, #KNMP
(the elimination effect) is not only obtained during the
PRODUCTION
sterilisation phase, but during the heating and cooling
preparation of the spores. For precise calculations the phase germs die as well. The phase of maximum process
D value must be obtained for each batch made from the temperature can be shorter in that case (but shortening of
supplier. This is particularly important where Geobacillus the sterilisation time at maximum temperature is not used
stearothermophilus is used as biological indicator. when not necessary). The contribution of these three phases
and subsequently the total lethality of the sterilisation pro-
cess are dependent on the Z-value of the micro-organism(s)
30.3 Sterilisation Time concerned. Autoclaves are equipped with computer soft-
ware that can easily calculate these parameters.
The sterilisation time that is required to obtain sterility at a For both the calculation of the lethality during the heating and
certain temperature is dependent on the number and the cooling phase and the comparison of sterilisation processes at
resistance of the micro-organisms present in or on the prod- various temperatures, the F-value has been introduced. The
uct. An initial contamination with 106 of a certain micro- F-value of a sterilisation process at a certain specified temper-
organism requires twelve decimal reduction times to obtain ature (not the reference temperature) is the number of minutes
the SAL of 106, see equation 30.3. that a sterilisation process would need to last at a reference
In theory two sterilisation processes can be distinguished: temperature (usually 121 C) to obtain the same degree of
the overkill process and the bioburden process. elimination. This is expressed by the equation:
The overkill process is often used in daily practice and is
based on the principle that the process should be sufficiently logFzT1 ¼ ðTR T1 Þ=Z þ logFzTR ð30:6Þ
powerful to reduce a severe contamination with a very
thermo-resistant organism, i.e. circa 106 spores of In which FzT1 is the time at temperature T1, and FzTR is the time
Geobacillus stearothermophilus, to the SAL 106. The stan- with the same lethality at the reference temperature TR and Z
dard process for steam or hot water sterilisation in the is the Z-value.
For example, if after the calculation of the contribution of between filling the primary packaging and sterilisation
heating and cooling a sterilisation is performed that should be kept short, usually maximal four hours. However
corresponds to 15 min sterilisation at 121 C, the F-value this time period may be somewhat longer in special cases,
is 15 (F121 ¼ 15). according to a risk assessment.
The Z-value is a measure for the change in resistance of Final filtration through a sterile 0.2 μm membrane filter is
the micro-organism following the change in temperature. not only a sterilisation method, but also an effective way to
Therefore, the Z-value should always be mentioned in the reduce the initial level of contamination. A pre-filtration
notation of the F-value. For steam and hot-water (often in-line) with a coarser pre-filter (for example
sterilisation, usually a Z-value of 10 C is used. 1.2 μm) is necessary to reduce coarser foreign particles and

F121 C10 C ¼ 15 thus means an F-value of 15 min at contamination and to prevent early clogging of the 0.2 μm

121 C calculated with a Z-value of 10 C. membrane filter.

F121 C10 C can also be simplified to F0. In general, the Because products that require sterilisation are often aque-
F0-value of a sterilisation process stands for the lethality of ous solutions, the initial microbiological contamination can
that process expressed as the time at 121 C calculated with a easily be determined in the quality control laboratory by the
Z-value of 10. membrane filtration method (see Sect. 19.6.3).
For hot air sterilisation, the influence of the temperature
on the elimination of the micro-organisms is characterised
by the Z-value as well. Moreover, the effectiveness of two
30.5 Terminal Sterilisation Methods
hot-air processes can also be compared with the F-value.
The sterilisation methods (methods of preparation of sterile
products) described in the Ph. Eur. are terminal sterilisation
30.4 Initial Contamination methods and filtration [1]. See for filtration Sect. 30.6. In this
section an overview of terminal sterilisation methods is
The initial contamination, also referred to as pre-sterilisation given.
bioburden, is the contamination of a starting material or Terminal sterilisation methods are:
product just before sterilisation or before a disinfection • Steam sterilisation (heating in an autoclave): steam
procedure is performed. The initial contamination depends sterilisation or sterilisation with hot water in a closed con-
on the degree of contamination of the starting materials tainer, minimum 15 min at 121 C (F0 ¼ 15). The humid
(including water), the packaging material, the storage heat denatures proteins and DNA of micro-organisms.
conditions, the storage time, the preparation processes, and • Dry heat sterilisation: hot air sterilisation at least 2 h at a
the circumstances during production (hygiene). When filtra- minimum of 160 C. Dry heat at temperatures higher than
tion is not performed as a final sterilisation process but as 220 C is used for sterilisation and depyrogenisation of
part of the preparation (removal of particles and lowering of glassware. Sterilisation by dry heat is mainly caused by
the bioburden by membrane filtration), the initial contami- oxidation of micro-organisms.
nation is determined after filtration and measured in the • Ionising radiation sterilisation: an absorbed radiation
filled container, ready for sterilisation. dose of at least 25 kGy. This method leads to breaks in
Bacteria may negatively influence product quality even the DNA of micro-organisms and, in presence of water,
after thermal destruction, for example when pyrogens are the formation of free radicals.
formed from the destruction of bacteria (see Sect. 19.3.4). • Gas sterilisation including gas plasma sterilisation: Gas,
Therefore, it is essential to reduce the initial contamination penetrated with moisture, enters the material to be
as much as possible before sterilisation. This can be done by sterilised, which is followed by the elimination of the
choosing starting materials with a low level of contamina- gas. The gas (ethylene oxide or hydrogen peroxide)
tion, such as containers with sterilised water for injection, alkylates the purine and pyrimidine bases in the RNA
hot or freshly cooled water for injections in bulk or sterilised and DNA of micro-organisms.
base solutions for the preparation of eye drops. Furthermore, All mentioned sterilisation methods allow for different
the equipment and primary packaging should be clean, ster- conditions, as long as the procedures and precautions are
ile, and pyrogen free and direct contact should be avoided chosen as such that a SAL of 106 is obtained [1]. However
between the product, critical unsterile spots on the primary broad sterilisation experience, good knowledge of GMP and
packaging and the hands of the operator. To reduce the process validation are necessary to work with different
growth of micro-organisms and the development of conditions. In many pharmacies and industries the standard
pyrogens in the product that is to be sterilised, the time methods are used in practice.
30.5.1 Steam (and Hot Water) Sterilisation Table 30.2 Temperature-pressure relation of saturated steam
Temperature ( C) Pressure (kPa)
The principle of steam sterilisation for medical devices, 100 101
pharmaceutical products and utensils is based on heat trans- 115 170
fer by hot condensing steam under pressure. The steam 121 204
condenses in the autoclave to pure water, releasing at that 134 304
moment its heat content. This is a very effective means of
heat transfer. Furthermore, the mechanism of inactivation by
saturated steam (denaturation of proteins) is also very effec-
possible to change them. The temperature-time course inside
tive. Therefore, steam sterilisation in an autoclave is the
the steam steriliser is shown in Fig. 30.3.
preferred method for medical devices, utensils and some
Manual control of a pressure cooker is not realistic and
pharmaceutical products. It is of critical importance that
GMP compliant in practice because it does not result in a
the steam in a steam autoclave is completely saturated and
reproducible process. Moreover incidental manual control
not superheated, because only then the sterilisation is effec-
by an operator is only allowed with the authorisation of a
tive. For the details of steam sterilisation reference is made
competent person. GMP compliant autoclaves are entirely
to other textbooks and guidance, such as [4, 5]. The pressure
computer-controlled using multiple pressure and tempera-
of saturated steam at different temperatures is shown in
ture sensors. Processes for control and operation administra-
Table 30.2.
tion are validated.
It is important that either the steam can penetrate into the
object to be sterilised (medical devices or utensils in dedi-
cated steam sterilisation packaging), or that the object in a 30.5.1.2 Process Description of Steam Sterilisation
closed container contains water (content of an ampoule, for Medical Devices
bottle, vial or plastic bag with aqueous solution). In contrast to the sterilisation of liquids in closed containers,
Also ‘empty’ sterile bottles must contain some water for medical devices, such as surgical instruments, require the
injections (and be closed under vacuum) before they can be sterilising steam to penetrate through the packaging material
sterilised by steam or hot water. Without water inside only to reach the surface of the device. The steam condenses on
radiation or heat sterilisation is effective to sterilise an the cold surface, thereby transferring heat to the medical
empty, washed and dried container. device, which results in heating up to the sterilisation tem-
perature. The result is that both the medical device and the
packaging become wet. Since wet packaging is not a barrier
PRODUCTION
30.5.1.1 Steam Autoclave or Steam Steriliser
to micro-organisms, the packaging should be dried during
The steam steriliser is commonly referred to as an autoclave.
and at the end of the sterilisation process. Moreover, the
The simplest steam steriliser, however, is a pressure cooker.
sterilisation agent (steam) should be dry and saturated,
In a pressure cooker, the added distilled or deionised water is
which means that the steam should not contain any air.
heated and eventually begins to boil. The steam that is
formed pushes the air out through the vent valve in the lid.
This is not a very effective process because the vent valve is 30.5.1.3 Packaging Medical Devices
in the upper part of the steriliser and it takes time to remove The packaging of medical devices after cleaning and before
the air just by continuous boiling. Air is heavier than steam, sterilisation should protect the content (against contamina-
so these gases are slowly removed by upwards displacement tion) as well as (during sterilisation) allow for removal of air
to the upper part of the pressure cooker. and penetration of steam. The classical and most often used
In a steam autoclave air is more effectively removed by packaging material is sterlisation paper. Instrumentation kits
downward displacement which makes loading with more are wrapped in sheets of sterilisation paper or non-woven
and differently shaped objects possible as well. After materials that are subsequently sealed with sterilisation tape,
removal of the air, the valve is closed and the steam pressure which usually has a sterilisation indicator.
gradually increases. A pressure control valve is used to set Smaller instruments are packed in sterilisation bags,
the desired pressure, and thereby the desired temperature, which are made of sterilisation paper and transparent plastic.
since these parameters have a fixed relation in the absence of Sterilisation bags are sealed with equipment designed for the
air (see Table 30.2). For control of the temperature and purpose.
duration of the sterilisation process a timer or Programmable The sealed packaging has a defined shelf life during
Logic Controller (PLC) can be used. A PLC is part of the which it should protect the sterilised content against contam-
computer of the autoclave. In a PLC the routine programs ination [5]. The user should be able to open the packaging
are factory set and fixed, so for the process operator it is not aseptically.
Fig. 30.3 Temperature-time temperature (˚C)

course (temperature profile)
during a sterilisation process in an
autoclave (Reprinted with
permission of the publisher [9])
sterilisation temperature
100
room temperature
0
0 sterilisation
heating time cooling time time
time
starting point of the effective sterilisation process
pressure (kPa)
300
200
normal room pressure

100
5 vacuum
1 2 3 4 6
0
time
vacuum and pulsating steam
Fig. 30.4 Sterilisation process for medical devices (Reprinted with permission of the publisher [9])
30.5.1.4 Process Description of Steam Sterilisation During the steam sterilisation of aqueous liquids in closed
of Aqueous Pharmaceutical Products containers (infusion bottle, bag, injection vial, ampoule,
The steam sterilisation process is pressure-controlled and etc.), saturated steam has to heat the container and product
temperature-monitored. The most important steps in the inside the container. Steam condenses first on the colder
steam sterilisation process are (see also Fig. 30.4): surface of the container, which is the method by which
1. Removal of air by repeated pre-vacuum heat is transferred to the aqueous content. In this way,
2. Heating/building up pressure by steam inlet every water containing container becomes a unique steriliser
3. Sterilisation in dry saturated steam itself.
4. Removal of the steam Sterilisation of aqueous liquids in closed containers by
5. Drying by post-vacuum the traditional steam sterilisation process has some
6. Letting in air until atmospheric pressure advantages and some important disadvantages:
The advantage of steam is that closed glass ampoules,

glass injection vials and glass infusion bottles can be
sterilised effectively. Filled and closed ampoules for injec-
heat exchanger
tion are sterilised upside down in perforated stainless steel
cassettes in streaming saturated steam. After sterilisation the
steam autoclave is brought to vacuum. The vacuum dries the
outside of the ampoules. This is used as leak test as well,
because leaking glass ampoules will lose their content in the
vacuum phase. The result is an empty container, which will
be detected in the visual quality control process after
sterilisation.
A disadvantage is that a higher pressure is created within Fig. 30.5 Schematic representation of a hot water steriliser. Source:
the container than outside, which may result in quick, Recepteerkunde 2009, #KNMP
unwanted massive deformation or damage of the heated
container, especially when the containers are made of poly-
During the sterilisation of aqueous solutions by steam or
propylene/polyethylene, flexible multilayer material or
hot water, the temperature within the closed containers
PVC. This may be prevented by adding extra air as
(ampoule, vial, bottle or bag) lags behind the temperature
supporting pressure into the steam autoclave before the
within the steriliser chamber, and during cooling the oppo-
sterilisation process starts. However, the difference in den-
site happens. Both effects are shown in Fig. 30.6.
sity between steam and air may easily lead to segregation
This delayed effect is influenced by the number of
due to a non-homogeneous temperature distribution within
sterilisation units (objects) in one batch: the load of the
an autoclave. Therefore such autoclaves require greater con-
steriliser. It is hard to take all the contributing factors into
trol. Another disadvantage is that the sterilised pharmaceuti-
account for the determination of the correct sterilisation
cal load stores a lot of heat. Natural cooling of the hot load
time. Therefore, the temperature sensor that provides the
under pressure after steam sterilisation takes a very long
input for the control of the sterilising process is placed inside
time in the absence of cooling water, especially when the
a container in the coldest spot of the load. The coldest spot is
steriliser is well insulated. The product temperature of
to be identified by validation studies in a standardised batch
liquids in closed containers remains high in a steam auto-
size and loading scheme.
clave for a too long period. This might result in too much
degradation of the content. These disadavantages of the use
PRODUCTION
of steam sterilisation for the sterilisation of aqueous liquids 30.5.1.6 Validation of Steam and Hot Water
in closed containers can be overcome by using hot water Sterilisers
sterilisation instead. Plastic containers (plastic bags and To ensure an effective and reproducible sterilisation process,
bottles for parenterals use) are sterilised in hot water the steriliser should be qualified (see Sect. 34.15) and all
sterilisers with air pressure support in the sterilisation cham- sterilisation processes and the empty steriliser have to be
ber. Also ampoules, glass vials and glass infusion bottles can validated before first use (see Sect. 34.14). Subsequently all
be sterilised in a hot water autoclave. sterilisation processes are revalidated periodically, mostly
each year. During process validation, the performance of the
combination of steriliser, specific load, and process is
30.5.1.5 Hot Water Sterilisation assessed. Different kinds of loads all require their own
Hot water sterilisers are also called hot water (immersion) validation protocol. For example, validation of the
autoclaves. In these sterilisers, hot distilled water, freshly sterilisation process of aqueous liquids often consists of an
filled in the stainless steel ‘steriliser bath’ and heated in a empty autoclave, an ampoule program and one or more
sanitary heat exchanger is pumped around inside the auto- programs for liquids for infusion in bottles, vials or bags.
clave and is continuously and with high flow sprayed top For medical devices, the load is never homogeneous: multi-
down over the load to be sterilised. The hot water autoclave ple types of loads are sterilised at once. Therefore, validation
contains a mixture of water and air before and during the of this process is done by a worst-case approach.
sterilisation process; no vacuum phase is used (see Validation requires specialised knowledge and calibrated
Fig. 30.5). expensive equipment and is, therefore, often outsourced to a
During the heating and sterilisation phases the circulating certified third party. Based on the validation reports, the
sterilising water is being heated by steam in a heat exchanger responsible person (pharmacist, sterile medical devices
and during the cooling phase the circulating water is being expert) can judge whether each steriliser functions well
cooled by sterilised cooling water in a sanitary heat exchanger. and authorises the final validation report.
Fig. 30.6 Temperature-time heating sterilisation cooling

course in the (steam or hot water)- pressure
steriliser and in the load during kPa
the sterilisation process of temperature inside
aqueous liquids. Source: the product container
Recepteerkunde 2009, #KNMP ˚C
121
water
temperature
O
sterilisation process time
Because of the fundamental difference between 30.5.2 Dry Heat Sterilisation

sterilisation of finished medicinal products and medical
devices (temperature-controlled hot water process vs. - Dry heat is used to sterilise materials that are heat-resistant
pressure-controlled steam process), both processes have but cannot withstand any contact with water or steam.
their own validation directive. Most countries have their Examples are powders, glassware, natural or synthetic oils,
own National legislation and standards on sterilisation and semisolids such as fats and paraffins. Also parts of pharma-
validation. International ISO standards are always useful or ceutical equipment made of stainless steel or glass can be
are implemented and commented in the own country; for sterilised by dry heat.
steam sterilisation see [6]. In a hot air steriliser, the air is heated by the use of
electrical heating elements. For an even temperature distri-
30.5.1.7 Monitoring of Steam and Hot Water bution in the entire steriliser, a forceful air stream (turbulent
Sterilisation Processes or laminar) is essential. For this, a fan and special ventilation
The temperature and pressure in the sterilisation chamber sleeves are placed in the sterilisation chamber. The air might
and in the product are saved on the computer and recorded be HEPA filtered through dedicated heat-resistant HEPA
on a digital and/or printed sterilisation report. After filters. The stainless steel racks on which the products are
sterilisation, release occurs based on a visual inspection of loaded must be perforated for a good circulation of the hot
the sterilisation curve in the report, knowledge of the GMP air. It is of great importance to check whether the content of
status of the facility, knowledge of the batch load and the all individual elements of the load reach the desired temper-
validation reports and the absence of critical deviations. ature. Therefore some reference temperature probes are
Generally, this is a comparison of the record with that of a placed in the product of containers to be sterilised. The
validated similar process. Critical points are whether the positioning of the items to be sterilised is very important
correct temperature and pressure were reached, whether the too, each item must have sufficient free surrounding space to
warming up, cooling down and sterilisation times were nor- allow contact with the hot sterilising air. This check and
mal and sufficient, and whether the desired lethality was correction is time-consuming but essential. The heat transfer
obtained. Sometimes biological or chemical sterilisation of dry air is much less efficient compared to steam or hot
indicators have been sterilised with the load. The informa- water sterilisation, thus the integrated process of heating and
tion from these indicators is used as part of the decision for cooling down of products in a hot air steriliser requires many
final release. The authorised person signs the report to prove hours. Because hot air sterilisation is less efficient than
that the final inspection took place and the autoclave load is steam sterilisation, and the killing mechanism (oxidation)
finally released for further processing. is different, the sterilising temperature is higher and the
sterilisation time longer. The standard conditions described the distance to the source, the residence time in the steriliser,
in the Ph. Eur. are minimally 160 C for at least 2 h and the density and distribution of the materials.
[1]. Sometimes higher temperatures and shorter sterilisation The quality control checks whether the product has been
times are used. For example 1 h at 170 C or 30 min at irradiated homogeneously and received the correct dose. The
180 C for a sterilisation time. Be aware that the Ph. Eur. controllable variables are the source intensity and the expo-
gives a clear guidance: 2 h 160 oC. It is recommended that sure time. The process control is performed with a dosime-
dry-heat sterilisation procedures be validated for each indi- ter, for example plates of polymethylmethacrylate (PMMA)
vidual product with standardised batch size and loading that discolours under the influence of gamma radiation. The
scheme. A new hot air steriliser is initially qualified by extent of discolouration is dependent on the absorbed dose.
acceptance tests (FAT, SAT) and IQ OQ and PQ respec- In one container several dosimeters are placed, which are
tively (see Sect. 34.15). analysed in the quality control laboratory afterwards in a
spectrophotometer.
30.5.3 Ionising Radiation Sterilisation

30.5.4 Gas Sterilisation
Ionising radiation contains a lot of energy. Therefore, it can
Gas sterilisation is performed with ethylene oxide or hydro-
inactivate micro-organisms. Ionising radiation – alpha, beta
gen peroxide gas. Sometimes peracetic acid is used, but this
or gamma radiation – is released when an unstable atom
method is too specialised to mention here in detail. In the
loses energy by decay. Alpha and beta radiation contain
past (from 1940) formaldehyde was used as well, but this
particles, gamma radiation consists of electromagnetic radi-
method is rarely used anymore. Gas sterilisation is used for
ation only. The penetration power of gamma radiation is
sterilisation of medical devices and of surfaces of pharma-
therefore much higher than that of alpha and beta radiation.
ceutical containers where the contents are too sensitive to the
For this reason, usually only gamma radiation is used for
high temperature of steam sterilisation and/or cannot with-
radiation sterilisation. By estimation, 40 % of the sterile
stand radiation sterilisation.
medical devices are sterilised by gamma sterilisation. Due
to the strict safety provisions, gamma sterilisation is
30.5.4.1 Ethylene Oxide
restricted to specialised companies. They are controlled by
Ethylene oxide is a gas under atmospheric conditions. Its
the (inter)national competent radiation authorities and by
boiling point is at 10.4 C and its vapour density is 1.5
auditing. Gamma radiation for sterilisation purposes is usu-
(air ¼ 1). Ethylene oxide is a highly reactive compound
PRODUCTION
ally obtained from the radioactive decay of the radio-isotope
60 that reacts irreversibly with DNA and protein molecules. It
Co into non-radioactive 60Ni, during which gamma radia-
is suitable as a sterilising agent because of its strongly
tion is emitted with an energy of 1.33 MeV. The half-life
alkylating properties. Ethylene oxide can form toxic
(the time span in which the radioactivity of the source is
products (toxic for the operator without shielding) and can
halved) is 5.27 years. Radioactivity is expressed in
polymerise relatively easily into polyethylene glycol.
Becquerel (Bq): 1 Bq is one disintegration (radioactive
Ethylene oxide is highly toxic; it irritates the mucous
decay of one atom) per second. The amount of absorbed
membranes, induces blisters and causes headache. More-
radiation is expressed as energy per mass-unit. For this, the
over, ethylene oxide is carcinogenic. The occupational expo-
unit Gray (Gy) is used: 1 Gy ¼ 1 J/kg. Both the Ph.Eur. and
sure limit (see Sect. 26.7.2) is 0.5 ppm. Furthermore,
the international standard ISO 11137-1 2006 require that
mixtures of air and ethylene oxide are explosive. For all
sterilisation is performed with a dose of at least 25 kGy [1,
these reasons, sterilisation with ethylene oxide is now only
7].
performed by specialised Units (in hospitals or industrial)
that can handle all of these risks.
30.5.3.1 Process Description of Radiation
Sterilisation 30.5.4.2 Process Description Ethylene Oxide
The product, preferably in the final container, and packaged Sterilisation
in dedicated packaging material that withstands radiation The sterilisation process is only described briefly. For more
and finally packed in for example a closed carton box, is information, reference is made to the literature [8]. The
moved around the radiation source in such a way that the sterilisation process consists of five phases: venting,
content is irradiated homogeneously and receives at the end humidification (preconditioning), sterilisation, degassing,
of the sterilisation a total dose of at least 25 kGy. In practice and aeration (see Fig. 30.7).
the products move on a conveyor belt alongside the radioac- During preconditioning, the load is brought to the desired
tive source. The dose depends on the intensity of the source, temperature and humidity. By applying vacuum, the air is
Fig. 30.7 Sterilisation process

with ethylene oxide (Reprinted
with permission of the publisher
[9])
removed from the steriliser, which improves the penetration irritates the mucous membranes, induces blisters and causes
of the gas into the load. In the second part of the conditioning headache.
phase, steam is brought into the chamber to humidify the The materials that need to be sterilised can be cleaned in
load as desired. This is important for rehydration of bacterial the usual way. The packaging materials should be
spores, since strongly dehydrated spores are very resistant to non-adsorbent to hydrogen peroxide. Therefore, plastics
ethylene oxide. such as polyethylene and polypropylene are used instead of
Shortly before the sterilisation phase, the ethylene oxide paper for wrapping the load.
is brought into the chamber. Sterilisation conditions that are
usually applied are: gas concentration 300–1,200 mg/L,
30.5.4.4 Process Description Hydrogen Peroxide
temperature 30–55 C, relative humidity 30–70 %, and
Gas (Plasma) Sterilisation
sterilisation time 1–4 h [9]. During the degassing phase,
In a sterilisation chamber, a very large vacuum is created
the gas is removed from the sterilisation chamber by
(about 50 Pa). This vacuum is maintained for some time to
alternating the application of vacuum and aeration.
dry the load and heat it to 40–45 C. Next, a concentrated
Materials such as plastics and rubber adsorb ethylene
hydrogen peroxide solution is injected into the chamber
oxide during the sterilisation phase. For a complete removal
(injection phase). The liquid turns into a gas due to the
of the adsorbed fraction, the chamber is rinsed with clean
large vacuum. Next, the pressure is increased to 100 kPa
sterile air for a prolonged period of time (hours to sometimes
using filtered air, which allows for the hydrogen peroxide to
days). This period is called the aeration phase.
thoroughly penetrate the packaging and in and onto the
Regarding in-process controls, the Ph. Eur. states:
medical devices (diffusion phase). When the diffusion
“Whenever possible, the gas concentration, relative humid-
phase is finished, the gas is exhausted from the chamber
ity, temperature and duration of the process are measured
and a radio frequency (RF) signal or electrical field is
and recorded” [1]. The validation of a gas sterilisation pro-
applied to convert the remaining mixture into plasma.
cess consists of a physical and microbiological
Plasma is created when energy is applied to a gas with
validation [8].
enough force to strip electrons from atoms. The resulting
mixture of free radicals, ultraviolet light, positive and nega-
30.5.4.3 Hydrogen Peroxide Gas (Plasma) tively charged particles is known as plasma. In other words:
Sterilisation gas plasmas are highly ionised gases, composed of ions,
Although hydrogen peroxide has been used as a disinfectant electrons and neutral particles that produce a visible glow.
for 150 years, the technique to reliably sterilise with this The benefit of low temperature gas plasma is that it has the
compound is 25–30 years old. The method is applied for ability to efficiently eliminate traces of residual hydrogen
sterilisation of medical devices in the hospital. peroxide from materials and devices. After the RF signal or
Hydrogen peroxide is – like ethylene oxide – a highly electrical field is stopped, the plasma converts into water and
reactive compound. In contrast to ethylene oxide, hydrogen oxygen, which are not toxic. The critical parameters are: the
peroxide does not form toxic products and it is not muta- concentration of hydrogen peroxide gas during the injection
genic or carcinogenic. The gas is however harmful, it phase, the pressure, temperature, and time during the
adsorption phase and, in the case of a plasma phase, the The depth filtration principle works with a filter that is
presence and capacity of the RF-signal or electrical field. build up from fibres. Besides the sieve effect that retains
The process is validated in accordance with ISO [10]. larger particles on the surface, smaller particles can be
retained within the filter by obstruction between the fibres
and by adsorption on to the fibres.
For obstruction, the shape and especially the
30.6 Filtration deformability of the particles are important. Rigid, long
fibres have more difficulty travelling a curvy road than
30.6.1 Sterilisation by Membrane Filtration
spherical or deformable particles, such as micro-organisms.
With increasing load, the filter will eventually clog. If this
Certain products that cannot be terminally sterilised may be
coincides with an increase in pressure, deformation of the
subjected to an aseptic filtration procedure [11] using a
filter material may occur, which can lead to the release of
satisfactory sterile membrane filter membrane, tightly fixed
particles that were previously retained.
in a filter holder. The operator passes the liquid product
Adsorption applies to even smaller particles. The load is
through a sterile and bacteria retentive membrane, mostly
often important in this process. The adsorption process can
with a nominal pore size of 0.2 μm or smaller. Such mem-
be compared to adsorption chromatography. Particles
brane filters can capture most bacteria, yeasts and fungi, but
migrate through the filter with a rate that is determined by
not all viruses and mycoplasms. The liquid should be asepti-
the relative affinity to the stationary phase (the filter mate-
cally collected in a sterilised dedicated clean container
rial) on the one hand, and the mobile phase (the to be filtered
directly after sterile filtration.
material) on the other. A high flow rate results in a lower
interaction probability, and thus decreased absorption. At a
higher load, saturation effects and the associated break-
30.6.2 Theory of Membrane Filtration through occur.
Particles that pass the screen mechanism, can be retained
Filtration processes can be divided into screen filtration and by the depth filtration mechanism. For membrane filters,
depth filtration. These processes are shown in Fig. 30.8. obstruction and adsorption occur to a certain extent as
The screen filtration principle can be compared to siev- well. The smaller the pore of the membrane filter is and the
ing. The particles are retained on the sieve. The capacity of larger the particles that should be filtered are, the more
the screen filter to retain particles is determined by the important is the screen function.
(statistical) pore size distribution. The sieve effect is depen-
PRODUCTION
dent on the total load, regardless of concentration or filtra-
tion rate, and the filter surface. Deformable particles like 30.6.3 Retention Capacity
micro-organisms can form a very compact plaque on the
filter surface. With increasing load the filter can therefore The pore size indicators 0.2 and 0.45 μm are indicative
clog. Smaller membrane filters, for single use, generally indicators that give an idea of the average of the pore size
work according to the screen filtration principle. distribution of the filter, but not of the spread of this
Fig. 30.8 Schematic representation of the screen filtration principle (a) and the depth filtration principle. Source: Recepteerkunde 2009, #KNMP
distribution. The procedure for determination of the pore Table 30.3 Factors that influence the flow rate through a membrane
size may vary per manufacturer. Since pore size does not filter
tell whether the filter can sufficiently retain bacteria, valida- High flow rate Low flow rate
tion of filters is based on the so-called retention capacity Large pore size Small pore size
instead. This is the capacity of the filter to retain micro- Thin membrane Thick membrane
organisms of specified dimensions. The best method to test Large surface area Small surface area
a membrane filter for germicidal properties, is to load the High applied pressure Low applied pressure
filter with large numbers of bacteria and subsequently mea- Low viscosity High viscosity
sure the number that passed the filter. For testing of filters High temperature Low temperature
with a pore size of 0.2 μm a standardised method is used, in
which is tested whether the filter is capable to retain 107
colony forming units (CFU) of Brevundimonas diminuta
(old name: Pseudomonas diminuta) per cm2 [12]. When
full-grown this bacterium measures about 0.3 μm. For a
positive control, often a 0.45 μm filter is used to show that
the bacterium is able to pass this pore size [12].
Membrane filters are available in a large variety of sizes,
configurations, and materials. Often used materials are
polyvinylidene fluoride (PVDF), polyethersulfone (PES),
nylon, cellulose esters, polytetrafluoroethylene (PTFE),
polyester and polypropylene. The choice for a material
determines, to a large extent:
• The flow properties
• The resistance against the fluid to be filtered
• The possibility to filter a hydrophilic, lipophilic or
organic solution
• Whether it is possible to sterilise the filter with steam or
with gas
Manufacturers give extensive specifications with their filters
which should include these properties. The user should
verify that the filter is suitable for the product he wants to
filter. In industrial setting, filter properties are usually
validated under the conditions in that setting before the filter
is allowed for use. Important considerations in such a vali-
dation are the adsorption of specific substances to the filter
Fig. 30.9 Cartridge filter with stainless steel filter case (Picture: Pall).
material and the release of unwanted substances from the Source: Recepteerkunde 2009, #KNMP
filter.
30.6.4.2 Membrane Filter Types

30.6.4 Application of Membrane Filters Membrane filter units for pharmaceutical use are available as
disc filter, cartridge filter or capsule filter.
30.6.4.1 Filter Size and Filtration Rate Small disc filters have a filtering surface area of approx.
The choice of a specific type of membrane filter for the 10 cm2 (diameter 37 mm) to approx. 50 cm2 (diameter 80 mm).
filtration of a solution depends, amongst others, on the vol- These filter membranes are fixed in a disposable filter unit or
ume to be filtered, the type (water or lipophilic/organic must be placed manually on the supporting plate of a stainless
solvent), temperature and viscosity and on the available steel filter holder, which always must be done very carefully to
filtration equipment. The larger the surface area of a mem- prevent damaging of the filter. Wetting of the support screen
brane filter is, the higher is the flow rate at a certain applied and the membrane itself with water for injections before
pressure. Table 30.3 summarises variables that influence the handling is essential for the integrity of the membrane after
flow rate through the filter. Filtration of viscous liquids is closure of the filter holder and may also ease positioning.
slow and sometimes difficult. In this case, heating of the In cartridge filters, also called filter candles, the filter
liquid, using a larger filter surface area or pre-filtration membrane is much larger, folded and fixed into a cartridge
through a coarse filter may help. (see Fig. 30.9). The filtering surface area of a cartridge of
Fig. 30.11 A disposable ready-to-use membrane filter unit (Picture:

Pall). Source: Recepteerkunde 2009, #KNMP
than the pore size of a filter (e.g. bacterial whole-cell

Fig. 30.10 Capsule filtration unit with folded membrane filter (Pic-
ture: Pall). Source: Recepteerkunde 2009, #KNMP vaccines).
10 in. length is 0.45 m2. Many lengths are available. One or

more (tightly connected) cartridges are placed in a filter case 30.6.5 Integrity Testing of Membrane Filters
(see Fig. 30.9). The filter case with the cartridge filter is
usually part of the filling line and is sterilised in-line with Filter tests must be performed by the manufacturer before
sterile steam (WFI quality) as such prior to filling. Filter release to the market and by the individual user also, to
cartridges can be purchased in a sterile disposable form, for ensure that the membrane filter complies with the
PRODUCTION
single use specifications, is undamaged, and is eventually placed
In a capsule filter, the filter membrane and filter case of correctly in the filter case by the user. As described before
hard plastic are provided as a whole. Also in a capsule filter, in this chapter, such a test should in fact be performed with
the membrane filter is folded, thereby creating a relatively Brevundimonas diminuta. However, in daily practice this is
large filtering surface area. In practice, capsule filters have not possible for the user in the pharmacy, and thus test
replaced, for a part, the larger disc filters. They have a methods have been derived, which are based on the physical
filtering surface area of approx. 0.015 m2 to 0.2 m2. An properties of the membrane filter. Such test methods are
example of a capsule is shown in Fig. 30.10. called filter integrity tests.
For the filtration of small volumes (up to 100 mL), gen- Important integrity tests are the bubble point test, the
erally a small disposable ready-to-use sterile membrane diffusive-flow (forward flow) test, and the pressure hold
filter unit is used. The diameter of these filters is usually test [12], which are described separately in the next
25 mm or more. They are sterile and free of endotoxins, paragraphs. These three tests are based on the retention of
packed individually, have a low dead volume, and are dedi- test fluid (usually cooled water for injections) by the filter
cated for single-use (see Fig. 30.11). membrane material by surface tension and capillary forces.
In Table 30.4, examples are shown of often used mem- When test pressure is applied on the membrane with a test
brane filters of this type (0.2 μm, 25 mm diameter). gas, this gas can diffuse through the test liquid, and when
The liquid to be sterilised is often pushed through this more pressure is applied, the fluid will be pushed out of the
type of membrane filter by using a plastic syringe. A filter filter membrane. At this moment, a larger volume of test gas
test prior to filtration is commonly not performed in daily begins to flow through the filter. The pore size of the (intact,
pharmacy practice. A successful integrity test, following the undamaged) filter membrane determines how much pressure
filtration, gives assurance of the proper functioning of the is required to overcome the capillary action in the filter. In
filter. Sterilising membrane filtration is not applicable to Fig. 30.12 the pressure is plotted against the volume of air
fluids containing active substances with particles larger passed through the filter.
Table 30.4 Properties of often used disposable ready-to-use membrane filters

Manufacturer: Pall Millipore Sartorius Millipore
Typ: DMSO-safe Acrodisc Millex GS Minisart NML Millex FG
Filter material: Nylon Cellulose esters Cellulose acetate PTFE with polyester
Filter case material: Polypropylene PVC MBS Polypropylene
Comments: Resistant to DMSO Compatible with various Compatible with various For hydrophobic solutions,
aqueous solutions aqueous solutions alcoholic solutions
the test can take place due to the effect that the filtered
measured (diffusion) airflow
product can have on the surface tension.

The relation between required pressure P and the pore
size is described in Laplace’s law:
d
P ¼ γ cos θ=25 K d ð30:7Þ
c In which γ is the interfacial tension, θ the contact angle, K a

correction factor for the shape of the pores and d the pore
b diameter. Cos θ is determined by the interfacial tensions
a between the three components filter membrane material,
liquid and air. It is the same angle as in the wetting theory
test gas pressure
as discussed in (Sect. 18.3.2). The manufacturer supplies the
Fig. 30.12 The airflow through a moistened membrane filter plotted value of the bubble point for hydrophilic filters for a filter
against the pressure. The meaning of the phases a, b, c, and d are moistened with purified water at a specified temperature. A
explained in the text. Source: Recepteerkunde 2009, #KNMP different liquid or product or different temperature in the
membrane results in a different interfacial tension and thus a
different bubble point.
Figure 30.12 consists of four characteristic phases: (a) a
In most pharmacies a simplified bubble point test is
phase of general diffusion of the test gas through the water in
performed. In this test, a moistened 0.2 μm filter should be
the membrane, (b) a phase of critical diffusion, (c) the bub-
able to resist the pressure of a syringe filled with air that is
ble point, when the water in the first pores is pulled out by
compressed down to 15–20 % of its original volume. For a
the test gas, and (d) a phase of free passage of air through the
1.2 μm filter, this value is less: 40–50 %. Therefore cracks in
filter. Especially the phases b and c are suitable for testing a
the filter or installation errors, as well as the mix-up of a
membrane filter.
0.2 μm and a 0.45 μm or 1.2 μm filter can be easily detected. ,
In practice the filter integrity tests are performed with a
The USP [13] doesn’t accept this syringe-piston resistance
dedicated filter test apparatus, suitable for the type and brand
test for pharmaceutical preparation [14] and regards only the
of membrane filter holders or filter candles in use. Most of
bubble point test with a manometer to be sufficiently reli-
the time all types of filter tests can be executed with this
able, see Fig. 30.13.
apparatus, and the results are printed or uploaded to a com-
puter file, for control by a qualified operator and release of
the tested filter. 30.6.5.2 Gas Diffusion Filter Testing
When a test gas (for example ambient air) is applied over a
30.6.5.1 Bubble Point Test water moistened filter, just below the pressure level of the
As described above, a test fluid (usually water) is retained by bubble point, test gas diffusion will occur through the water
the filter membrane material by surface tension and capillary in the wetted membrane filter. This diffusion happens in all
forces). This adhesion is, amongst others, dependent on the water filled pores, not only in the largest. This principle is
pore size of the filter. In the bubble point test air pressure is the basis for two tests, which use different approaches to
applied to the moistened filter and it is observed at which measure gas diffusion: the pressure hold test and the
pressure air bubbles are formed on the sterile side of the diffusive-flow (forward flow) test. Other names for the
filter. The pressure at which the first bubbles are formed is same principle tests exist. These tests are performed at a
called the bubble point. At this moment, the liquid is pushed pressure of about 80 % of the theoretical bubble point
out of the largest pores. pressure of the filter. It is important that the largest pores
When this test is performed after the filling process the are still filled with liquid. In this phase, diffusion occurs
filter has to be flushed first with water for injections before more or less linearly with the pressure drop over the
to enable detection of small defective holes in the filter.

20 40
Another disadvantage is that the pressure decrease depends
0
psi
60 on the type of membrane filter, the dead volume of the filter
case and any supply tubes. Therefore, the maximum allowed
pressure decrease should be determined for every combina-
tion of filter case and type of filter separately, or the manu-
facturer should provide these data. Be aware of the influence
of temperature on this test.
In the diffusive-flow test, also called the forward flow
test, the filter membrane or candle in its tightly closed case is
set under continuous test gas pressure. The amount of air that
diffuses through the filter membrane per time unit is
measured downstream, on the sterile side of the filter. The
pressure drop over the membrane should be constant during
the test to prevent variations in diffusion rate. Collection and
measurement of the air on the sterile side often require
Fig. 30.13 Determination of the bubble point using a simple manom-
eter and disposable syringe. Source: Recepteerkunde 2009, #KNMP
actions that may lead to contamination of the setup, and
thus these actions should be performed aseptically. Further-
more, for small filter surface areas the volume of air that
measured (diffusion) airflow
diffuses through the filter is small and therefore no accurate

measurements are possible for these small filters.
area of 30.6.5.3 Water Intrusion Test (for Hydrophobic

critical bubble Filters)
diffusion point Up to now, only hydrophilic filters have been discussed,
which are used for the filtration of aqueous solutions. Filters
that are used for gas filtration such as ventilation filters on
tanks and boilers are lipophilic filters. Some hydrophobic
filter membranes are used to filter oils and other lipophilic
solutions. A physical integrity test with water cannot be
PRODUCTION
test gas pressure performed with this type of filter. For moistening, isopropyl
alcohol has been used in the past, but the disadvantage of this
Fig. 30.14 The relation between the applied pressure drop over the substance is that it is highly flammable. Therefore, an alter-
membrane filter and the thickness of the liquid film. Source:
native method has been developed, which is called the water
intrusion test [15, 16].
The execution of this test with a 0.2 μm hydrophobic filter
membrane filter. Figure 30.14 shows the relation between membrane is as follows. The entire filter case is filled with
the applied pressure drop over the membrane filter and the water and brought under a pressure of about 200 kPa using
thickness of the liquid film. pressurised air. This pressure is not sufficient to fill the pores
The volume of air (test gas) that diffuses through the filter and cause a liquid flow through the filter; this would require
is influenced by the thickness of the liquid film and the around 1,200 kPa. Transport of water due to evaporation
fraction of the membrane surface area that is taken up by does occur. The amount of water that evaporates per time
the pores. When the filter is contaminated, or contains air unit is dependent on the pore size. As a result of this evapo-
bubbles by insufficient wetting, diffusion is reduced due to a ration, the pressure in the filter case would decrease. The
smaller membrane surface area. Thorough wetting is amount of air that is added to the filter case to maintain the
important. air pressure is measured. This amount should not exceed a
In the pressure hold-test, the filter membrane or candle in value provided by the manufacturer. The method strongly
its tightly closed case is set under test gas pressure. Next, the resembles the pressure hold test and can be regarded as the
test gas supply to the filter holder is shut. On the side where hydrophobic variant of this test.
the pressure was applied (measured in the filter case) the Figure 30.14: The amount of diffused air flowing through
pressure decrease, as a result from gas diffusion through the the filter membrane (in millilitres diffused air per minute)
wetted membrane filter element, is measured. Very sensitive and the thickness of the liquid film in the membrane filter,
and calibrated manometers in the testing device are required both plotted against the increasing test pressure. The phase
that applies to the diffusion test is to the left of the bubble manufacturer can explore the option of adding adjunct
point pressure. processing steps to increase the level of sterility assurance.
Modifications to, or combinations of accepted sterilisation
methods are accepted by the competent authorities, but
30.7 Heating at 100 C over Boiling Water proper scientific explanation and justification should be
provided in the dossier.
Heating in a steam autoclave or in a hot water autoclave and Heating in closed containers in a steam or hot water
also dry heat sterilisation are good sterilisation methods for autoclave is the method of choice for aqueous pharmaceuti-
many products, but pressure and temperature in these cal products.
autoclaves are high. Some substances in aqueous solutions For non-aqueous liquids, semisolids and dry powders 2 h
or in medicinal products formulated as a suspension, or sterilisation at 160 C in dry heat is preferred. Where it is not
containers do not withstand the high temperatures of possible to carry out terminal sterilisation by heat due to
121 C or the high pressure inside and outside the product formulation instability, a decision should be taken to utilise
container or both in a water or steam autoclave. Active an alternative method of terminal sterilisation, filtration
substances or excipients might be unstable at those higher and/or aseptic processing. It is recognised that new terminal
temperatures and suspensions tend to form an undesirable sterilisation processes other than those described in the
solid precipitate on the bottom of the container during pharmacopoeia may be developed to provide sterility assur-
autoclaving at high temperature and pressure. ance levels equivalent to present official methods and such
Membrane filtration is the usual alternative sterilisation processes, when properly validated, may offer alternative
method in those cases. However membrane filtration as a approaches. If necessary, a different time-temperature com-
sterilisation method is less effective and needs aseptic bination may be applied to obtain an SAL of 106. If too
circumstances. If the product withstands a heat treatment at much degradation occurs in dry heat, ionising radiation or
lower steam temperature (100 C) for 30 min and no pres- gas sterilisation can be applied. If these methods are not
sure, this treatment contributes to the effectiveness and suitable either, sterilising membrane filtration and validated
safety of the membrane filtration process. If the solution aseptic processing, sometimes robotised or with barrier sys-
contains a preservative, as is often the case with eye drops, tem technology are considered as a last resort.
the effectiveness of the 100 C treatment may increase
considerably. Heat treatment at 100 C for 30 min over
boiling water as such (without additional measures) is not a
reliable sterilisation method and hence not recommended by 30.9 Sterility Testing and Parametric Release
the Ph. Eur.
As shown in Table 30.1, non-spore forming bacteria do The Ph. Eur. includes a sterility test for the determination of
not survive 30 min at 100 C, and neither do yeasts, fungi, sterility (see Sect. 19.6.1). Due to the limited statistical size
and viruses. Combination of this process with sterilising of the sample – the sterility test is a destructive test – this test
membrane filtration and aseptic circumstances, gives a has in theory limited value. This is acknowledged by the
higher degree of certainty than aseptic filtration alone as is authorities. It is recognised that a comprehensive set of
applied in preparation of eye drops, see Sect. 10.7, notably in-process tests and controls may provide greater assurance
Tables 10.18 and 10.19. of the finished product meeting sterility than finished steril-
ity testing (see Sect. 34.9.3). The release process without
sterility testing before release is called parametric release.
30.8 Choosing the Best Sterilisation Method Parametric release is only allowed when a number of
for Medicinal Products preconditions are met. Parametric release may be authorised
for certain specific parameters as an alternative to routine
What is the best sterilisation method for your product? Is testing of finished products. Authorisation for parametric
terminal sterilisation better than aseptic processing? See release should be given, refused or withdrawn jointly by
references [17, 18]. The objective of aseptic processing in those responsible for assessing products, together with the
general is to maintain the sterility of a product that is assem- GMP inspectors. Parametric release often requires retrospec-
bled from components, each of which has been sterilised. tive sterility testing.
Sterile medicinal products should be manufactured using In conclusion the essence of parametric release is Good
aseptic processing only when terminal sterilisation is not Manufacturing Practice. Furthermore, it is important to have
possible. Some types of final packaging and some medicinal a good understanding of the initial contamination, aseptic
products do not withstand the temperatures and/or pressure conditions and deviations taken place in the manufacturing
of a terminal sterilisation process. In such cases a process.
9. Huys J (2010) Sterilization of medical supplies by steam, 3rd edn.

References Mhp-Verlag, Wiesbaden, Germany ISBN 90-75829-01-9
10. ISO 14937 (2009) Sterilization of health care products – General
1. European Pharmacopoeia. Strasbourg, EDQM 2014 version 8.0. requirements for characterization of a sterilizing agent and the
Chapter 5.1 General texts on microbiology, 5.1.1. Methods of development, validation and routine control of a sterilization pro-
preparation of sterile products cess for medical devices
2. ISO/TS 11139 (2006) Sterilization of health care products – 11. ISO 13408-2 (2003) Aseptic processing of health care products –
Vocabulary Part 2 Filtration
3. Guide to Good Manufacturing Practices for Medicinal Products. 12. Technical Report No. 26 (2008) Sterilizing filtration of liquids.
Annex 1; 2008: Manufacture of Sterile Medicinal Products PDA J Pharm Sci Technol 62:S-5
4. Boom FA, Paalman ACA, Stout-Zonneveld A (1984) 13. <797 > Pharmaceutical compounding – sterile preparations.
Microbiological aspects of heat sterilization of Medicines. II. A United States Pharmacopoiea USP 37/The National Formulary 32.
method for the determination of the effectiveness of a sterilization United States Pharmacopoeial Convention. Rockville 2014
process using the bioburden and the bioburdens heat resistance. 14. Newton DW (2008) Membrane-filter bubble-point test. Am J
Pharm Weekbl Sci 6:209–215 Health Syst Pharm 65:2210–2212
5. Welsh Health Technical Memorandum WHTM 01-05 Parts A to D 15. Haenchen R, Schubert J, Jafari S et al (1997) Studies on the theoreti-
6. ISO 17665-part 1-3 (2006) Sterilization of health care products – cal basis of the water intrusion test (WIT). Eur J Parent Sci 2:39–45
Moist heat 16. Bardat A, Chatenet E, Schmitthaeusler R (1997) Automatic integ-
7. ISO 11137-1 (2006) Sterilization of health care products – Radia- rity testing of autoclave and freeze dryer inlet filters. Pharm Engin
tion – Part 1: Requirements for development, validation and routine 17:108–122
control of a sterilization process for medical devices 17. Morris JM (2000) Sterilisation decision trees development and
8. ISO 11135 (2014) Sterilization of health-care products – Ethylene implementation. PDA J Par Sci Technol 54:64–68
oxide – Requirements for the development, validation and routine 18. EMEA: Decision trees for the selection of sterilization methods
control of a sterilization process for medical devices (CPMP/QWP/054/98)
PRODUCTION
Aseptic Handling
31
Frits Boom and Alison Beaney
Contents Abstract
Aseptic handling is the process to enable sterile products
31.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
to be made ready to administer, using closed systems. The
31.2 Aseptic Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 starting materials are sterile and must be kept sterile
31.3 Aseptic Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 during the process. This chapter describes the conditions
31.3.1 Guidelines for Aseptic Handling . . . . . . . . . . . . . . . . . . . . . . . . . 696 to do so (sterility assurance). The most important points
31.3.2 Complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
31.3.3 Staff and Personal Hygiene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
are trained staff wearing special clothes and sterile
31.3.4 Working Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697 gloves, working ‘non touch in a Grade A zone (LAF
31.3.5 Aseptic Handling of Antineoplastics . . . . . . . . . . . . . . . . . . . . 698 cabinet, safety cabinet or isolator) and using materials
31.3.6 Storage Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 and equipment with a low bioburden.
31.4 Cleaning and Disinfection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 If antineoplastics (cytostatics) are involved requirements
31.4.1 Cleaning of Clean Rooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 are not only to protect the product against contamination of
31.4.2 Cleaning of LAF Cabinets, Safety Cabinets and Isolators 700
micro-organisms, but also to protect the operator and the
31.4.3 Disinfection of Clean Rooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
environment from these hazardous medicines.
31.5 Aseptic Work Session . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 Microbiological checks are carried out firstly to see if
31.6 Microbiological Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 staff are sufficiently skilled in aseptic activities, secondly
31.6.1 Microbiological Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 to determine the microbial risk from the environment and
31.6.2 Microbiological Validation of the Process . . . . . . . . . . . . . . 704
thirdly to validate the aseptic procedures.
31.6.3 Individual Qualification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
This chapter does not cover the situation where
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 medicines that cannot be sterilised in their final container
are sterilised by aseptic filtration.
Keywords
Aseptic handling Aseptic processing GMP Annex 1
Antineoplastics Microbiological controls Monitoring
Validation Qualification
31.1 Definitions
Based upon the chapter 25 Aseptisch Werken by Frits Boom, Hans van Aseptic The process used for products that cannot
Doorne and Marco Prins in the 2009 edition of Recepteerkunde.
Processing be sterilised in their final container,
F.A. Boom (*) i.e. cannot be terminally sterilised.
Zaans Medisch Centrum, Koningin Julianaplein 58,
1502 DV Zaandam, The Netherlands
A.M. Beaney
Newcastle upon Tyne Hospitals NHS Foundation Trust,
Newcastle-upon-Tyne, UK

696 F.A. Boom and A.M. Beaney
For more information about membrane filtration see

Conflicting Definitions for the Term “Aseptic Sect. 30.6.
Preparation”
In the EU GMP Annex 1 “aseptic preparation” is used
for the preparation of sterile products that cannot be
sterilised in their final container [1]. In the UK the
31.3 Aseptic Handling
term “aseptic preparation” is used for aseptic handling
Within pharmacy, aseptic handling is carried out in a con-
without a manufacturing licence granted by the Com-
trolled environment by trained staff. In any hospital, how-
petent Authority.
ever, aseptic handling also takes place in clinical areas such
as wards and operating theatres [4, 5]. This chapter only
discusses aseptic handling in pharmacy. Aseptic handling
Aseptic Handling The process to enable sterile products in clinical areas is described in Sect. 13.8.
to be made ready to administer, using
closed systems.
Closed Procedure A procedure whereby a sterile pharma- 31.3.1 Guidelines for Aseptic Handling
ceutical product is prepared by trans-
ferring sterile ingredients or solutions In 2008 the Pharmaceutical Inspection Convention
to a pre-sterilised container, either published the PIC/S guide to good practices for the prepara-
directly or using a sterile transfer tion of medicinal products in healthcare establishments
device, without exposing the solution [2]. Although this document is a stand-alone document and
to the external environment [2]. should be used for PIC/S related inspections, it is used more
Bioburden Total number of viable micro- and more as a reference for preparation including aseptic
organisms on or in a health care prod- handling in pharmacies in Europe.
uct prior to sterilisation [3]. USP Chapter <797> Pharmaceutical compounding –
Colony Forming One or more micro-organisms that Sterile preparations describes the conditions and practices
Unit (CFU) produce a visible, discrete growth for all sterile preparations in compounding pharmacies in the
entity on a semisolid, agar-based United States [6]. The so-called compounded sterile
microbiological medium [3]. preparations (CSPs) are divided into low-risk level,
medium-risk level and high-risk level. Low- and medium-
risk levels use closed systems and cover aseptic handling in
controlled environments.
31.2 Aseptic Processing In the United Kingdom “Quality Assurance of Aseptic
Preparation Services” are the national NHS standards for
Medicines, which cannot be sterilised in their final container, aseptic preparation in hospital pharmacies [7].
are sterilised by aseptic filtration. The standards required for In 1996, the Dutch Association of Hospital Pharmacists
aseptic processing are laid down in Annex 1 of EU GMP wrote, in close cooperation with the Dutch Healthcare
[1]. Aseptic processing is called aseptic preparation in Inspectorate, a GMP guide for hospital pharmacy. The
Annex 1 (see Sect. 31.1). Chapter Aseptic Handling in this guide has been reviewed
To reduce risks of microbial contamination, aseptic in 2005 and 2013 and covers aseptic handling in the hospital
processing is executed in a controlled environment, in pharmacy as well as in clinical areas [8]. Different levels of
which the air supply, facility, materials, equipment and product protection are defined.
personnel are regulated to control microbial and particulate In 2012 the German Organisation of Hospital Pharmacy
contamination to acceptable levels [3]. Contact between published the ADKA guideline on Aseptic Preparation and
product and environment should be minimised, sterile equip- Quality Control of ready-to-administer parenterals. All
ment should be used, and there should be two consecutive precautions to be taken to keep the products sterile are
filtration processes through sterile 0.2 μm filters. The first described systematically [9].
filter will minimise the microbial challenge to the second The differences between these guidelines and standards
filter, which should be just before the sterile final container. are not huge. They all focus on preventing microbiological
The shelf-life of the product is often restricted and it may be contamination and more or less on medication errors,
stored in the refrigerator to further reduce the risks of micro- e.g. due to incorrect calculations. This chapter only
bial growth. discusses preventing microbiological contamination.
31 Aseptic Handling 697
Some authors have developed risk assessment tools for

Levels of Product Protection in the Netherlands [8] injectable medicines [11–13]. These tools can be helpful in
The sterility of the product is maintained by using a determining if a process is simple or complex, and hence a
controlled environment and trained staff. Depending higher risk, see Table 31.1.
on how well these can be controlled, three levels of
product protection can be distinguished [8]:
• Limited product protection is the lowest of these 31.3.3 Staff and Personal Hygiene
three levels, and refers to a doctor or nurse carrying
out the aseptic activity on a clean worktop. The greatest source of contamination in any clean room is the
• Increased product protection is the middle of the operator [15]. He or she spreads micro-organisms directly
three levels. This can be carried out in a clinical into the surrounding air and either directly or indirectly onto
area in a separate room within a laminar airflow surfaces in the room. This can be minimised by the operator
(LAF) or safety cabinet or isolator by a member of donning suitable clean room clothing such as non-shedding
pharmacy staff or by a nurse or doctor. suits or coats (depending on the EU Grade of environment),
• Maximum product protection is the highest of the hair cover, shoe covers or dedicated clean room shoes,
three levels of product protection. In this case the gloves, and a mask covering the nose and mouth.
aseptic activity is carried out within a LAF or safety The operator remains a source of microbiological con-
cabinet or isolator sited within at least an EU Grade tamination, nonetheless, and so aseptic technique is impor-
D of controlled background in the hospital tant to protect the product [16]. The principle is to avoid
pharmacy. direct contact between the operator and the product
(non-touch technique) and hence it is essential to have suit-
ably trained operators whose competency is regularly
assessed and who are appropriately supervised.
Before any aseptic activity, hands should be thoroughly
31.3.2 Complexity washed and disinfected, usually with an alcohol-based gel.
The skin flora is both transient and resident. Resident flora is
Aseptic handling varies in complexity from drawing up the difficult to remove, so it is recommended to always use
contents of a vial or ampoule into a syringe, to compounding gloves within the clean room suite. Whilst carrying out
a parenteral nutrition mixture from several separate starting aseptic handling in a Grade A environment, sterile gloves
materials. Complexity of aseptic activity has been defined in are required.
PRODUCTION
several texts [6, 10, 11].
As complexity increases so does risk of microbiological
contamination, although there is little evidence to support 31.3.4 Working Area
this. Other risk factors for microbiological contamination
include the extent to which the product is a good growth The working area is the immediate environment in which the
medium, and the time between its preparation and adminis- aseptic handling is performed. It is the working surface
tration to the patient. (EU Grade A zone) of the LAF or safety cabinet or isolator.
Table 31.1 Examples of simple and complex activities [8]

Simple activities
Drawing an injection liquid from a vial or ampoule* into a syringe
Dissolving a powder for injection and drawing it into a syringe
Injecting a few injections into an infusion liquid
Complex activities
Preparing a medication cassette (several additions, de-aerating, long-term use at room or body temperature)
Preparing parenteral nutrition from components (several additions, mixing large volumes, good growth medium)
Preparing parenteral nutrition starting from a registered all-in-one commercial product with more than two additions (several additions, good
growth medium)
*Transferring injection liquid from an ampoule involves more risk of microbiological contamination than from an injection vial as a vial is a truly
closed system [14]
The background area is the room in which the LAF or pharmacy GMP [8] at least EU Grade D and the
safety cabinet, or isolator is housed. In the case of open- requirements in the UK are harmonised with Annex 1 of
fronted cabinets there is a distinction in background EU GMP, i.e. Grade B. For isolators the requirement for the
requirements between the different guidelines mentioned background in all guidelines is at least Grade D [1].
before. The PIC/S guide [2] and the German ADKA guide- Reference is made to Sect. 28.3 for more information on
line [9] require at least EU Grade C, the Dutch hospital clean rooms, LAF cabinets, safety cabinets and isolators.
The precautions for the different kinds of product

protection (see Sect. 31.3.1) as used in the Netherlands
are summarised in Table 31.2.
Table 31.2 Level of product protection (Example from the Netherlands)
Level of
product Air quality in
Protection Clothing and hand hygiene Working area Background area background area
Limited Clothing, daily cleaned Table top, disinfected Quiet No
Hands: cleaned and disinfected, per session requirements
single use gloves for each session
Increased Clothing: overalls, daily cleaned, Horizontal LAF cabinet, Separate, limited access; No
hair cap, mouth-nose mask safety cabinet or easy to clean requirements
Hands: cleaned and disinfected, overpressure isolator
sterile single use gloves
for each session
Maximum Clothing: overalls, daily cleaned, Horizontal LAF cabinet, safety In accordance with GMP Grade D
hair cap, mouth-nose mask, cabinet or overpressure Grade D: smooth surfaces,
special shoes (positive pressure) isolator interlocked changing rooms etc.
Hands: cleaned and disinfected,
sterile single use gloves for each
session
31.3.5 Aseptic Handling of Antineoplastics • Attaching an infusion system, partly filled with Sodium
Chloride 0.9 %, to the infusion bag with antineoplastics
A relevant therapeutic group of active substances, handled to reduce the chance of leakage of antineoplastics when
aseptically, are parenteral antineoplastics. Many are classi- the bag is attached to the patient)
fied as very toxic for the operator, mainly because of carci- To protect the operator and the environment, the most effec-
nogenicity and reprotoxicity [17], see also Sect. 26.3.3. tive measure is working in a safety cabinet or in an isolator
Therefore, if antineoplastics are involved in aseptic with underpressure (negative pressure). Ideally the exhausts
handling, requirements are not only to protect the product of these cabinets should be connected to the open air. An
against contamination of micro-organisms, but also to pro- isolator gives more protection than an open-fronted cabinet.
tect the operator and the environment from the product. The See Sect. 28.3.
first measure however is a working procedure to minimise The safety cabinet or the isolator should be placed in a
exposure to antineoplastics. This involves well-ventilated and classified background room. To protect
• Working with closed systems (this is good practice for all surrounding rooms from airborne contamination of
aseptic handling) antineoplastics the USP advises negative pressure in the
• Using injection vials and needle-free devices, as far as background room [6]. However, a study in the
possible, to minimise needle-stick injuries. If sharps can- Netherlands, carried out by the Netherlands Organisation
not be avoided, their use should be minimised [18], see for Applied Scientific Research (TNO) concluded that
also Sect. 26.10 airborne contamination from a grade D background (over-
• Using an aeration spike with a hydrophobic filter to avoid pressure 15 Pa) to the surrounding environment is not a
overpressure in vials risk issue.
Table 31.3 Shelf life and administration period for aseptic handling [8]
TNO Study: Risk During Aseptic Handling Shelf life Administration period*
of Antineoplastics Complexity Time Condition Time Condition
Risk from airborne contamination of antineoplastics Simple 1 month 2–8 C 7 days Room temp.
from a background room (with overpressure) to Complex 7 days 2–8 C 7 days Room temp.
surrounding rooms is only a question of concern in *Shelf life and administration period are two separate periods. For
the case of a huge calamity such as a spill or breakage example: if the administration with a medication cassette is started
involving a large amount of antineoplastics as a dry 6 days after preparation of that cassette, the administration period still
will be 7 days
powder. Calamities are rare (less than once a year in a
Dutch hospital pharmacy) and when it occurs, it is
nearly always with a solution in which the handling is acceptable. In the UK, aseptic products made in
antineoplastics are dissolved. The risk of transferring pharmacy can only be given a shelf life of seven days unless the
antineoplastic residues to the environment by hands or pharmacy is licensed with the MHRA (Medicines and
the outside of vials or finished products is much Healthcare products Regulatory Agency) for these activities.
greater (see also Sect. 26.5.4). Measures to prevent Medicines produced by aseptic handling are sometimes
this occurrence and also regular training in emergency administered for more than one day (medication cassette,
procedures are most important to protect people and parenteral nutrition etc.). During the administration the
environment from the risk of antineoplastic residues. product temperature is higher than the storage temperature,
which influences the shelf life. Therefore a second period
has to be used, the administration period, which is defined as
Further protective measures are: the maximum time from start to the end of the administra-
• Personal protection by wearing coveralls and sleeves made tion. Both, shelf life and administration period for simple
of impermeable material and sterile gloves into which and complex aseptic handling at maximum level of product
antineoplastics do not easily permeate, see Table 26.6 protection as used in the Netherlands are summarised in
• Working on a sterile preparation pad and removing the pad Table 31.3 [8].
after each session as antineoplastic-contaminated waste
To prevent contamination with residues it is important to know
that cross contamination of antineoplastics from one room to 31.4 Cleaning and Disinfection
another by direct contact (outside of vials, outside of finished
products) is a real risk [19, 20]. This risk can be significantly The emphasis on providing the correct level of cleanliness is
PRODUCTION
reduced by a validated cleaning procedure for the safety cabinet to ensure that the properly designed and maintained area is
or isolator and the background room, and by properly packing clean and dry. Depending on monitoring results, the use of a
the finished products before transport to nursing and treatment disinfectant may need to be considered. However, disinfec-
centres. Additionally a procedure for removing (potentially) tion is difficult to achieve in an area with even small amounts
antineoplastic-contaminated waste and a procedure on how to of dirt [21].
handle spillages or in an emergency are important to prevent Disinfectants and detergents should be monitored for
contamination with residues. Environmental sampling by wipe microbial contamination; dilutions should be kept in previ-
tests should demonstrate that all those procedures are effective. ously cleaned containers and should only be stored for defined
In the Netherlands and in Germany a surface contamination periods unless sterilised. Disinfectants and detergents used in
limit of less than 0.1 ng/cm2 is becoming used more and more Grades A and B areas should be sterile prior to use.
as a guideline value, see Sect. 26.5.4.
31.4.1 Cleaning of Clean Rooms

31.3.6 Storage Periods
A suggested cleaning regime is that floors and work surfaces
Wherever possible, aseptic products should be stored at 2–8 C. are cleaned daily and walls, ceilings and storage shelving at
The shelf life depends on the chemical stability of the product least monthly [6]. All cleaning materials, such as swabs and
and the potential for microbial contamination [6, 8]. In the mops, shall be nonshedding and must be disposable or suit-
Netherlands, from a microbiological point of view, a shelf life ably washed after each cleaning session. Mops and swabs
at 2–8 C for 1 month for simple and 1 week for complex aseptic used in Grade A or B areas must be sterile.
cleanliness may be checked with a white non-shedding

Swabs and Mops Used in Clean Rooms cloth. Contact the person responsible for the cleaning
Clean rooms have to be wet cleaned with the aid of process if the background room or changing rooms are
polyester or microfibre swabs or mops. Polyester is not sufficiently clean.
used for light cleaning and disinfecting. The polyester
fibres adsorb dirt and if wetted with a disinfectant the
disinfectant will be evenly spread out on the surface.
31.4.2 Cleaning of LAF Cabinets, Safety
Microfibre swabs and mops are used for cleaning only.
Cabinets and Isolators
The microfibres ensure that particles are not only
removed from the cleaned surface but are firmly cap-
It is advisable to leave LAF cabinets, safety cabinets and
tured within the fibres. Dry polyester swabs or mops
isolators running (possibly in standby mode if this can be
are only used for removing wet product or other wet
validated) to avoid dirt and micro-organisms accumulating
waste.
on the clean side of the HEPA filters, i.e. in the Grade A
working zone. Because of the frequent disinfection of these
devices, separate cleaning with a detergent is not neces-
Some general remarks on cleaning of clean rooms:
sary. Any spills must be cleaned as quickly as possible
• Approved standard operating procedures should state
with a non-shedding cloth and, if necessary, with sterile
how the various rooms are to be cleaned, what materials
water.
have to be used and how adequacy of cleaning is checked.
• Cleaning materials for clean rooms should not be used in
other rooms.
• Thorough rubbing is important for the effectiveness of the 31.4.3 Disinfection of Clean Rooms
cleaning process.
• Spilt materials must be removed immediately with a Using good cleaning procedures, the disinfection of a Grade
non-shedding absorbing cloth. D room should not be necessary. Disinfection of a Grade C
• Floors and walls must be cleaned in a fixed order from room can be a necessity, depending on monitoring results.
cleanest to least clean. The air stream and position of the Grade B rooms need a precise disinfection procedure.
exit determine where to start and where to finish. Clean room disinfection should be performed with a
• Cleaning of clean rooms requires specially trained staff. broad spectrum (non aggressive) disinfectant. Most com-
• The same clothing regulations apply for cleaning staff as monly used are alcohols, chlorine compounds, hydrogen
well as for staff preparing the product. peroxide, phenolic compounds and quaternary ammonium
• The effectiveness of the cleaning should be checked. compounds. Table 31.4 gives an overview of the
• Cleaning must be recorded in a log which gives details of microbiological inactivation. Alcohols and hydrogen perox-
the cleaning agent used in addition to the person who has ide do not leave residues after evaporation. Sodium hypo-
performed the cleaning. chlorite is very corrosive towards many materials, including
Regularly (monthly) a general check is advised on the stainless steel. For more information about the disinfectants
level of cleanliness, paying particular attention to corners in Table 31.4 see [6] and [22].
and ridges. The cleanliness of the surface is best assessed Normally two disinfectants are used alternately to prevent
by floodlight. Specialist ultraviolet lamps are also avail- accumulation of resistant micro-organisms, however there is
able for this purpose. If necessary, however, the little evidence to support this [23].
Table 31.4 Classes of commonly used disinfectants [6, 22]

Chemical class Examples Common activity range
Alcohols 70 % ethanol Bactericidal, fungicidal (limited range) virucidal (limited range)
70 % isopropanol
Chlorine compounds 0.5 % sodium hypochlorite Bactericidal, fungicidal, mycobactericidal, virucidal, sporicidal
Hydrogen peroxide 0.5 % hydrogen peroxide solution Bactericidal, fungicidal, mycobactericidal, virucidal, sporicidal
Phenolic compounds 0.4–1.6 % chlorocresol Bactericidal, fungicidal, mycobactericidal, virucidal
0.4–1.6 % orthophenyl phenol
Quaternary ammonium 0.4–1.6 % benzalkonium Bactericidal (not all gram-negative types), fungicidal, virucidal
compounds chloride (limited range)
31.4.3.1 Disinfection of LAF Cabinets, Safety

Cabinets and Isolators 31.5 Aseptic Work Session
Commonly used disinfectants are ethanol 70 % or isopropyl
alcohol 70 %. The disinfectant must be sterile and spore- Remove as much secondary packaging as possible before
free. This can be achieved by adding 0.125 % hydrogen transfer into the background area to minimise dust and
peroxide, sterilisation by 0.2 μm filtration, or sterilisation bioburden. Transfer materials into clean rooms via
by gamma radiation. Neither ethanol nor isopropyl alcohol interlocking hatches. Minimise storage of starting materials
are sporicidal, i.e. they are not effective against bacterial and components in the background area and, if stored, use
spores (see Table 31.4). Unless there are validation data closed cupboards. Documentation and labels should be
from the manufacturer, it is recommended that the maximum generated in outer support areas.
in-use period for sterile disinfectants is limited to one week Work with a ‘sterile area’ where materials can be placed
after opening. This should be noted on the container after it after they have been disinfected and before they are put into
is opened. (Often the contents will be used well before then.) the grade A zone if the quantity of materials to be processed
LAF cabinets, safety cabinets and isolators should be is too large to have in the grade A zone simultaneously. A
disinfected from cleanest to less clean areas, e.g. from back ‘sterile area’ may be (part of) a work top or the top of a
to front for a horizontal LAF, in overlapping strokes. The trolley.
non-shedding cloth (polyester is advisable due to its low It is recommended that two people perform an aseptic
particle load) has to be wetted regularly to make sure there work session [26]. One (the preparer) works in the Grade A
is a constant film of liquid on the surface, and this will dry in zone and the other (the helper) carries out the disinfection
the airstream. An extension to hold the cloth may be used to and assists the preparer with getting materials to and from
disinfect surfaces that are difficult to reach. the working area.
Staff should be fully trained in good aseptic techniques.
Special attention has to be given to ‘non-touch’ manipula-
31.4.3.2 Disinfection of Materials and Equipment tion, which means that critical places like syringe tips should
The initial microbiological surface contamination never touch non-sterile surfaces. Disinfected surfaces (work
(bioburden) of materials and equipment used in LAF top) and hands (even when sterile gloves are worn) must be
cabinets, safety cabinets and isolators (Grade A zone) should considered as non-sterile surfaces.
be as low as possible. Surfaces of sterile devices (tubes, An example of a working procedure step by step:
syringes, needles etc.) are presented sterile. Surfaces of • Remove secondary packaging as much as possible before
ampoules, vials and bottles however are not presented sterile materials are placed in the interlocked hatch (in UK the
PRODUCTION
and must be disinfected before being transferred into the first disinfection stage is at this point).
Grade A zone. Although 70 % alcohol is widely used for • Prepare documents and labels outside the background room.
disinfection, it is non-sporicidal. The most effective method • Wash hands in or adjacent to the changing room.
with liquid disinfection is a combination of spraying and • Change clothes according to the clothing procedure in the
wiping [24]. The physical movement of the wipe over the changing room, disinfect hands and put on non-sterile
surface will help to remove the organisms. Nevertheless, gloves.
spore forming bacteria will not be totally eliminated [24, • Enter the background room.
25]. Beware of excessive spraying, as the maximum allow- • Collect all necessary materials and check these according
able concentration of alcohol in the air can easily be to the preparation document.
exceeded, see Sect. 26.7.2. • Hang preparation document in an easy-readable place.
There are no formal regulations on how often and where • Disinfect the work top in the grade A zone and if neces-
the transfer disinfection has to be carried out. In general, sary disinfect the ‘sterile area’ outside the grade A zone.
regular microbiological monitoring of gloved hands, • Disinfect the non-sterile gloves and
materials and equipment has to show that the chosen disin- – Disinfect the outside of the materials and place them in
fection procedure is effective (see Sect. 31.6.1). In the phar- the grade A zone or on the ‘sterile area’.
maceutical industry, disinfection between each clean room – Remove the outer layer of the wrapped, sterilised
level is common. In the UK, during aseptic handling, disposable equipment and place them in the grade A
materials and equipment undergo at least two separate disin- zone or on the ‘sterile area’.
fection steps. In the Netherlands only one step is common. • Disinfect hands.
Just before use, critical spots (vial stoppers, ampoule • Put on sterile gloves (this can be done outside the grade
necks) should be disinfected again. A zone).
• Place materials in the correct order in the grade A zone.

• Disinfect critical spots (vial stoppers and ampoule
necks).
air
• Carry out the aseptic handling. surface
• Label the product.
• Remove the product and waste material from the grade
A zone.
product equipment
Keep Sterile Gloves Sterile!
It is essential to keep the outside of the gloves sterile or operator
at least low bioburden. Thoroughly disinfecting the & process
outer surface of the materials before transferring to
the LAF cabinet, safety cabinet or isolator and keeping raw material
& package
the gloved hands in the LAF cabinet or safety cabinet
are most important. Sterile gloves can be disinfected,
but disinfected gloves are slippery. So, don’t disinfect
too often and dry gloves in the sterile airflow. A Fig. 31.1 Microbiological threat to the product. Source:
Recepteerkunde 2009, # KNMP
disinfection frequency of 30 min is satisfactory in
general, however gloves should be disinfected after
removal from the work station before returning to the 31.6.1 Microbiological Monitoring
Grade A working zone. Every pharmacy should moni-
tor this process using finger dabs (see monitoring). Microbiological monitoring is applied to determine the
Check gloves constantly for damage (at least every extent of environmental contamination. Figure 31.1 states
30 min as a minimum) and change gloves immediately which environmental factors are important: the nearer to the
if they are damaged. Avoid changing gloves during a (open) product, the more risk of contamination.
session unless they are damaged, however. It is most important, therefore, to monitor the areas
nearest the product for microbiological contamination. Mon-
itoring generally focuses on counting the numbers of micro-
organisms. Where products with a shelf life of several
Sterile filtration is not by definition included in aseptic months are concerned, monitoring results have to be consid-
handling. For aseptic handling, the starting materials and all ered before product release. In the case of aseptic handling,
equipment are sterile and closed procedures are used. When however, monitoring results are often not available at the
drawing up from glass ampoules (risk of glass particles) point of release of the aseptic product.
a sterile filter straw or filter needle should be used. Replace
the filter straw or needle with a fresh needle before adding
31.6.1.1 What has to be Monitored?
the solution to another container. In the case of complex
For monitoring the air, settle (sedimentation) plates and
aseptic manipulations like filling a medication cassette, ster-
volumetric air samplers are used. The latter come in various
ile filtration (0.2 μm) may be used as an additional precau-
types [27]. Most of them suck up a fixed volume of air and
tion, however.
the micro-organisms are deposited on a growth medium.
With settle plates, the micro-organisms fall onto an opened
90 mm Petri dish containing an agar medium (see Fig. 31.2).
31.6 Microbiological Controls The opening time has to be 4 h [1]. If the preparation time
is shorter (usual in case of aseptic handling) the settle plates
Although aseptic handling differs significantly from aseptic have to be closed at the end of the preparation.
processing, the principles for microbiological controls, like Monitoring of flat surfaces is carried out with contact
monitoring and process validation, are the same. As most plates of agar medium in a 55 mm dish. The medium has a
aseptic work is done manually, the aseptic technique of the slightly convex surface which can be gently pressed on the
operators has to be checked with additional microbiological surface to be examined, see Fig. 31.2. These plates are
controls. sometimes known as RODAC plates (RODAC is the brand
activities. For settle plates and contact plates in the Grade A

working zone, this is underneath the place where the aseptic
contact plate settle plate activities are carried out.
The sampling frequency during/after aseptic handling in
swab the Netherlands consists of every working day one settle
plate and one contact plate in the Grade A working zone
Fig. 31.2 Techniques for monitoring and immediately after the session one gloved finger print
with the most used hand [8]. The frequency of monitoring
the background Grade D room can be lower. A sampling
name meaning Replicate Organism Duplicate Agar Con- plan of contact plates for the critical spots on the bench top
tact). Remnants of the growth medium may stay on the (s) and several settle plates both every month, will give
sampling spot so cleaning and disinfection after sampling enough information about the contamination levels.
must be a standard component of the sampling procedure. Before starting aseptic handling in a new facility or after a
If the surface is not flat and or accessible, a swab has to be major process change, initial validation should be carried
used. This is a small wad of cotton on the end of a short rod, out. Part of this is frequent monitoring of all the locations to
see Fig. 31.2. First this has to be wetted with sterile water. determine the average contamination level. After that, mon-
After that it can be swabbed onto the surface to be examined itoring results should be reviewed on a periodic basis as a
and finally it has to be wiped across an agar medium in a means of evaluating the overall control of the aseptic pro-
petri dish. The recovery from a contact plate is 30–50 % and cess. A graphical representation will help to determine
from a swab around 10 % [24]. whether there is an upward increase (trend) in the level of
Monitoring of the gloved hand is done by fingerprints contamination present. An example of a graphical represen-
(finger dabs). At the end of each session the tip of the five tation is shown in Fig. 31.3.
fingers of the gloved hand should be pressed gently but
firmly on an agar surface in a petri dish. Use one plate per
hand. In Dutch hospital pharmacies printing is only done 31.6.1.4 Limits, Alert and Action Levels
with the most used hand [8]. In the UK and USA both gloved What are the criteria for monitoring results during aseptic
hands are monitored [6, 27]. handling? Table 31.5 gives the recommended limits for
microbiological monitoring of clean areas during operation
from the EU GMP guide [1].
31.6.1.2 Media and Incubation Time
As stated before, the sampling frequency during/after
PRODUCTION
The agar medium in the petri dishes and the contact plates is
aseptic handling in the LAF cabinet, safety cabinet or isola-
Tryptone Soy Agar (TSA) on which most micro-organisms
tor in the Netherlands is only one settle plate, one contact
that we can expect in the environment grow. Incubation
plate and one finger print. When there is growth, the average
temperature is 30–35 C and the incubation time is at least
will be 1 CFU or more and that is above the limits for Grade
3 days. Especially for yeast and moulds Sabouraud dextrose
A in Table 31.5. However, when aseptic handling is
agar is used. The incubation temperature and time for this
performed in the right way the frequency of samples with
medium are 20–25 C and 5 days. Investigation in Dutch
growth is low and the average CFU over a longer period will
hospital pharmacies has shown that a broad spectrum of
be far below one [29].
bacteria, yeast and moulds grow well on TSA at 30 C within
When the average contamination level (in CFU) is
3 days [28].
known, alert and action levels have to be determined. The
Colonies, which may be counted, grow from the micro-
alert level is the early warning level; a drift from normal
organisms on the agar surface. As it is not known whether
conditions. When this level is exceeded it is recommended
the colony has developed from one or several micro-
that the previous results are checked (is there a trend?) and
organisms, the expression colony forming units (CFU) is
that the following results are monitored more closely. When
used. The results after incubation are expressed as CFU per
the action level is exceeded a thorough investigation should
plate.
be made into the nature of the contamination, including
identification of the isolates, and subsequent corrective
31.6.1.3 Environmental Sampling Plan actions should be implemented immediately. This may lead
An appropriate sampling plan has to be part of the environ- to adjusting the procedure and/or retraining the staff. More
mental monitoring programme. It consists not only of the intensive monitoring will be necessary to be able to quickly
sampling locations but also of the sampling frequency. The assess if the adjustments have been successful. Action may
locations should be based upon a risk analysis to determine also be required if the trend exceeds 50 % of the base
the spots most likely to be contaminated during the aseptic line [30].
4
settle plates
kve 3
positive
2 mean value last
100 samples
1
0
date of aseptic handling
4
glove prints
3
kve
positive
2 mean value last
100 samples
1
0
contact plates 3
kve
positive
2 mean value last
100 samples
1
0
Fig. 31.3 Monitoring results over 1 year during/after aseptic handling in a Dutch hospital pharmacy. Every bar is a positive, the continuous line is
the mean values over the last 100 samples
Table 31.5 Limits for microbiological contamination [1]

Recommended limits for microbiological contamination (a)
Grade Air samples CFU/m3 Settle plates (diameter 90 mm) Contact plates (diameter 55 mm) Glove print 5 fingers
CFU/4 h (b) CFU/plate CFU/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
Notes: (a) these are average values; (b) individual settle plates may be exposed for less than 4 h
31.6.2 Microbiological Validation of the Process withdrawing a solution from a vial or an ampoule, dissolving
a powder in a vial and adding a solution to an infusion bag or
The goal of microbiological validation of the process is to a vial. Working with double or quadruple strength TSB can
demonstrate that the procedures used during aseptic be helpful to simulate aseptic handling.
handling and the staff undertaking aseptic processes, are The simulation can be carried out daily at the end
capable of maintaining the sterility of the product [31]. In of a work session or periodically with a number of
this validation the aseptic handling is simulated with an simulations together. Bringing all the results together, in
appropriate broth solution, typically Tryptone Soya Broth the long run, provides good information about the overall
(TSB). The final product is incubated for 7 days at 20–25 C quality of aseptic handling, however the total number of
and 7 days at 30–35 C successively and should not show TSB simulations is limited in comparison to aseptic produc-
any growth (in some countries, such as the Netherlands, tion in industry.
14 days at 30 C only). The simulation should comprise all In judging the results, a validation curve can be
critical steps that occur in standard aseptic handling like drawn [31].
technique of each individual operator is satisfactory, stan-

Validation Curve [32] dard assessments for operator technique have been devel-
For judging the results of the microbial validation of oped. In the Netherlands this assessment is known as
aseptic handling by TSB simulation, a validation curve “Individual Qualification” and in the UK as “Universal
has been developed. The curve rises one unit after a Operator Broth Transfer Validation” [8, 32]. Both tests
simulation without growth and falls 100 units after a consists of a repeated number of key techniques such as
simulation with growth. The maximum is fixed at withdrawing a solution from a bag, vials or ampoules and
299 and the minimum at 0. Three levels of perfor- adding it to empty sterile vials or infusion bags. The solution
mance are distinguished, see Fig. 31.4. used is a growth medium (mostly TSB) and the filled vials or
bags are incubated for 7 days at 20–25 C and 7 days at
299 30–35 C successively (some countries like the Netherlands,
14 days at 30 C only) and must not show any growth to pass
level 3 the test. Qualified operators have to be re-qualified at least
200 every year with the same test.
1 2
level 2
Score
References
3
100
level 1 1. The rules governing medicinal products in the European Union. EU
4 Legislation – Eudralex -Volume 4 Good manufacturing practice
(GMP) Guidelines. Annex I. Manufacture of sterile medicinal
products. March 2009. http://ec.europa.eu/health/documents/
number of TSB simulations eudralex/vol-4/index_en.htm
2. Guide to good practices for the preparation of medicinal products in
Fig. 31.4 Example of a validation curve Healthcare establishments. PIC/S Guide-010-04. March 2014.
www.picscheme.org
3. Parenteral Drug Association (2013) Recommended practice for
Like the validation of aseptic manufacturing manual aseptic processes. Technical report no. 62. www.pda.org
according to GMP Annex 1 [1], corrective measures 4. Boom FA, Bouwman-Boer Y, Kruik-Kolloffel WJ, Pluim MAL,
Rendering J, Simons KA (2005) Hoofdstuk
in the case of growth are made, depending on the total GMP-Ziekenhuisfarmacie herzien. Verantwoordelijkheid voor
number of simulations without growth. This will be aseptische handelingen buiten de ziekenhuisapotheek. Pharm
indicated by the level in the validation curve. For Weekbl 140:350–352
PRODUCTION
example: 5. Beaney AM, Goode J (2003) A risk assessment of the ward based
preparation of parenteral medicines. Hosp Pharm 10:306–308
• Positive simulation 1 (see Figure above), the curve 6. The United States Pharmacopeia USP 35 (2012) The United States
falls down to 199. The corrective actions belonging Pharmacopeial Convention. Rockville. <797> Pharmaceutical
to level 2 have to be executed. For example: identi- compounding – sterile preparations
fication of the micro-organism(s) found in the posi- 7. Beaney AM (2006) Quality assurance of aseptic preparation
services on behalf of the NHS pharmaceutical quality assurance
tive simulation and careful checking of the committee, 4th edn. Pharmaceutical Press, UK
monitoring results. 8. Z3 Aseptic Handling (2013) In: GMP-Hospital, version 2013.
• Positive simulations 2 and 3 (see Fig. 31.4), again Dutch Association of Hospital Pharmacists. http://www.nvza.nl
corrective actions belonging to level 2 have to be 9. Leitlinie ADKA (2013) Aseptische Herstellung und Prüfung
applicationsfertiger Parenteralia. Krankenhauspharmazie 34:93–106
executed. 10. ASHP (2014) Guidelines on compounding sterile preparations. Am
• Positive simulation 4 (see Fig. 31.4), the curve falls J Health-Syst Pharm 71:145–166
down to level 1. The corrective actions belonging to 11. National Patient Safety Agency (NPSA) (2008) Promoting safer use
this level have to be executed. For example: as well of injectable medicines. Patient safety alert 20. http://www.nrls.
npsa.nhs.uk
as the corrective actions for level 2, an audit of 12. Ris JM, van Leeuwen RWF, Boom FA (2010) VTGM op de ICU:
aseptic handling has to be performed and TSB mind the steps! Pharm Weekblad 4:11–17
simulations should be undertaken more frequently 13. Beaney AM, Black A, Dobson C, Williamson S, Robinson M
for a specified period. (2005) Development and application of a risk assessment tool to
improve the safety of patients receiving intravenous medication.
Hosp Pharm 12:150–154
14. van Grafhorst JP, Foudraine NA, Nooteboom F, Crombach WH,
31.6.3 Individual Qualification Oldenhof NJ, van Doorne H (2002) Unexpected high risk of con-
tamination with staphylococci species attributable to standard prep-
aration of syringes for continuous intravenous drug administration
As microbiological validation of the process will not gener- in a simulation model in intensive care units. Crit Care Med
ate sufficient data to give assurance that the aseptic 30:833–836
15. Stucki C, Sautter AM, Jocelyne Favet J, Bonnabry P (2009) Micro- 24. Cockroft MG, Hepworth D, Rhodes JC, Addison P, Beany AM
bial contamination of syringes during preparation: the direct influ- (2001) Validation of liquid disinfection techniques for transfer of
ence of environmental cleanliness and risk manipulations on components into hospital pharmacy clean rooms. Hosp Pharm
end-product quality. Am J Health-Syst Pharm 66:2032–2036 8:226–232
16. Sigward E, Fourgeaud M, Vazquez R, Guerrault-Moro MN, 25. Mehmi M, Marschall LJ, Lambert PA, Smith JC (2009) Evaluation
Brossard D, Crauste-Manciet S (2012) Aseptic simulation test of disinfecting procedures for aseptic transfer in hospital pharmacy
challenged with microorganisms for validation of pharmacy departments. J Pharm Sci Tech 63:123–138
operators. Am J Health-Syst Pharm 69:1218–1224 26. Technical Report no. 62 (2013) Recommended practices for man-
17. Schierl R, Hlandt AB, Nowak D (2009) Guidance values for surface ual aseptic processes. Parenteral Drug Association
monitoring of antineoplastic drugs in German pharmacies. Ann 27. The United States Pharmacopeia USP 35 (2012) The United States
Occup Hyg 53:703–711 Pharmacopeial Convention. Rockville. <1116> Microbiological
18. EU Occupational Safety and Health Agency. Directive 2010/32/EU control and monitoring of aseptic processing environments
– prevention from sharp injuries in the hospital and healthcare sector 28. Werkgroep Microbiologie and Hygiëne (2013) Onderzoek
19. Brouwers EE, Huitema AD, Bakker EN, Douma JW, Schimmel KJ, vergelijk incubatietemperaturen. http://www.nvza.nl
van Weringh G, de Wolf PJ, Schellens JHM, Beijnen JH (2007) 29. Postma DJ, Boom FA, Bijleveld YA, Touw DJ, Veenbaas T,
Monitoring of platinum surface contamination in seven Dutch Essink-Tjebbes CM, Verbrugge P (2012) Microbio: a web based
hospital pharmacies using inductively coupled plasma mass spec- program for processing and evaluation of microbiological controls
trometry. Int Arch Occup Environ Health 80(8):689–699 on aseptic dispensing. Eur J Hosp Pharm 19:143
20. Van der Aart AB, Klok H, Moes JR, Visser T (2005) Omgevings- 30. Moldenhauer J (2011) Development and implementation of a pro-
monitoring cytostatica. Contaminatie kan beneden detectielimiet gram for environmental monitoring in the compounding Pharmacy.
worden gehouden. Pharm Weekbl 11:358–361 In: Moldenhauer J (ed) Environmental monitoring a comprehensive
21. Murthough SM, Hiom SJ, Palmer M, Russel AD (2000) A survey of handbook, vol 5. Parenteral Drug Association, Bethesda
disinfectant use in hospital pharmacy aseptic preparation areas. 31. Boom FA, van Doorne H, Moes-ten Hove JE (2012) Microbio-
Pharm J 264:446–448 logische validatie van aseptische handelingen: wat zijn de criteria?
22. Priscott PK, Yung Dai (2008) Disinfectants program. In: Prince R Pharm Weekblad 6(6):90–94
(ed) Microbiology in pharmaceutical Manufacturing, vol 2. Paren- 32. Pharmaceutical Aseptic Services Committee (2005) Universal
teral Drug Association, Bethesda operator broth transfer validation, 7th edn. http://www.civas.
23. Akers J, Agelloo J (2001) Environmental monitoring: myths and co.uk
misapplications. J Pharm Sci Tech 55:176–184
Quality Requirements and Analysis
32
Oscar Smeets, Mark Santillo, and Hans van Rooij
Contents 32.11 Particle Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719

32.1 Quality Requirements and Regulations . . . . . . . . . . . . . . 708 32.12 Particulate Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
32.2 The European Pharmacopoeia . . . . . . . . . . . . . . . . . . . . . . . 709 32.13 Physical Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
32.3 Identity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710 32.14 Herbals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
32.4 Average Content of Active Substance . . . . . . . . . . . . . . . . 710 32.15 Quality Requirements, overview . . . . . . . . . . . . . . . . . . . . . 722
32.4.1 Content of the Raw Material and Factorisation . . . . . . . . 711
32.4.2 Preparation Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712 32.16 Analytical Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
32.4.3 Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712 32.16.1 Purpose of Analytical Validation (AV) . . . . . . . . . . . . . . . . 722
32.4.4 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712 32.16.2 Guidance from EDQM and European Pharmacopeia . . 722
32.4.5 Analytical Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 32.16.3 Performance Properties of an Analytical Method . . . . . . 724
32.4.6 Interpretation of the Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 32.16.4 European Regulations and Impurities in Active
Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
32.5 Chemical Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 32.16.5 Selection of Test Samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
32.16.6 Reference Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
32.6 Average Mass, Volume and Content . . . . . . . . . . . . . . . . . 714 32.16.7 Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
32.6.1 Average Mass and Theoretical Mass of Single Dose 32.16.8 Different Applications Require Different Validation
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
32.6.2 Volume and Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
32.7 Uniformity of Mass and Content of Single Dose
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
32.7.1 Uniformity of Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
32.7.2 Uniformity of Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Abstract
32.8 Microbiological Purity, Sterility, Pyrogens For the control of the production of medicines quality
and Bacterial Endotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
requirements are essential. Quality requirements cover
32.9 Disintegration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718 the quality of the preparation throughout the whole shelf
32.10 Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719 life, from release until the end of the shelf life. Medicines
that are produced by the industry or prepared in a phar-
macy have to meet the requirements of the European
Pharmacopoeia. Status, type and structure of its
Based upon the chapter Kwaliteitseisen by Oscar Smeets and Rik
Wagenaar in the 2009 edition of Recepteerkunde. monographs are dealt with. This chapter explains what
O.S.N.M. Smeets (*)
quality requirements are. Also the background to the
Royal Dutch Pharmacists Association, Laboratory of the Dutch general quality requirements such as identity and content
Pharmacists, The Hague, The Netherlands are discussed.
e-mail: [email protected] In this chapter the following quality requirements that
M. Santillo are specific to pharmaceutical dosage forms are
Regional Quality Assurance, South Devon Healthcare NHS Foundation described: chemical purity, average mass, average vol-
Trust, Torbay Hospital, Torquay, UK
ume, average content, uniformity of mass, uniformity of
content, uniformity of dosage units, microbiological
H.H. van Rooij
purity, sterility, endotoxins, disintegration, dissolution,
Independent Consultant and Qualified Person, OZ Voorburgwal 109 N,
1012 EM Amsterdam, The Netherlands particle size, particulate contamination and physical
e-mail: [email protected] parameters such as pH, relative density and osmolality.

708 O.S.N.M. Smeets et al.
An overview of relevant quality requirements of quality requirements, possibly with a certain safety margin.
important pharmaceutical dosage forms in practice is Narrow limits, and hence stricter quality requirements, may
given at the end of this chapter. Analysis needs analytical not lead to a more clinically effective or acceptable prepara-
validation; this is generally discussed as well. tion but may possibly lead to higher costs. In practice it is
often true that stricter quality requirements are achievable,
Keywords within acceptable costs, than are strictly necessary from the
Pharmacopoeia Quality requirements Assay Identity point of view of effectiveness, safety and user-friendliness.
Content Purity Content uniformity Disintegration The high level of pharmaceutical sciences and technology
Dissolution Particles FRC Analytical validation available today certainly contributes to this fact.
The limits that medicinal products must comply to are
generally specific for each individual product, however,
there are some limits that are general valid for dosage
32.1 Quality Requirements and Regulations
forms such as particulate matter in solutions for injections.
For industrially prepared licensed products the specification
The characteristics of a medicine are that the product is
is a part of the marketing authorisation.
effective, safe and user-friendly, these are the primary
Medicines that are produced by the industry or prepared
requirements of the patient and are also important quality
in a pharmacy have to meet the requirements of the
targets for those who formulate and produce medicines.
European Pharmacopoeia (Ph. Eur.). The monograph Phar-
When a medicine is developed, the requirements of the
maceutical Preparations in the Ph. Eur. became effective on
patient are translated into an actual product (see Chap. 17).
the first of April 2013. This is a framework monograph
The qualitative and quantitative composition are chosen, as
regarding the preparation or production of pharmaceutical
well as the pharmaceutical dosage form, the preparation
preparations.
method, the container and the accompanying information
The monograph does not officially cover medicinal
for the patient. Pharmacy preparations should have a
products used in clinical studies (Investigational Medicinal
pharmacotherapeutic as well as technically sound product
Products, IMPs), but authorities may still refer to it. The
design. Formulation, preparation method, container and
monograph gives, amongst others, guidelines for the
labelling have to meet the relevant requirements.
requirements for active substances and excipients that are
In the medicine design process the requirements that
processed in pharmaceutical preparations and for the
describe and control the quality are stated, including:
requirements for the final dosage form. The pharmaceutical
• Identity
preparations, made in pharmacies, are explicitly covered by
• Content
the monograph. In the Ph. Eur. pharmacy preparations were
• Chemical purity
not explicitly defined until the appearance of supplement
• Average of mass of single dose preparations
7.7. Publishing the monograph Pharmaceutical Preparations
• Uniformity of mass of single dose preparations
has changed this and the Ph. Eur. now accepts that pharmacy
• Uniformity of content of single dose preparations
preparations may be “needed to meet the special needs of the
• Uniformity of dosage units
patient”. The British Pharmacopoeia [2] has had, for a num-
• Microbiological purity, sterility, pyrogens and bacterial
ber of years, a general section on unlicensed medicines and
endotoxins
also contains monographs for a variety of unlicensed
• Disintegration
medicines frequently prepared in the pharmacy.
• Dissolution
Medicines that are prepared by the pharmacy have to
• Particles (visible and sub-visible)
meet the specific national law. This depends on the country
Additionally other requirements may be included with
in Europe. As an example the situation in the Netherlands is
regard to certain physico-chemical parameters, for example
described here. Regulations about the quality requirements
pH, relative density, viscosity, optical rotation, conductivity
for medicines prepared in the pharmacy are from 2007. It is
and osmolality.
stated that medicines prepared in a pharmacy, not being
These requirements are from now on referred to as quality
investigational medicines, may only be dispensed when
requirements. With the exception of the identity, which can
they meet the instructions of the European Pharmacopoeia
only be positive or negative, all mentioned quality
(Ph. Eur.) or, in the absence of a monograph, meet the
requirements can be indicated with a numerical specifica-
monographs of an officially used Pharmacopoeia in a mem-
tion, either as range or as a limit e.g.: “less then . . .”.
ber country, or of an officially used Pharmacopoeia in the
Specifying quality requirements means stating limits or
United States [3] or Japan [4]. Raw materials of good quality
margins for these parameters. The allowed limits should be
must be used.
set such that the product meets the earlier mentioned primary
32 Quality Requirements and Analysis 709
The Ph. Eur. contains, with exceptions (haemodialysis Pharmacopoeia for all the concerned countries. They also
solution and radiopharmaceuticals), no monographs for fin- agreed on taking necessary steps to make sure that the
ished products. However general monographs for pharma- monographs that are based on this convention will be
ceutical forms are described. The general monographs for accepted and will form the Ph. Eur., and become the official
pharmaceutical forms are included in a separate chapter standards in the relevant countries.
Monographs on dosage forms, separated from the The Ph. Eur. has legal force for both human and veteri-
monographs for raw materials. The mentioned quality nary medicines. The Ph. Eur. has various monographs. More
requirements in there are related to disintegration, dissolu- than half of all the monographs concern raw materials from
tion, uniformity of weight, uniformity of content, sterility chemical, herbal or animal origin. Raw materials that are
and more. In the British Pharmacopoeia [2], the United used in the pharmacy for preparing medicines should be of a
States’ [3] and the Japanese [4] Pharmacopoeias suitable standard. If medicines meet the quality requirements
monographs for finished products are included. Deviation of the Ph. Eur. then they are of a suitable standard for patient
is only allowed when stated and justified in the product file. use within any restrictions noted.
This concerns, for example pH, requirements to aqueous For raw materials there is a general monograph available
solutions or quality requirements to the chemical purity. and there are also specific monographs on specific active
The sequence in the mentioned Pharmacopoeias above is substances.
not arbitrary, if for a certain product a monograph is Starting materials for the chemical synthesis of active
included in the British Pharmacopoeia [2], then these quality substances are outside the scope of Ph. Eur.
requirements are valid and not the requirements of a possibly All organic and inorganic pharmaceutical raw materials
existing monograph in the United States [3] or Japanese that are processed in medicines should meet the general
Pharmacopoeia [4]. Quality requirements are not cumulative monograph Substances for Pharmaceutical Use. This mono-
and a product does not have to comply with every Pharma- graph describes how a Pharmacopoeia monograph is com-
copoeial monograph available just the first of the above posed and is valid for raw materials of which a specific
sequence in which it appears. monograph is included in the Ph. Eur. as well as for raw
It is also stated that the amount of a drug substance of a materials of which no specific monograph is available. There
medicine prepared in the pharmacy does not deviate more are more than 1900 specific monographs for raw materials
than 10 % of the amount of that substance that is mentioned included in the Ph. Eur. For pharmaceutical raw materials of
on the label of the container. For the average content of the which no specific monograph is available, the user of the raw
active substance the quality requirements from a foreign material should formulate a specification in the style of a
Pharmacopoeia are not applicable. It is important to note monograph, which minimally meets the requirements of the
PRODUCTION
that all quality requirements are valid in principal until the general monograph Substances for Pharmaceutical Use.
expiry date of the product. A monograph of a raw material consists in principle of
The Netherlands have not had their own national Phar- the following parts: name and definition, characteristics,
macopoeia, since 1993. Various other countries in Europe identity, purity, assay, labelling and a list of known
have retained their own national Pharmacopoeia. Examples impurities. The data mentioned in the section characteristics,
are the British Pharmacopoeia (BP) [2] and the Deutsches such as appearance, odour and solubility are not obligatory.
Arzneibuch (DAB) [5, 6]. In these countries the national They cannot be considered strict standards. On the other
Pharmacopoeia is part of the legislative framework of phar- hand one would not expect large deviations from the
macy preparations. However, throughout Europe, the characteristics listed, for example a substance that is
Ph. Eur. is the accepted standard and legally enforced. described as white or light yellow, crystalline powder,
should not be dark brown.
The sections identity, purity and assay are obligatory, all
32.2 The European Pharmacopoeia pharmaceutical grade materials must comply with the
standards within them. It may be that certain tests are only
Before separate quality requirements are discussed, this sec- applicable when the raw material is meant for a specific use.
tion is about the status and the importance of the Ph. Eur. A For purified water for example there is a limit test for
Pharmacopoeia is an official, legally enforceable, published aluminium, which is only applicable when the water is
handbook with instructions for the preparation of medicines meant for use in dialysis solutions.
for human and veterinary use and the requirements which The section titled labelling describes any specific infor-
they have to meet. mation that should be included on the label, including any
Almost 40 countries in Europe are party to the convention quality relevant parameters, for example a certain viscosity
regarding the composition of the Ph. Eur. The parties that gradient for cellulose derivatives. Those parameters are
enter into the treaty have agreed to compose a single called functionally related characteristics (FRCs).
Next to monographs for raw materials the Ph. Eur.

contains monographs about the various dosage forms such 32.3 Identity
as capsules, suppositories, tablets, creams and ointments.
These monographs also have specific sections including The identity of a pharmacy preparation must obviously be
definition, production, tests, storage and labelling. correct. Four factors need to be considered when assessing
Furthermore the Ph. Eur. contains some general identity:
monographs including, for example, vaccines for human • What is prescribed
use, radiopharmaceutical preparations and homeopathic • What is specified on the batch preparation instruction/
preparations. record
The most important monograph for pharmacy • What is specified on the label
preparations however is the monograph Pharmaceutical • What is the actual composition of the product
Preparations. Theoretically these factors match precisely, but in practice
This monograph is intended to be the reference source of for instance a codeine containing cough syrup may contain
applicable standards in the Ph. Eur. on active substance, codeine or codeine phosphate or codeine phosphate hemihy-
excipients and dosage forms, used in the preparation of drate. However, the identity must be clear and comply (see
pharmaceuticals. Pharmaceutical preparations are medicinal also Sect. 23.1)
products generally consisting of active substances that may With the preparation of medicines the pharmacist has
be combined with excipients, formulated into a dosage form some freedom to choose excipients. The active substance
suitable for the intended use, where necessary after reconsti- should however be identical to those mentioned on the
tution, presented in a suitable and appropriately labelled prescription. Sometimes there are pharmaceutical reasons,
container. Pharmaceutical preparations may be licensed by for example the stability of the product, to change the active
the Competent Authority, or unlicensed and made to meet the substance for a more appropriate clinically equivalent
specific needs of patients according to legislation. There are substance.
two categories of unlicensed pharmaceutical preparations: Generally this will be about the choice of another chemi-
extemporaneous preparations and stock preparations. cal form, for example theophylline instead of aminophylline
Ethical aspects of the preparation of unlicensed or carbasalate calcium instead of acetylsalicylic acid. It is
medicines are also discussed. The monograph discusses the important to pursue a consistent policy on this, for both the
special position of pharmacy preparations as medicines. stock preparation as well as the extemporaneous preparation
Because, contrary to licensed medicines, independent super- and the policy should be clear and consistent. The prescriber
vision is lacking, attention is asked for the extra responsi- should be consulted in order to explain changes to the
bilities that professional caregivers have when prescribing prescription and in many Countries should be asked consent.
and preparing medicines (see further Sect. 35.5.3). A risk When considering a stock preparation the substances will
analysis is indicated to help guarantee that the preparation be described precisely on the batch preparation instruction.
keeps an acceptable quality during its shelf life and is suit- This description should also contain quality indications such
able for the intended use. The pharmacist gives an interpre- as water content and particle size. If deviations are made
tation to these definitions by assessing the quality of the then the original design may not be met. This can lead to
design and the practical feasibility of the preparation related unexpected influences on the pharmaceutical quality and
to the (therapeutic) value for the patient. See further Sect. possibly even on the primary quality requirements.
2.2. See Sect. 37.3 for requirements to the labelling and infor-
In separate sections the importance of choosing and defin- mation for the patient.
ing relevant quality parameters to guarantee the required
quality of the medicine is discussed. It is explicitly men-
tioned that stock preparations are generally tested more 32.4 Average Content of Active Substance
extensively than extemporaneous preparations. It is also
mentioned that if it is not practical to perform tests on In the monograph Pharmaceutical Preparations of the
pharmacy preparations, for example because the batch is Ph. Eur. there are no requirements for the content of the
too small or because of the delivery time, other suitable active substances. In some European countries, such as
methods may be used to guarantee that the required quality the Netherlands, it is stated in national law that the amount
level is met. With this, the process validation has obtained an of an active substance of a preparation prepared in the
official position next to the end control of products. It should pharmacy should not deviate more than 10 % of the amount
be stressed, however, that when tested at any point during of that substance that is stated on the label.
the product shelf life the product must meet the specification The limits 90–110 % contain the total variation caused by
in the monograph. preparation and analysis. In practice some variation in
average content of active substance in various batches of the assay method. It is principally incorrect to factorise at a
same finished product will be inevitable. The size of that preparation based on the outcome of such a determination.
variation depends on: One issue with factorisation is that the quantity of mate-
• The variation in the content of the raw materials rial to be included in each batch needs to be calculated
• The variation in the preparation process separately and cannot be exactly stated in the master batch
• The stability of the active substance in the finished preparation instruction (see Sect. 33.4), this is a potential
product source of preparation error.
The sample size and the variation in the analysis of the Contrary to this there is, in principal, a ‘quality gain’
finished product also play a part. These do not influence because the content of the substance lies closer to the
the actual content of the product, but do influence the declared content. For most of the raw materials only a
obtained results from a testing laboratory on which a deci- small percentage of impurities (mostly water) is allowed in
sion on whether or not a product meets its specifications has the Pharmacopoeia. The quality gain that would follow from
to be made. See Sect. 20.3 on the statistical background. the correction for that is not at all relevant to the patient, and
Every item mentioned will be discussed further below. is therefore outweighed by the previously mentioned
disadvantages. E.g. a cough syrup with codeine is often
prescribed by the physician either to a patient weighing
70 kg or 85 kg, being 1.21 times heavier. He will not
32.4.1 Content of the Raw Material
consider dose adjustment based on body weight.
and Factorisation
Considering the above, factorisation should be avoided as
much as possible. The requirement of 90–110 % for the
Usually the declared content of the active substance in a final
content in the finished product, which is official in the
product is based on the chemically pure substance. The
most of the European countries, usually offers enough
chemically pure substance is the substance that is described
space for that. For countries with tighter limits than
by the header of the Pharmacopoeia monograph for the
90–110 % for the content of active pharmaceutical sub-
specified raw material. The molecular formula and the
stance a different approach may be necessary.
molecular weight are given. For substances with a varying
Factorisation is clearly necessary when the amount of
amount of water this refers to the dried substance. For
impurities is so large that there is significant risk that the content
substances with a sharply defined amount of water of
in the final product will be outside of the specification limits.
crystallisation the compound including the water of
In the Netherlands it is common to factorise if the amount
crystallisation is considered the chemically pure substance,
of known impurities in the raw material is more than 4 % .
PRODUCTION
provided that this is clear from the declaration.
To obtain the labelled content of the substance as close as
possible to the required declared content, factorisation might It is possible to work with the standardised batch
be used. preparation instructions by correcting the amount of
Factorisation is correcting the amount of raw material to raw material to be weighed with a constant factor,
be taken into production prompted by the content of sub- corresponding with the most probable amount of
stance in the specified raw material batch. There are however impurities. So prednisolone sodium phosphate is
some problems. allowed to contain up to 8 % water according to the
The content of the raw material should be known to be Ph. Eur. In practice the water content is generally close
able to factorise. Factorisation however is only useful when it to the 8 %. In the batch preparation instructions for
is certain that the content of the raw material does deviate Prednisolone Oral solution (see Table 23.23) a
significantly from 100 %. To assess this, insight in the selec- surplus of 8 % of the active substance would then be
tivity and uncertainty of the method of analysis used by the included. However with this approach care should be
raw material supplier or testing laboratory is important. taken to confirm that the level of impurity is within a
In practice a deviating value from 100 % for the content specified level before the raw material is approved
on the analysis report often will be only the consequence of for use.
the uncertainty in the analysis. This is certainly true when Examples of other substances that may contain
the deviation is smaller than 1–2 %, but may also hold with more than 4 % impurities are dexamethasone sodium
larger deviations for certain products. phosphate, ergotamine tartrate, erythromycin,
Consequently the Ph. Eur. allows, for certain substances, codergocrine mesilate, cyanocobalamin,
a margin in the content of 97.0–103.0 % or 96.0–104.0 %. hydroxycobalamin, thiamine hydrochloride and fer-
The symmetrical limits around 100 % indicate that these rous fumarate.
margins are connected to the uncertainty in the chosen
With factorisation a consistent policy should be pursued, Insufficient mixing will usually result in insufficient con-
hence when factorisation is done for a raw material with a tent uniformity, but with complex processes such as the
stock preparation this should also be done for an extempora- preparation of suppositories, it may even result in a deviation
neous preparation. In such cases there is an extra danger for in the average content, see Sect. 11.8.3.
calculation errors; after all factorisation has to be combined When the content deviations are too large this will result
with all the other necessary calculations. in an out of specification or at least an out of trend result and
the whole preparation process will need to be investigated in
a step by step manner to find the causes; an example of such
32.4.2 Preparation Process an investigation can be found in [7].
As a result of the preparation process content deviations may

occur. Process steps including weighing, measuring, heating, 32.4.3 Stability
mixing, transferring and filling can all introduce deviations.
Weighing and measuring can be done so precisely that The instability of an active substance can have significant
they should not significantly contribute to deviations in the consequences for the content in the finished product. This
content. Loss by evaporation can be prevented usually by usually concerns the chemical stability, however also loss by
making the product up to its final volume as the last step of evaporation and sorption on storage may play a part. Stabil-
any process. The other preparation steps usually result in ity issues may arise at any point during processing and
a loss. storage.
Often there is a proportional loss, for example because a Because the above-mentioned content requirements are
proportion of the intermediate or finished product remains valid from the preparation date until the expiry date, any
on or within the mixing device. A proportional loss of a final instability has to be taken into account when stating the
product will not have impact on the product quality but may content limits. For licensed products usually the content on
result in a decrease in the yield, for example when filling a expiry date is allowed to be maximally 5 % or 10 % less
batch of suppositories. than the declared content. This only applies if the toxicity of
Inclusion of air into a product that is filled to volume can the degradation products or perceptible cosmetic changes in
lead to an apparent increase in the yield, as occurs for the external characteristics of the product allow. To extend
example with a zinc oxide cutaneous suspension the shelf life a ‘stability overage’ of, for example, 5 % or
(Table 12.21). 10 % of the declared content may be included in the prepa-
When the complete mixture is divided over the number of ration as long as the levels of degradation products will not
dosage units to be prepared, for example with the prepara- be clinically significant. Note that this process is not in line
tion of capsules with a capsule device, then the loss in terms with Committee for Medicinal Products for Human Use
of percentage is related to the decrease in the average con- (CHMP) guidelines and good formulation practice. The
tent in terms of percentage per dosage unit. inclusion of an overage to account for loss on storage
If there is a loss of content of raw materials or intermedi- (i.e. a stability loss) rather than for in process losses is not
ate product ahead of the incorporation into the final product accepted practice. Products with very short shelf life may only
then this will be carried over into that final product. If this be prepared if a stability overage is allowed. Reformulation
will lead to a significant deviation then the loss needs to be into a more stable preparation is however preferred. Another
taken into account when designing the formulation, for option for pharmacy preparations it is to limit the decrease in
example by including an overage for the lost materials. the content to maximally 5 % by shortening the shelf life or
When the amount of active substance per container unit decreasing the storage temperature (see also Sect. 22.6).
decreases by air absorption, as for zinc oxide cutaneous The use of an overage may result in an upper release limit
suspension, this does not result in a lower content, in the of for example 110 %.
case of suppositories (single dose form) then it does have an
impact on the content.
The loss can also be selective, for example by evapora- 32.4.4 Sample Size
tion of one of the components, or by adsorption to the vessel
wall. A selective loss of the active substance will usually For determination of the average content of pharmacy
result in a lower content in the final product, as is the case preparations the sample size has to be sufficiently large for
with the preparation of capsules. With the preparation of a statistically significant conclusion. With preparations in
small batches of suppositories the selective loss of the which the active substance is dissolved, then problems with
melted suppository base may however lead to a higher uniformity of content (see also Sect. 32.7) should be rare and
content (see also Sect. 11.5.2). therefore smaller samples will give a suitable level of
assurance. With preparations in which the active substance non-homogeneous preparation, a dispersion, not only the
is suspended in a base, such as with ointments or creams or standard deviation of the duplicates count but also the stan-
oral suspensions, the sample size should be sufficiently large dard deviation from the single samples. The standard devia-
to get a representative image of the content. With a sample tion has to be taken into account when deciding if the
that is too small very local concentration differences may average content meets the requirements The separate values
give an incorrect picture of the real content. This problem is will be important in order to make a judgement on extent of
even more important with single dose preparations. Because variation and on content uniformity in case of separate units.
the contents of the individual units always show a certain
degree of variation, this introduces an uncertainty when
assessing the average content. As a result of this, more 32.4.6 Interpretation of the Result
units have to be assessed to get a reliable average.
The Ph. Eur. does not make a recommendation on the The assay method can be carried out following the methods
minimum number of units to be tested, or the minimum size described on the analytical protocol. When the result lies
of the sample. The British Pharmacopoeia (BP) [2] is within the release limits, the batch may be released.
clearer. The BP describes that the average content of It has been found in the Netherlands by proficiency test-
capsules or tablets has to be determined on 20 units. From ing that the average content of most pharmacy preparations
this a mixed sample is taken, on which the content is lie between 95 % and 105 % of the stated content. So when
assessed. The BP does not describe a general amount for accepting a content limit of 90–110 %, the product will be
suppositories. In most of the separate monographs for released without further consideration if an assay result is
suppositories however a mixed sample of 10 units is taken. between 95 % and 105 %. Trends in results (up or down)
should be investigated as part of product quality reviews.
When the result lies frequently outside 95 % and 105 %
32.4.5 Analytical Error but within the 10 % product specification limits then the
cause of such a deviation should be investigated and correc-
When assessing the result of an assay method the analytical tive measures should be taken.
error has to be taken into account. The result of an assay Note that the product shelf life may also be reviewed if
method does not give the actual content, but only an esti- the expected level of degradation would predict that the
mate. In other words, when the result of an assay method is product is out of specification before the end of its usual
just within the limits, there is a degree of risk (usually taken shelf life.
as 5 %) that the content is outside the limit. The preparer When the result is outside the product specification limits
PRODUCTION
may state release limits within the 10 % content limits in the batch should not be released and the assignable root
order to avoid the release of products that do not meet the cause must be established and fully investigated. Hopefully
specification. For that purpose the lower as well as the upper this will lead to process improvement or elimination of
release limit has to be ‘narrowed’ with the unilateral 95 %- analytical errors.
confidence interval of the analysis (see Sect. 20.3). In gen- This general guidance is applicable to homogeneous
eral release specifications that are stated on the basis of preparations such as solutions. The interpretation of the
analytical error will be 1 % to 2 % from the official limits. result for inhomogeneous preparations is connected to infor-
Conversely an independent testing authority (for example mation about the inhomogeneity of the sample. The average
an inspector) should only disqualify a product when it is content and the content of the individual dosage units will
sufficiently sure that the real content is outside the official enable a decision on mixing efficiency i.e. homogeneity of
limit. He also has to take the analytical error into account. It the batch. With single dose preparations such as capsules or
is common practice to state the rejecting limits by extending suppositories the knowledge of the individual contents is
the official limit with the unilateral 95 %-confidence interval essential to get an impression of the uniformity of content
of the analysis. When both parties keep within these rules the and by consequence the correct preparation by the operator.
chance is small that a batch is released by a producer and This subject will be discussed further in Sect. 32.7.
consequently rejected by an independent testing authority.
Assays should be conducted in duplicate and ideally the
results should be reported individually or as an average and 32.5 Chemical Purity
standard deviation where higher replicates are used. With
homogeneous preparations, preparations consisting of one When designing quality requirements for a substance a dis-
phase such as solutions, a duplicate value usually gives tinction has to be made between impurities that are process
sufficient information for a product release decision. When contaminants of the synthesis (for example the related
the average content is assayed by analysing several units of a compounds in clioquinol) and those present due to
degradation of the substance in the course of time (for the United Kingdom the limits are stated in the British
example salicylic acid from acetylsalicylic acid). Pharmacopoeia [2]. In the Netherlands pharmacy prepared
products have also to meet the relevant purity requirements
as stated in monographs of for example the British Pharma-
Although when epimerisation of active substances
copoeia or if not available in another international
occurs, it will be during synthesis and during prepara-
Pharmacopoeia.
tion of the finished product as well. The manufacturer
will set different specifications for active substance
and finished product, but always as low as possible.
32.6 Average Mass, Volume and Content
Unless it appears that epimer formation is a major
(more than 10 %) metabolic pathway in the body
Medicines clearly need to contain the correct quantity.
making an impurity specification of less than 0.4 %
Therefore requirements are set for deviation from the
rather improper.
declared weight, or for the minimal amount in a container
that is available for administration. Extractable volume is an
Impurities resulting from the synthesis of the raw mate- example of such a specification. It may also be necessary to
rial that are not degradation products, will not be influenced set an upper limit to the available amount particularly where
by the preparation process of the final dosage form. It is the whole content is given as a dose
therefore reasonable to set an identical requirement for raw
material in the Pharmacopoeia and for any final products
32.6.1 Average Mass and Theoretical Mass
made from it. Analysis of such impurities will not take place
of Single Dose Preparations
on the finished product, but solely on the raw material and by
consequence a specification in the end product has no
A difference between the average mass and the theoretical
significance.
mass will show deviations in the content in a simple way: a
When the impurities arise as degradants of the main
deviating average mass often corresponds with a deviating
product, then it is likely that, during the preparation process
content. For suppositories this can occur when the wrong
(dissolving, heating, light influence), the content of such
molds have been used. With capsules loss during the prepa-
impurities increases. Also during storage the content of
ration may be the cause. The Ph. Eur. doesn’t set a require-
these impurities may increase further. The final product
ment to the deviation of the average mass from the expected
specification for such impurities will need wider specifica-
value, probably because the theoretical value is only known
tion than that specified for the raw material. However, this
to the preparer and not to an independent testing laboratory.
can only occur provided that the amount of impurities stays
In the Netherlands it is common to use a requirement of
within the acceptable criteria from a patient safety perspec-
3 % as a limit to the deviation of the average mass towards
tive which has to be demonstrated, from preclinical studies
the calculated mass for capsules and suppositories. For sin-
or literature, on safety. Generally such products will have a
gle dose powders this requirement is 5 %. In practice these
clearly defined shelf life and possibly special storage
limits appear to be acceptable and are achievable. When
conditions.
these limits are exceeded, then there are, in principle, two
Chemical impurities may also be generated as reaction
possibilities: reject the preparation or check the average
products of components, for example of the active substance
content. When the content complies, the preparation need
and excipients. For example degradation of acetylsalicylic
not be rejected on the basis of the average mass discrepancy.
acid may occur in hard fat with a high hydroxyl value. It is
However the cause of the deviation should be investigated
obvious that such interactions should be prevented best at
and traced and corrective measures should be taken for
the product design phase, by choosing the appropriate
future batches.
excipients.
The percentage of degradation product at the end of the
shelf life is generally limited to 5 % of the parent substance. 32.6.2 Volume and Content
From this percentage generally a requirement for the amount
of impurities immediately after preparation can be derived. The Ph. Eur. states requirements to the extractable volume of
Obviously other more stringent criteria will be required parenterals: ‘The volume of the injection in the container is
when the nature of the impurity is such that there can be sufficient to permit the withdrawal and administration of
safety issues for the patient (see also Sect. 22.4.2). the nominal dose using a normal technique’. In Ph. Eur.
Official limits for impurities in products prepared in chapter 2.9.17 ‘Test for extractable volume of parenteral
pharmacies are not in force in most European countries. In preparations’ the method of analysis is described.
In some cases it may be necessary to set an upper limit to Weigh individually 20 units taken at random or, for
the amount available per container. A reason may be the risk single-dose preparations presented in individual containers,
of overdosing if the entire contents of the container are the contents of 20 units, and determine the average mass.
expected to be given. For suppositories not more than 2 of the individual
For eye ointments and creams the Ph. Eur. determines an masses deviate more than 5 % of the average mass and no
upper limit of 10 g per container, in order to reduce the risk suppository may deviate more than 10 % of the average
of contamination during the period of use. Eye drop mass. For capsules with a content weight less than 300 mg
containers may contain maximally 10 mL and containers these percentages are respectively 10 and 20 %, for capsules
for irrigations for the eye maximally 200 mL. with a content weight equal to or more than 300 mg respec-
For drops for oral use it is required that the average tively 7.5 % and 15 %. For other pharmaceutical forms
weight of 10 units of the size of a usual dose may not deviate reference is made to the monograph.
more than 15 % of the nominal value. Also, if necessary, the This Ph. Eur. test is clear and unambiguous, but has the
average volume delivered should meet this requirement. disadvantage that the conclusion can only be: ‘satisfactory’
With respect to dosage forms such as oral preparations, or ‘not satisfactory’. In other words the Ph. Eur. does not set
rectal preparations and preparations for cutaneous applica- a specific limit. Only when units are deviating too far those
tion the Ph. Eur. states that during the development it must deviations may be used to give some insight in the unifor-
be demonstrated that the nominal volume or content can be mity of mass. A numerical criterion would be useful for
obtained from the container.. comparison of batches or for trend analysis of preparation
results. All the tested units should be included in this crite-
rion. The variation coefficient (or relative standard deviation
32.7 Uniformity of Mass and Content (rsd)) can serve this purpose. It is calculated as follows:
of Single Dose Preparations rsd ¼ s/m 100 %, in which s is the standard deviation
and m is the average mass.
The requirements and assay of average content has been Modern balances have a calculator-printer installed,
discussed in Sect. 32.4. When a medicine consists of single that provide the Ph. Eur. test as well as the calculation of
dosage units, the contents of those separate units (tablets, the rsd.
capsules, suppositories)have to meet content requirements. For pharmacy prepared capsules the assessment of the
The separate assay values are used for estimation of the uniformity of mass is a meaningful test. The Ph. Eur.
average content but also to estimate the variation between requirements are generally easy to be met. Inappropriate
the units (uniformity of content). The separate mass values use of the capsule filling device or a badly flowing mixture
PRODUCTION
also have to meet requirements. The mass variation may give may lead to deviations. For divided powders that are filled
some indication of the content variation. and weighed by hand no uniformity of mass needs to be
The Ph. Eur. has several monographs on the analysis of determined as long as all weights are recorded on the balance
single dose preparations: print out. It may be prudent however to conduct a random
• 2.9.5 Uniformity of mass of single dose preparations weight determination for monitoring the quality level and
• 2.9.6 Uniformity of content of single dose preparations enable trend analysis. For divided powders that are prepared
• 2.9.40 Uniformity of dosage units (also including unifor- with a powder folding machine a uniformity of mass analysis
mity of mass) is meaningful; a deviation may occur when a mixture flows
Monograph 2.9.40 will become the only valid monograph badly or when equipment is not used appropriately.
in due time. Many licensed medicines have been designed Pharmacy prepared suppositories are required to meet the
to meet the requirements of 2.9.5 and 2.9.6 and are expected Ph. Eur. specifications for Uniformity of mass. Batches that
or known not to meet the requirements of 2.9.40. The do not meet the requirements can often be rejected by visible
monographs 2.9.5 and 2.9.6 therefore will be kept for the irregular filling of the molds, air bubbles, etc.
time being. Drops for oral use have to meet the requirement that the
separate masses of 10 units equivalent to the normal dose
deviate maximally 10 % from the average mass. The total of
32.7.1 Uniformity of Mass 10 masses does not differ by more than 15 % from the
nominal mass of 10 doses.
The uniformity of mass is easy to determine and it gives an The uniformity of mass test does not have to be
indication of the uniformity in the content as far as this is performed when the test on uniformity of content according
caused by mass deviations. to 2.9.6 has been performed for all the active substances
According to Ph. Eur. monograph 2.9.5 the assay and included in a preparation. The test on uniformity of content
requirements read as follows: gives much more information about the variation in the
amount of active substance per dose unit in the product than the required limits are normalised towards the average con-
does the uniformity of mass test. tent and not to the declared content.
The content uniformity test according to the Ph. Eur. The requirements apply to single dosage forms with less
2.9.40 also regards uniformity of mass. than 2 mg of active substance per dose or less than 2 % of
the total mass.
As with Uniformity of Mass this Pharmacopoeia test for
32.7.2 Uniformity of Content Uniformity of Content is clear and unambiguous, but less
suitable to compare batches. For that purpose, as said, the rsd
32.7.2.1 Content Variation is much more appropriate.
Variation in the content of single dosage units depends on
the dispersion type of preparations (see Sects. 18.4 and 32.7.2.3 Content Uniformity and Mass Variation
29.7): mixtures of two or more solid substances (powders, According to Ph. Eur. 2.9.40 Uniformity
capsules), dispersions of a solid substance in a semisolid of Dosage Units
substance (ointments, creams) and dispersions of solid This test is a requirement of content uniformity but it is
substances in liquids (suppositories, suspensions). Solutions actually a requirement for the average content as well. As
do not show content variation between single dose units, just opposed to the monograph 2.9.6 the requirements for unifor-
mass variation may occur. Content variation is caused by mity of content of single-dose units refer to the ‘label claim’
poor dispersion, by poor mixing in the bulk or by de mixing (declared content) of the batch and not to the average con-
at filling, rather than by mass variation due to poor filling/ tent. This characteristic also makes the test tighter than the
dividing. 2.9.6 test.
The mixing variation is low when the distribution of the This monograph has been harmonised with the United
active substances in the excipients is as homogeneous as States Pharmacopoeia (USP) [3] and Japanese Pharmaco-
possible and when this homogeneity is maintained during poeia (JP) [4].
filling. The monograph defines the application of Content Uni-
A measure for content variation is the rsd of the assays of formity (CU) and Mass Variation (MV) on different dosage
single dosage units. If the mass variation is determined as forms that contain <25 mg active substance per dose unit or
well, the actual mixing variation can be calculated (see Sect. where the active substance comprises <25 % of the mass of
29.4). In this way it can be investigated whether poor mixing the dosage unit. A random selection of 30 units is required
or poor filling/dividing (or both) is the cause of the content and the separate units have to be assayed individually.
variation. When a poor filling or dividing process is the But the test may be applied as well for the assessment of
cause of content variation then the uniformity of mass varia- the MV of dosage forms, e.g. tablets, containing 25 mg or
tion would be expected to be about the same size as the when the active substance is equal or more than 25 % of the
observed content variation. If the mass variation is much mass of the dosage form.
smaller then poor dispersion or mixing is the most probable Unless otherwise stated, the uniformity of dosage units
cause. specification is not intended to apply to suspensions,
For monitoring a production process the rsd can be emulsions or gels in single-dose containers intended for
recorded to compare batches in a trend analysis or by control cutaneous administration. The test for content uniformity is
charts (see Sect. 20.4.4). not required for multivitamin and trace-element
In order to validate the quality of the mixing process the preparations.
following may be considered regarding the sample size. Variation in unit content based on individual masses
When the active substance is dispersed in the vehicle, the (w1. . .wn) is related to label claim by an assay on a represen-
content variation depends on the size of the samples that are tative sample of the batch. This assay must have a relative
assayed. Small samples contain smaller particle numbers of standard deviation of not more than 2 %, based on validation
active substance, which increases the chance of an irregular studies and development data.
distribution. It is logical and practical to take the dose unit as The assay result is expressed as percentage (A) of label
sample size for dispersed systems. For dosage forms for claim, assuming the concentration in all dosage units to be
cutaneous application the smallest amount in which the uniform. The individual contents of a unit then equals xi ¼
preparation is used by the patient may be used as ‘dose unit’. wi A/W in which W is the mean of individual masses.
The requirements for dosage uniformity are met if the
32.7.2.2 Content Uniformity According acceptance value of the first 10 dosage units is less than or
to Ph. Eur. 2.9.6 equal to L1 per cent. If the acceptance value is >L1 per cent,
For the specific requirements reference is made to the the next 20 units have to be tested, followed by calculation of
Ph. Eur. The notable characteristic of this method is that the acceptance value.
Table 32.1 Content Uniformity sampling plan for smaller sample 32.7.2.4 Content Uniformity of Liquid
sizes (ni sample size, ki acceptability constant Dispersions
Sampling plan n1 k1 n2a k2 A method for the determination of homogeneity (as well as
n ¼ 10/20 (Ph. Eur.) 10 2.4 30 2.0 resuspendability) of oral suspensions is described in the
n ¼ 8/32 8 2.6 20 2.0 British Pharmacopoeia [2]. At first the suspension should
n ¼ 7/13 7 2.8 20 2.0 settle, undisturbed, for 24 h. After shaking for 30 s
n ¼ 6/14 6 3.0 20 2.0 10 samples should be removed at a depth of 1 cm below
n ¼ 5/15 5 3.2 20 2.0 the meniscus, while between every sample an additional 10 s
a
n2 is the sum of the total number of units in the sample shaking is performed. The sample size should match the
usual dose unit. The doses are assessed individually
The requirements are met if the final acceptance value of according to the method specified in the individual mono-
the 30 dosage units is L1 percent and no individual content graph. The preparation complies with the test if each dose is
of the dosage unit is less than [1 (0.01 L2)]M or more between 85 % and 115 % of the average dose. The prepara-
than [1 + (0.01 L2)]M in the Calculation of Acceptance tion fails to comply if more than one dose (out of 10) is
Value under Content Uniformity or under Mass Variation. outside these limits or if one individual dose is outside the
Unless otherwise specified, L1 is 15.0 and L2 is 25.0. limits of 75–125 % of the average dose.
The assessment and calculation of the content uniformity
is done by means of the acceptance value (AV).
32.7.2.5 Content Uniformity of Semisolid
The number of prescribed assays (10 units at first, proba-
Dispersions
bly followed by another 20 units) is rather large in the
Although, in practice, when dispersing solid substances with
situation of small-scale preparation. However it appeared
an ointment base several problems can arise (see Sect. 29.3),
to be possible to reformulate the test into a more acceptable
the Ph. Eur. does not set quality requirements. At the design
set-up with the same statistical confidence. More details on
phase of a semisolid dosage form for cutaneous application
sampling plans are to be found in Sect. 20.4.4. The resulting
in which an active substance is dispersed, the dispersion
sampling plan is given in Table 32.1. Statistical background
quality can be validated with, as in ‘dose unit’, an amount
is further given in Sect. 20.4.6 Content uniformity of dosage
that approximately equals the minimal dose that is applied
forms.
by the patient. After validation of the preparation method,
As said the 2.9.40 test is more tight than the 2.9.6 test.
the dispersion quality is usually monitored with an
The current advice is that, from a pharmaceutical quality
in-process control: spreading a sample between glass plates
point of view, the approach taken in the harmonised general
PRODUCTION
and controlling the absence of visible agglomerates.
chapter on uniformity of dosage units (2.9.40) is considered
equivalent to what was previously required in the Ph. Eur.
through the general chapters on uniformity of mass of single-
dose preparations (2.9.5) and uniformity of content of 32.8 Microbiological Purity, Sterility,
single-dose preparations (2.9.6). These general chapters, Pyrogens and Bacterial Endotoxins
2.9.5 and 2.9.6, are still included in the current version of
the Ph. Eur. The assessment methods and quality requirements for the
Taking this into account, the decision on what approach microbiological purity of the finished products and raw
to take is left to the applicant (who is submitting a dossier for materials have been harmonised worldwide since 2009.
registration). Application of either the Ph. Eur. harmonised The Ph. Eur. summarises the quality requirements for the
general chapter on uniformity of dosage units (2.9.40) or the microbiological purity of non-sterile preparations in mono-
Ph. Eur. general chapters on uniformity of mass of single- graph 5.1.4 ‘Microbiological quality of non-sterile pharma-
dose preparations (2.9.5) and uniformity of content of ceutical preparations and substances for pharmaceutical
single-dose preparations (2.9.6) are both considered accept- use’. For raw materials quality requirements are described
able options to demonstrate compliance with the Ph. Eur. in individual monographs or in the general monograph
with regard to uniformity of dosage units. ‘Substances for Pharmaceutical Use’.
Requirements are in principle valid across the shelf life of Quality requirements regarding microbial enumeration
the medicine. The monograph ‘Pharmaceutical tests and limit tests for specific microorganisms, see further
Preparations’ however makes an exception for the test on Sect. 19.6.2.
uniformity of dose units, being valid at release only, because For the methods of performing enumeration of
homogeneity of active substance in dosage units does not microorganisms (TAMC and TYMC) see Sect. 19.6.3 and
change on storage only the content of active substance. for specified micro-organisms see Sect. 19.6.4.
As part of the quality control of sterilised products the method of reference. On the condition that they are suffi-
Ph. Eur. requires the performance of the test for sterility. The ciently validated the other methods may be used as an
test for sterility as described in Ph. Eur. chapter 2.6.1 ‘Ste- alternative to the gel-clot-method. See Sect. 19.3.4 for back-
rility’ is of relative value only, assuring only the actual units ground information on these tests. Ph. Eur. describes an
tested, see Sect. 19.6.1. In practice in some countries this can in-vivo test for the investigation of pyrogens in Ph. Eur.
be replaced by validation of the sterilisation process or by chapter 2.6.8 ‘Pyrogens’. This test is based on the measure-
validation of the aseptic method of preparation. For products ment of the increase of body temperature of rabbits after
with a short shelf life then it is not practical to obtain sterility intravenous administration of the substance to be analysed.
testing results prior to product release and in these cases a Over the years this test is being replaced by the test for
parametric release process needs to be carried out. This endotoxins, the LAL-test, with the exception of those
process should consider all of the data available at the time products which interfere substantially with the LAL test.
of release, retrospectively obtained sterility testing results
should be considered as part of the ongoing process valida-
An example of calculating the limits for endotoxins
tion. Process validation and end of session media transfer
A morphine containing injection solution with the
tests may be used in lieu of sterility testing where appropri-
strength of 100 mg/5 mL has been prepared. Because
ate, for example where the final products are hazardous
the product will be administered parenterally a bacte-
Sterile products with an extended shelf life, including those
rial endotoxins test has to be performed. Therefore the
subjected to sterilisation and those made aseptically, should
administration route has to be known: is this intrave-
be subjected to a prospective sterility test and/or a batch
nous or intrathecal or epidural. For endotoxins in
specific media fill process validation. Parametric release
intravenous administration the requirement is: maxi-
may be carried out on condition that the competent authority
mally 5 EU/kg body weight during 1 h. Based on a
has given approval. In the Dutch hospital pharmacy
body weight of 70 kg this means 350 EU/h. Secondly
parametric release of sterilised preparations is a generally
the maximal dose (in volume of the product per hour)
accepted by the professional group, in the UK it is generally
will determine the actual limit. This depends on the
only accepted where the product has a short shelf life. The
need of the patient as well. If he needs the full 5 mL,
conditions under which parametric release is carried out
this makes the requirement for the product to be
need to be well defined and controlled. The starting point
350 EU/5 mL ¼ 70 EU/mL.
for parametric release is the acknowledgement that tests and
checks that are performed during the production process
may give at least the same level of guarantee that the finished
product corresponds to the specifications than when the
finished product is tested, see also Sect. 34.14.1.
Quality requirements as to the effectiveness of the pres- 32.9 Disintegration
ervation are mainly relevant for preparations in dosage
forms for multiple use. The Ph. Eur. thereby distinguishes Only a dissolved active substance can be absorbed in the
preparations for parenteral and ophthalmic use, locally used bloodstream. To be able to dissolve the active substance first
preparations and oral preparations. The product has to has to be released from the pharmaceutical form. The disin-
undergo stress testing with various prescribed strains of tegration of oral dosage forms such as capsules and tablets
micro-organisms. The quality requirements are defined as a and the disintegration of rectal and vaginal dosage forms
decrease (or no increase) in populations at stated points in such as suppositories are therefore important pharmaceutical
time. The Ph. Eur. describes in chapter 5.1.3 ‘Efficacy of parameters for the effectiveness of the medicine.
antimicrobial preservation’ the determination methods of Ph. Eur. 2.9.1 ‘Disintegration of tablets and capsules’
study. For effectiveness of preservation and minimal level describes the equipment and the method of analysis. The
of preservation, requirements are given. This differentiation disintegration medium that has to be used as well as the
is useful because some preparations are only marginally quality requirements are specific for the dosage form and
preserved. In those cases specific requirements are added can be found in the appropriate monographs. The require-
to decrease the contamination risk, such as restricting the ment for solid capsules is for example disintegration in water
number of doses that can be removed or the in-use shelf life. within 30 min.
For dosage forms for parenteral administration the For disintegration of suppositories the equipment and
Ph. Eur. sets limits for bacterial endotoxins and pyrogens. determination method are described in Ph. Eur. chapter
For definition and difference see Sect. 19.3.4. Ph. Eur. chap- 2.9.2 ‘Disintegration of suppositories and pessaries’. Fat
ter 2.6.14 ‘Bacterial endotoxins’ describes six different suppositories have to melt within 30 min, water-soluble
methods of which the LAL test (gel-clot-method) is the suppositories after 60 min.
These quality requirements are mainly tested in the The Ph. Eur. specifies (for information only and so not
design phase and probably repeated as a release control. compulsory) that about the determination of the dissolution
Disintegration may however decrease on storage and hence of a capsule or tablet the following points should be
it is recommended to include it in stability testing of the recorded: type of equipment; composition, volume and tem-
product. The quality requirements of the Ph. Eur. apply up to perature of the dissolution medium, rotation speed, sampling
the expiry date. times, sample volume and sampling method, method of
Meeting the requirements for disintegration is a minimum analysis, acceptance criteria.
condition for the release of the active substance from the Ph. Eur. requires for conventional release preparations
dosage form. For solid dosage forms and dispersions that the dissolved amount of active substance from every
(suspensions, most suppositories) the active substance still dosage unit after 45 min should be at least 80 % of the label
has to dissolve to be available for absorption (see Sect. claim. Other requirements apply to delayed-release and
16.1.4). prolonged-release dosage forms.
Ph. Eur. doesn’t give requirements for specific medicinal
products because it doesn’t describe products. The British
Pharmacopoeia [2] and the United States Pharmacopoeia [3]
32.10 Dissolution
describe dissolution rate requirements for almost all capsule
and tablet products.
The determination of the dissolution rate of the active sub-
The British Pharmacopoeia [2] gives requirements for the
stance from the dosage form is relevant for solid dosage
dissolution rate of oral suspensions in the general mono-
forms and dispersions, especially when the substance is
graph for ‘Unlicensed Medicines’. These quality require-
poorly soluble (see Sect. 16.1.4). Only dissolved substances
ments are similar to the advice of the Ph. Eur. for capsules
are available for absorption. Ph. Eur. describes in chapter
and tablets. The dissolution rate of an oral suspension, being
2.9.3 ‘Dissolution test for solid dosage forms’ the equip-
prepared in pharmacies for instance for patients with
ment, the method of analysis and the interpretation of the
swallowing problems or for children, and how it compares
determination of the dissolution rate of tablets and capsules.
to the comparable licensed oral dosage form, is an important
For suppositories it is described in Ph. Eur. chapter 2.9.42
consideration when designing such liquid medicines.
‘Dissolution test for lipophilic solid dosage forms’.
The general monographs for capsules, tablets and
suppositories refer to the dissolution test when relevant.
The Ph. Eur. describes for capsules and tablets different 32.11 Particle Size
PRODUCTION
equipment, most important variants being the paddle-
method and the basket-method. Next to these the flow- For the significance of the particle size of the raw material
through-cell method is described, especially intended for reference is made to Sect. 29.2. For terminology and deter-
the determination of the dissolution rate of poorly soluble mination methods reference is made to Sect. 23.1.8.
substances. The particle size is determined in the raw material. In the
With the paddle-method the product to be analysed is design phase the effective dispersion of agglomerates (see
brought into a vessel with the prescribed dissolution Sect. 29.3) and possible particle growth during storage (see
medium, and mixing is performed by a blade attached to a Sect. 18.4.2) have to be validated.
shaft (the ‘paddle’). The Ph. Eur. sets quantitative requirements for the size of
With the basket method the product to be analysed is particles in finished products for suspension eye drops and
brought into a cylindrical basket that also provides the eye ointments. Per 10 micrograms solid substance maxi-
stirring. mally 20 particles may be larger than 25 μm, maximally
The choice between both methods is to be made in the 2 particles larger than 50 μm and no particle larger than
product design phase. Ideally these in vitro methods are 90 μm. These quality requirements are valid until the
meant to mimic the behaviour in the intestinal environment: expiry date.
in vivo. In practice the determination of the dissolution rate For semisolid preparations with dispersed particles for
is meaningful as a tool in the design phase and as a means to dermatological use the Ph. Eur. specifies that care should
monitor possible changes in (particle size of) raw materials be taken to control particle size to a suitable level during
and the production process. If changes are under control production. Also for liquid dosage forms with dispersed
(no changes happen) then this test may not be required as particles for oral use (oral suspensions) the Ph. Eur. gives
part of the batch release specification. an indication of controlled particle size.
In cases of small batches of product produced in

32.12 Particulate Contamination pharmacies a random sample of 10 units can present a
large proportion of the produced batch, meaning that quality
The Ph. Eur. describes methods of analysis for the determi- control becomes very costly. The Ph. Eur. gives some lati-
nation of visible and non-visible particles in parenteral dos- tude to use a smaller random sample than 10 units under
age forms. Particles in parenterals, also called particulate certain conditions. With the aid of statistical analysis it is
contamination, consist of extraneous, mobile undissolved possible to derive the same level of quality assurance with a
particles, other than gas bubbles, unintentionally present in smaller sample size. Taking into consideration the unifor-
the solutions. Because of their small mass and heterogeneous mity/variability of the quantity of counted particles, the
chemical composition they cannot be quantified with a minimum sample size always has to be five units in order
chemical analysis method. Particles in parenterals can to achieve a sufficient level of assurance.
cause harm in patients, including phlebitis, emboli and gran- Particles that are unintentionally present are also relevant
uloma formation. or ophthalmic preparations.
Because most parenteral are made particle free by filtra- Only the Japanese Pharmacopoeia [4] and USP [3] set
tion through a membrane filter just before filling, the con- limits for levels of particles in eye drops. The Japanese
tainer has a relatively large influence on the final level of Pharmacopoeia requires that eye drops after filtration and
particles in the product. Anecdotally it appears from results assessment with a microscope must have a maximum of
of particle counting studies that infusions in glass usually 1 particle of 300 μm or larger per millilitre. The
contain more particles than those in plastic packaging requirements of the USP are considerably stricter.
materials. Also small units often contain more particles per Chapter 789 (Particulate matter in Ophthalmic Solutions)
unit volume than large ones [8–10]. requires that maximally 50 particles of 10 μm and maxi-
For the determination of visible particles in parenteral mally 5 particles of 25 μm per mL eye drop fluid may be
dosage forms the Ph. Eur. describes a visual method under present. The method used is the light obscuration method.
standardised conditions in chapter 2.9.20 ‘Particulate con- The Ph. Eur. has set no specification, firstly because it is
tamination: visible particles’. Here the background, the type difficult to assess the risks posed by particles in eye drops. In
and the intensity of the light source of the equipment are general these risks are deemed to be very small to absent as
stated. is highlighted by the use of suspension eye drops. In Europe
For the determination of sub-visible particles the the United States specification is found to be too strict for all
Ph. Eur. describes two methods of analysis in chapter eye drops. According to reports the USP rationale is based
2.9.19 ‘Particulate Contamination’. One method concerns on the concept that the acceptable particle load of ophthal-
the light obscuration particle count test and the second one mic preparations should be related to its use in a damaged
the microscopic particle count test. The results of both eye or by means of an intravitreal or intracameral injection.
methods are not always mutually comparable. For quanti- In the latter case the presence of particles is considered
tative purposes the light block method is mainly used. The totally unacceptable. However, there is no study that could
microscopic method can be used for viscous products or for be the basis of such a judgement.
those which are problematic in the light obscuration Conversely the specification should consider what is
method practically achievable in the pharmaceutical industry with
The light obscuration method is harmonised between the the so-called Blow-Fill-Seal (BFS) production process, can-
Ph. Eur., the United States Pharmacopoeia and the Japanese not necessarily be extrapolated for the quality control of
Pharmacopoeia, with regard to the equipment, the determi- pharmacy made preparations. The USP requirement appears
nation method, the number of units to be analysed and the not to be based directly on the control of any apparent
quality requirements. For parenterals with a volume larger clinical risk. The USP standard leads to the monitoring of
than 25 mL 10 separate units from a batch have to be particle contents in BFS eye drops, performance of trend
counted. Parenterals with a volume smaller than 25 mL analysis and to investigate causes that lead to increased
have to be combined to a minimal volume of 25 mL that particle loads in that type of production process.
will be counted.
The quality requirements are as follows:
• For units larger than 100 mL: in 10 units an average of not 32.13 Physical Tests
more than 25 particles 10 μm and 3 particles 25 μm
per millilitre should be present Physical tests including pH, relative density, optical rotation,
• For units smaller or equal to 100 mL: in 10 units an refractive index, conductivity, viscosity and osmolality are
average of not more than 6,000 particles 10 μm and generally used as in-process controls or as simple laboratory
600 particles 25 μm per dosage unit should be present tests for the finished product.
pH requirements may be set for some medicines by the eye drops especially those used for eye lubrication. A vis-
British, United States of Japanese Pharmacopoeia. If not a cosity that is too low or too high may determine the thera-
general rule is that the pH, in the case of a buffered system, is peutic usability of a product. Similarly viscosity can be an
given to one decimal place and the limits for a preparation important parameter for suspensions when viscosity should
should be within 0.5 unit of the declared value. In prac- sufficiently high to reduce settling speed and sufficiently low
tice a requirement immediately after release 0.1 unit is to enable resuspendability. Hence a requirement for mea-
often achievable. However the requirement also has to cover surement of viscosity may be of added value to the quality or
the shelf life of the preparation. Values outside these limits relevant products. For some products for example eye drops
could indicate a deviation of the declared composition or to containing hypromellose the nominal viscosity should be
significant product degradation. stated on the label. Often viscosity is studied in the design
Density requirements may also be set by the mentioned phase of a formulation but it can also be used as a routine
Pharmacopoeias, for the relative density of a liquid or solu- quality control test.
tion. For alcoholic solutions such a requirement may be The osmotic value of a solution (see Sect. 18.5) may be an
useful to determine whether the correct quality and the important quality parameter for parenterals, but also for eye
correct volume of ethanol have been used in the preparation or nose drops which should, in principle, be isotonic. Values
process. The same is true for other preparations of which the outside the physiologic limits point to a deviation in the
density deviates strongly from water, for example because of declared composition. The osmolality will be studied in the
the presence of dissolved substances. Preparations that, for design phase of the preparation and later often will only be
example, contain a high percentage of sorbitol or glycerol checked as in-process control.
are well characterised by their density and a determination of
the density actually becomes an important identity criterion.
The requirements for the relative density are not strictly 32.14 Herbals
defined, because the nature and amounts of the excipients
may have a significant impact on the density of a product. As Medicinal plants are either cultured under controlled grow-
guidance a precision of maximally three decimal places may ing conditions, or collected from the wild under natural
be appropriate, with limits of 0.020 unless there is practi- growing conditions (wild-crafted herbs).1 Herbal raw mate-
cal information available that requires wider or stricter rial for herbal medicinal products is not referred to as a
limits. herbal active substance by the Ph. Eur. but as a herbal
Optical rotation requirements may be found for some drug. Probably because it is not one ‘substance’ but usually
solution preparations. is a mixture of plant material. The quality of herbal drugs as
PRODUCTION
This is a measure of the angle of rotation of plane a raw material must be controlled according to pharmaco-
polarised light and is often used as an identity criterion for poeial standards. The Ph. Eur. includes as general
certain materials, especially sugars. When these substances monographs on herbals:
are present in a significant proportion in the final product and • Herbal drugs
when few other excipients are present, the optical rotation • Herbal drug preparations
can be used as a characteristic that gives quantitative infor- • Extracts
mation to the product concentration. • Herbal teas
Refractive index is also generally used as identity crite- • Essential oils
rion for various oils and sugars, but the technique can be Quality-related problems are mostly associated with unreg-
used for multicomponent products such as parenteral nutri- ulated herbal drugs and include the (deliberate) inclusion
tion solutions as well. In general the absolute scale is used of prohibited or restricted substances (e.g. admixture of
for identification test purposes and the second sugar scale synthetic actives, adulteration with toxic plants), contamina-
can be used for product analysis for either simple sugar tion with toxic substances (e.g. heavy metals, residues) and
solutions or complex mixtures. incorrect declaration of constituents and content on the
A conductivity measurement is often used as a limit test, packaging labels.
for example, when testing water for injection (see Sect. The Ph. Eur. describes general methods of analysis to be
27.5.2) but can also be used as part of the quality applied to herbal drug products as well as more specifically
characteristics for other materials. The principle is to mea- dedicated methods (2.8. Methods in pharmacognosy). Iden-
sure the resistance of a column of liquid in a conductivity tity tests must be specific for a particular herbal drug as
cell. For water testing it is generally an in-process control.
The viscosity may be relevant for some pharmacy
preparations, for example for gels or certain cutaneous 1
This section was contributed by Herman Woerdenbag, Groningen,
liquids that have to be applied onto the scalp as well for The Netherlands
adulterations and falsifications must be excluded. Macro- GACP, GMP and GLP standards. During the industrial
scopic and microscopic evaluation and organoleptic assess- manufacturing of herbal medicinal products not only the
ment are important for the authentication of the botanical raw material is subject to rigid quality control, but also the
identity. In addition, simple chemical tests (colour reactions, quality of the semi-manufactured and finished product is
precipitation reactions, chromatographic tests) are carried monitored (in-process controls) and evaluated (end controls
out. To assure a constant quality of the plant material and on content, identity, purity). Finally a pharmaceutical dosage
to compare different batches, analytical methods yielding a form should comply with the applicable pharmacopoeial
profile of the constituents are often applied. standards (e.g., crush strength of tablets, disintegration
TLC-fingerprints are relatively easy to make and cheap, time of tablets and capsules, uniformity of mass and content
but GC- and HPLC-fingerprints are used as well. [11–13]).
Purity control of an herbal drug is not only relevant for
the quality of a finished herbal medicinal product, but also
for its safety. According to the Ph. Eur. herbal drugs are, as 32.15 Quality Requirements, overview
far as possible, free from impurities such as soil, dust, dirt
and other contaminants such as fungal, insect and other Table 32.2 summarises the quality requirements of the most
animal contaminants and that they are not subject to decay. important pharmaceutical dosage forms that occur as phar-
Purity control limits contamination with pathogenic bac- macy preparations.
teria (Staphylococcus aureus, Escherichia coli, Salmonella-
species, Pseudomonas aeruginosa, Clostridium-species and
others), yeasts, moulds, microbial toxins (aflatoxins, 32.16 Analytical Validation
endotoxins), toxic heavy metals (lead, cadmium, mercury,
arsenic; e.g. from industrial emission), pesticide and herbi- 32.16.1 Purpose of Analytical Validation (AV)
cide residues, fumigants (ethylene oxide, methyl bromide,
phosphine) and radionuclides. Furthermore, impurities with Validation is defined as the documentation of evidence of
other plants parts (“foreign organic matter”) are limited. performance properties of a method, procedure or process. A
Moist levels must be below a certain maximum to avoid method is valid, when it achieves its expected outcomes in a
deterioration by microorganisms. Excreta of animals and consistent manner. Many chemical and physical analytical
dead insects must be absent. The ash value and acid- methods are subject to the need for validation. Process
insoluble ash limits the amount of inorganic impurities validation is discussed in Chap. 34 concerning validation
(soil, sand). of processes, equipment, procedures, premises.
Assays are carried out specifically, to quantify either Analytical validation is essential in pharmaceutical
single (biologically active) constituent(s) or non- operations as the accurate measurement of a characteristic
specifically, to quantify a group of closely related or quantity in a dosage form is critical to the correct
compounds (e.g. flavonoids, anthocyanidines, essential oil). decisions being reached as to its disposition. An accurate
Generally, criteria are set for a minimum accepted percent- and highly precise method will reduce the risk of rejecting
age and sometimes for a maximum as well. If it is unknown batches when, in reality they do comply with the specifica-
which constituents are responsible for an alleged action tion and also to reduce the risk of falsely accepting batches
of the herbal drug, analytical procedures can be used to which in reality are non-compliant with specifications.
assay characteristic marker compounds (quality markers,
indicators for consistent quality) of the plant. The specificity
of a general assay for a group of constituents can be 32.16.2 Guidance from EDQM and European
enhanced by combining it with another analytical procedure, Pharmacopeia
which is based on a different principle. An example is a
spectrophotometric assay combined with TLC- or HPLC- EDQM has issued an update of an early ICH document [14]
fingerprinting. on validation of analytical procedures [15]. EDQM has
The production process of a typical industrially manufac- published a Technical Guide for elaborating monographs
tured herbal medicinal product includes cultivation or col- [16] that contains essential information for the characteristics
lection from the wild followed by harvesting, drying and of analytical methods. These documents contain definitions of
fragmentation of the plant material, the preparation of a the terminology used (accuracy, precision etcetera) in analyt-
semi-manufactured product (extract) and the preparation of ical validation and refer to pharmacopoeial monographs and
a finished product. Quality assurance and quality control pharmacopoeial methods.
should be part of all of stages in the process. Good quality The documents emphasise that verification of the suitabil-
herbal medicinal plant products are prepared according to ity of the method for its intended use is still needed when
Table 32.2 Quality requirements pharmaceutical dosage forms that occur as pharmacy preparations
Intravesical Oral Rectal Semisolid preparations Parenteral
Irrigations Fluid Capsules Oral powder Suppositories Enemas Various forms Injections
Identity + + + + + + + +
Content active substance + + + + + + + +
Content preservative
Content anti-oxidant
Content alcohol
Relative density
pH + +
Viscosity
Resuspendability
Disintegration + +
Dissolution +
Max. volume/content weight
Particulate matter +
Available volume + +
Uniformity of weight + + +
Uniformity of content + + +
Appearance + + + +
Particle size
Chemical purity
Microbiological purity + + + + + +
Bacterial endotoxins + +
Sterility + +
Cutaneous E.N.T. Ocular
Semisolid Liquids Powders Nose drops Ear drops Various formsa Drops, lotions Ointment
Identity + + + + + + + +
Content active substance + + + + + + + +
Content preservative
Content anti-oxidant
PRODUCTION
Content alcohol
Relative density
pH + +
Viscosity
Resuspendability
Disintegration
Dissolution
Max. volume/content weight + +
Particulate matter +
Available volume
Uniformity of weight
Uniformity of content
Appearance + + + + + + + +
Particle size +
Chemical purity
Microbiological purity + + + + + +
Bacterial endotoxins
Sterility + +
a
Other parameters depending of the dosage form
+always
if relevant
not
validation is not required by licensing authorities (usually Recommendations below may provide guidance on how
when pharmacopoeial methods are being used). When used to understand elements of an analytical validation study and
for medicines it must be demonstrated that the outcome of avoid any pitfalls.
that method is not affected by the presence of excipients and
by the formulation (dosage form) itself. The Technical guide 32.16.3.1 Specificity
provides more detailed information how to design a study Specificity of a method refers to the extent to which it can
method such as how to measure (im)precision. It also determine unequivocally analytes under given conditions in
provides details on instrumental pitfalls such as the matrix mixtures or matrices, simple or complex, without
effect in atomic absorption spectrometry. interferences from other components [16].
The Ph. Eur. monograph Pharmaceutical Preparations, The term selectivity is similar and a preferred term by
applicable to both pharmacy preparation and manufacturing, IUPAC: while specificity is the ultimate of selectivity, most
requires that, unless otherwise justified and authorised, the well designed assays with have a high degree of selectivity
content of specific excipients such as preservatives need to without being truly specific, here we will use the term
be determined in pharmaceutical preparations. specificity.
An identification test requires a high degree of selectivity
especially if similar active substances are used in production
where a mix-up may occur. The use of highly selective
32.16.3 Performance Properties of an techniques such as IR will provide a high level of assurance.
Analytical Method Discriminating power (DP) is used to define the capabil-
ity of the method to discriminate between compounds that
Properties of an analytical method including (im)precision, strongly resemble each other. An example is the identity
accuracy and repeatability are commonly studied and testing of quaternary ammonium compounds. When poorly
reported in validation studies and are properly defined in designed TLC systems are used, all compounds may elute in
[14–16]. Those definitions are not repeated here. An interna- the same way, determined by the same strong interaction of
tional vocabulary containing sound scientific definitions the quaternary nitrogen and the TLC support. The Discrimi-
from metrological experts [17] is referred to for additional nating Power of the system is then zero and the method is not
information. For example, the expression analyte is com- suitable for purpose.
monly used in chemistry meaning the compound to be Therefore, in order to demonstrate selectivity for identity
measured. However, one measures the quantity of the com- testing or impurity testing one must demonstrate the influ-
pound and therefore sound science should call it a ence of other components in the sample on the robustness of
“measurand”. Here we will continue to use the expression the method.
analyte.
When designing an analytical procedure one has to con- 32.16.3.2 Linearity and Range
sider the major pharmaceutical objectives in Quality Con- A linear relationship must be demonstrated across the range
trol, being methods for identity, purity and assay. Those of an analytical procedure. Where a 10 % deviation from
objectives may require different approaches depending on linearity occurs will be the upper limit of the calibrated
dosage form or depending on how, where and when the range of the technique. In general, five concentrations over
method is applied. Examples which require different a relevant range are required. Mathematical transformation
considerations include, assays used for a product release of data may be useful. Ideally the range of the method should
decision, in-process controls (IPC) stability testing or mea- cover 70–130 % of label claim, to allow for variation within
suring contamination of surfaces with antineoplastics. the product to still be measured accurately.
The validation exercises should demonstrate that the In order to measure within the linear range for a certain
method delivers conclusions with a high degree of confi- method then it may be necessary to include an additional
dence in relation to the intended use of the finished product. dilution step.
Therefore, each study protocol should have clear aims and There are many examples of non-linearity in analytical
relevance. For example, if the method for measurement of methods including HPLC, refractometry, spectrophotometry
surface contamination with antineoplastics is found to have a and in radiometric devices used for measurement of
limit of detection of 5 ng/cm2, while the intended patient radiation.
dose is 1,000 mg, one may expect the data generated to meet
the purpose of the study. One may question whether a very 32.16.3.3 Accuracy
sensitive and costly HPLC/MS method provides relevant Accuracy is a measure of systematic error in the method, and
information or that a threshold has to be proposed as part is the ability of the method to give the expected result. This
of an AV study. can be compared to precision which is a measure of random
error. A systematic error is defined [17] as a component of method. In daily practice, it is important to document the
measurement error that in replicate measurements remains expected precision value from replicate measurements as a
constant or varies in a predictable manner, in contrast to control and check those values against a specification. Such
random errors that vary in an unpredictable manner and are data is important, as it will demonstrate the methods
often related to operator performance. continued ability to perform. Analytical validation data
The accuracy of a method is demonstrated on a sample should be available and reviewed when problems are found
with a known purity or known matrix composition or by with a method including if the product gives out of trend or
comparing the method with a second well-characterised out of specification results
method if the composition is not known. The influence and Data treatment, ANOVA and other statistical approaches
dependence of other components in the sample on the out- are not discussed, although of importance in reproducibility
come of the procedure can be shown by preparing differing studies, where different conditions prevail like different
matrices. For stability indicating methods it is critical to instruments or several technicians.
demonstrate that impurities and degradation products will For the statistical background see Sect. 20.2.3 and for
not interfere with the method. precision of weighing and volume measuring see Sect.
External factors such as the background temperature, 29.1.1.
variability in reagents etc. may also influence the robustness
of the method to produce accurate results. 32.16.3.5 Detection Limit and Sensitivity
HPLC data may be influenced by the presence of back- The limit of detection is generally important when detecting
ground matrix components if we consider the presence of impurities and degradation products and it is required to
compounds in the matrix that have a high retention time then demonstrate that such impurities are detectable below their
after several runs in which the analyte is determined a major specification limit. This normally involves determination of
baseline drift (¼ background) may occur, hindering further the signal to noise ratio for the method.. Determination of the
quantitation caused by the slowly eluting component. detection limit is performed by comparison of measured
Applying a gradient as wash procedure to clear the column signals from samples with known low concentrations of
may substantially increase the analysis time. It may be better analyte with those of blank samples, subsequently
to develop another method for this analysis. establishing the minimum concentration at which the analyte
For the statistical background see Sect. 20.2.3, and for can be reliably detected. Blank samples could be matrix
accuracy of weighing and volume measuring see Sect. sample or a reagent blank. A signal-to-noise ratio between
29.1.1. 3 or 2:1 is generally acceptable. Other methods for
establishing detection limits are based on calibration
PRODUCTION
32.16.3.4 Precision/Reproducibility curves [16].
While the term precision relates to the variation around the The methods for measuring impurities in samples should
mean and hence the random error of the method, in fact, we be sensitive. In contrast identification tests should be rather
measure the imprecision of the method by the standard insensitive. For example the flame test for sodium ions will
deviation. However as the Ph. Eur. uses ‘precision’ as give a positive even with trace amounts present hence the
term, this is used in this chapter. use of the precipitation method with zinc uranyl acetate in
In simple terms precision is demonstrated by repeating pharmacopoeias.
the analysis multiple times. Reproducibility in its most sim-
ple form is repeating the analysis on multiple days or with 32.16.3.6 Quantitation Limit
multiple analysts or both and is more extreme when we A quantification or quantitation limit differs from the detec-
incorporate multiple laboratories as well. tion limit. Detection limits are based on the noise of the
Precision should in general be demonstrated with a mini- analytical method or on background from reagents or matrix
mum of 9 determinations (e.g. 3 concentrations /3 replicates) components that cannot be compensated for and accurate
or 6 determinations at 100 % of the test concentration measurement at the detection limit will generally not be
(within- laboratory precision). Include, where possible, an possible. Ten times the average noise signal is a commonly
experimental design (matrix) in the study describing typical used measure for the quantitation limit. Then an observed
variations such as days, analysts from another department, signal differs statistical significantly from the average noise
equipment. Analysis of variance is usually applied. signal and that signal is considered to be the quantitation
When precision is measured in one sample by the same limit. The error generated by noise contributes to the signal
person who injects more than one aliquot into an HPLC from the analyte but is negligible at this high signal/noise
machine on one single day, this is referred to as repeatability. ratio.
When a method becomes routine, it will still be useful to Quantitation and detection limits may be determined by
add limits on imprecision to the written instruction for the the variability in background conditions or reagents. For
example analytical instruments may be sensitive to Licensing authorities claim not to be interested in reporting
variations in room temperature but the impact may not be impurities of less than 0.1 % or 0.05 %, based on raw data
well understood. This can lead to an uncontrolled systematic [18]. The quantitation limit for the analytical procedure
error in the method, if this error is small it may be ignored should be not more than the reporting threshold, according
but at extremes of temperature it may have a significant to regulations. Identification above 0.2 % is required and
impact and out of trend or specification results may be seen. above a threshold of 0.5 % qualification of the impurity is
Limits of quantification of impurities in dosage forms are required. Thresholds for identification and qualification vary
often required by licensing authorities depending on actual depending on Maximum Daily Dose of active substance and
levels of those impurities and the toxicological impact. Total Daily Intake (TDI) of the degradation product. Higher
In conclusion, specifications to limit impurities in TDI of degradation product lowers thresholds, see
pharmaceuticals can only be based on proper validated Table 32.3. An example of the application of these
quantitation limits in order to avoid rejecting batches that guidances is shown in Table 32.4.
are maybe of acceptable quality. In practice, identification (“yes”) means: establishment of
chemical structure, determination of detection and quantifi-
32.16.3.7 Robustness cation limit. If the impurity is unusually toxic then it has to
Robustness is evaluated during development of a method be qualified in all above cases, meaning the demonstration of
and may give information on the critical steps within a biological safety. An impurity may stay below the threshold,
procedure. It may provide information to estimate the effect making any action superfluous.
of steps within the measurement procedure on the overall Sometimes it is not possible to identify degradation
precision. products and “unidentified impurities” are then reported.
32.16.3.8 Ruggedness
This is the degree of precision of test results obtained by the
32.16.5 Selection of Test Samples
analysis of the same samples under a variety of typical test
conditions such as different analysts, instruments and
Validation starts by specifying the intended use and the
reagent lots.
primary objective of the method. The choice of study mate-
rial remains important. Normally artificial mixtures with
32.16.3.9 System Suitability Test
varying composition are prepared on a laboratory scale,
The system suitability test is carried out to test critical
including a blank matrix. Samples from production may be
instrument and method related parameters. In HPLC system
suitability us determined ahead of running a method and
Table 32.3 Quantitation limits
checks that the parameters which can influence the outcome
of the analysis are within specification. This normally Reporting thresholds
includes reproducibility, peak shape and tailing and resolu- Maximum daily dose active Threshold
substance
tion of the ingredients.
1 g 0.1 %
>1 g 0.05 %
Identification thresholds
32.16.4 European Regulations and Impurities Maximum daily dose active Threshold
in Active Substances substance
<1 mg 1.0 % or 5 micrograms TDI, whichever
Requirements from regulatory bodies may generate analyti- is lower
cal validation studies of impurities in active substances. If a 1 mg 10 mg 0.5 % or 20 micrograms TDI,
whichever is lower
degradation product has been observed in a new active
>10 mg 2 g 0.2 % or 2 mg TDI, whichever is lower
substance then data regarding this will need to be submitted
>2 g 0.10 %
for a Market Authorisation. Validation data for quantitation
Qualification thresholds
limits are useful for industry in dealing with regulatory Maximum daily dose active Threshold
threshold values, results found in ongoing stability studies substance
and decisions on further qualification of impurities. <10 mg 1.0 % or 50 micrograms TDI,
The following example refers to a 50 mg daily dose of an whichever is lower
active substance showing which analytical validation data 10 mg 100 mg 0.5 % or 200 micrograms TDI,
are required. The table below refers to raw data such as whichever is lower
>100 mg 2 g 0.2 % or 3 mg TDI, whichever is lower
obtained in chromatographic analysis, meaning peak area
>2 g 0.15 %
is the first raw criterion for a decision upon taking actions.
Table 32.4 Application of guidance values for quantitation limits if the maximum daily dose is 50 mg
‘Raw’ Action?
result Result to be reported? Total Daily Intake (TDI) of the Is identification threshold Is qualification Threshold of
in % (Reporting threshold is 0.1 %) degradation product in micrograms: of 0.2 % exceeded? 200 micrograms TDI exceeded?
0.04 Not to be reported 20 No: no action No: no action
0.2134 0.2 100 No: no action No: no action
0.349 0.3 150 Yes No: no action
0.550 0.6 300 Yes Yes
used during validation of the analytical method but we need 32.16.6.2 Chemical Quantities
to understand that the true assay value of these may not be The primary standard is the reference standard used in other
known. Proposals to change an analytical method can be methods and is characterised by its high purity and stability.
initiated following multiple failures or problems. In this A primary standard has its purity determined by mass bal-
case it is useful to have samples of both compliant and ance and can be used to calibrate secondary standards such
non-compliant batches when validating this change. as volumetric solutions. These secondary standards are then
When considering method validation it must be realised that used in the titrimetric analysis of samples. The titrant may
each analytical procedure consists of three distinctive steps: degrade over time so this may need to be checked by titration
sample pretreatment, purification or separation, and detection. with another secondary standard
Each step may be of influence or may be critical for each other
step. So each step has to be considered separately.
32.16.6.3 Validation of Reference Standards
The frequency and extent of validation studies should be
Reference standards having a declared composition and
sufficient to demonstrate that the validation study provides
content are obtained from an official laboratory with a cer-
assurances at a 95 % confidence level. The main conclusion
tificate but can be expensive or unavailable. Therefore, sec-
would be that the method is suitable for its intended use.
ondary standards are preferred and they need to be bought in
certified against a primary standard or certified within the
laboratory.
Storage of reference standards is critical: they must be
32.16.6 Reference Standards
stored in well-sealed containers in accordance with instruc-
tion (often in a refrigerator) and must not be used beyond
32.16.6.1 Physical Quantities
PRODUCTION
their shelf life, at least not without recalibrating them against
Section 32.13 describes physical quantities that are fre-
a new standard.
quently encountered in Production and in Quality Control.
Physical quantities include, pH, relative density, optical
rotation, refractive index, light absorption, light emission,
conductivity, viscosity and osmolality and mass. Physical 32.16.7 Technology Transfer
quantities can be measured and expressed as a value in
numbers greater or smaller than a unit. Transfer of products and processes from one laboratory or
Some are considered as in-process controls (IPC), others even one company to another and outsourcing of analytical
are for the characterisation of the finished product. HPLC testing to an independent control laboratory are two
with UV detection is in principle using light absorption as a examples where transfer of knowledge needs to be robustly
physical quantity, while retention is inversely proportional organised. General principles of technology transfer are not
to the velocity of the solute in the column. only applicable to analytical methods but also to production
Reference standards have to be used in those methods for processes, quality control procedures, packaging and
calculating content within samples for example where the cleaning validation.
procedure asks for a calibration curve that requires weighing Technology transfer is well described in the WHO Tech-
of substances on a mass balance (calibrated previously by nical Report Series, Annex 7 WHO guidelines on transfer of
certified masses). See also Sect. 29.1. technology in pharmaceutical manufacturing [19]. The
Apart from this approach reference standards referred to a report describes the management of the transfer between
reference materials are used for calibrating or checking both parties (the sending (or transferring) and the receiving
physical devices, such as refractometers and thermometers. unit) Monograph <1224> from USP 37 on transfer
For example, the melting point is an excellent identification emphasises the need to lay down proper protocols prior to
tool, if the thermometer is calibrated or certified by a the start [20]. The WHO report lists all responsibilities,
regulatory body. Table 1 of that report ‘Possible experimental designs and
acceptance criteria for analytical testing’, contains proposals 32.16.8 Different Applications Require
for experimental designs and acceptance criteria for analyti- Different Validation Approaches
cal testing, such as identity, assay for potency (assay), con-
tent uniformity, dissolution, cleaning validation Analytical procedures for quantitation of active substances
microbiological testing and impurities. Recommendations (including preservatives) in finished pharmaceutical
are given for replication and for set-up of the validation products require a conventional validation approach.
experiments. Statistically derived acceptance criteria are Another approach is needed for procedures for the deter-
proposed such as two one sided t-test with intersite mination of impurities in active substances and excipients or
differences or just comparing mean and variability. degradation products in finished pharmaceutical products.
Experimental designs in transfer protocols should con- These procedures may include quantitative assays as well
sider the use of good and bad batches in a comparison as limit tests. Impurities of interest are various, including
test, where criteria are the release specifications and not metals such as lead and other inorganic substances, catalysts,
the intercompany outcomes of the validation, e.g. mean genotoxic impurities, residual solvents etc. Details can be
and variability. The USP [20] recommends “that expired, found in the scientific guidelines on e.g. quality from EMA
aged, or spiked samples be carefully chosen and [22], see also Sect. 22.4.2.
evaluated to identify potential problems related to Analytical procedures for the determination of dosage
differences in sample preparation equipment and to eval- form performance characteristics (e.g. dissolution rate)
uate the impact of potential aberrant results on marketed may be different from the assay of the active substance in
products”. the medicinal product as stated above and will also need
Validation studies involving technology transfer from the method validation.
original industrial party to a smaller party are frequently Proper identification methods are important when
performed by Validation and R&D personnel and transfer assessing purchased materials from brokers or suppliers. For
may be considered as cumbersome. Both departments are example when buying glycerol or propylene glycol as an
fully equipped with numerous qualified and highly educated excipient or solvent a simple identity test such as complexing
personnel, but the receiving party, the Quality Control with Copper (II) in alkaline conditions is not sufficient. In this
department has to perform the routine analyses with a sig- case high selectivity is required to discriminate from ethylene
nificant less number of personnel, lesser qualified, higher glycol, a nephrotoxic substance [23] the use of which has
workload, but fortunately often has broader practical resulted in worldwide scandals and accelerated the involve-
experience. ment of licensing authorities in pharmaceutical industry.
Another useful policy type document is USP 37 mono- Finally microbiological tests and alternative non official
graph <1226> on Verification of compendial procedures tests for e.g. assaying antibiotics are subject to validation,
[21], if you consider a pharmacopoeia as an analytical con- including equivalence testing when there are differences
trol laboratory transferring his methods to laboratories of with official methods.
companies. Documented evidence of suitability should be Table 32.5 presents examples of analytical validation
established under actual conditions of use. objectives in relation to the type of analytical test:
Table 32.5 Examples of objectives in AV (from [16])

Type of analytical procedure
Testing for impurities Assay
Characteristic Identification Quantitative Limits Dissolution measurement only Content/potency
Accuracy + +
Precision
Repeatability + +
Intermediate precision +* +*
Specificity** + + + +
Detection limit *** +
Quantitation limit +
Linearity + +
Range + +
Signifies that this characteristic is not normally evaluated
+ Signifies that this characteristic is normally evaluated
* In cases where reproducibility (inter-laboratory trial) has been performed, intermediate precision is not needed
** Lack of specificity of one analytical procedure, could be compensated by other supporting analytical procedure(s)
*** May be needed in some cases
identification, impurity or assay [16]. The table is created by 10. Boom FA, van der Veen J, Verbrugge P, Van der Vaart FJ, Paalman
EDQM and may not have full relevance for analytical ACA, Vos TH (2000) Particulate matter determination in LVPs
produced in Dutch hospital pharmacies, Part 2: Overview of the
methods that are applied by QC in an industrial setting. results from 1989 up to 1996. J Pharm Sci Techn 54:343–358
The comments under the table are from EDQM. 11. Veitch NC, Smith M, Barnes J, Anderson LA, Phillipson JD (2013)
The expression “may be needed in some cases” requires Herbal medicines, 4th edn. Pharmaceutical Press, London
explanation. Competent Authorities may ask for additional 12. Woerdenbag HJ, Pras N, Van Meer JH (2001) Nature as an uncer-
tain supplier. Quality assurance and quality control of medicinal
information, if they consider a method critical for the prod- plant products. Pharm Weekbl 136(18):635–639
uct. Industry as well as hospital pharmacists may have their 13. Heinrich M, Barnes J, Gibbons S, Williamson EM (eds) (2012)
own validation policy. Fundamentals of pharmacognosy and phytotherapy, 2nd edn.
Elsevier/Churchill Livingstone, Edinburgh
14. European Medicines Agency (EMA): Note for Guidance on Vali-
dation of Analytical Procedures: Text and Methodology (CPMP/
References ICH/381/95). http://www.ema.europa.eu
15. EDQM: Validation of analytical procedure PA/PH/OMCL
1. European Pharmacopoeia 8.0. Council of Europe, Strasbourg, 2013 13 (82) 3R, 2014
2. British Pharmacopoeia 2015. The Stationery Office, London, 2014 16. EDQM: Technical guide for the elaboration of monographs, 2011
3. The United States Pharmacopeia 2014, USP 37, NF32. The United 17. International vocabulary of metrology — Basic and general
States Pharmacopeial Convention, Rockville, 2013 concepts and associated terms (VIM) Joint Committee for Guides
4. The Japanese Pharmacopoeia, 15th edn. English Version. Society in Metrology (JCGM/WG 2) JCGM 200:2008 (E/F)
of Japanese Pharmacopoeia, Tokyo, 2006 18. European Medicines Agency (EMA): Note for guidance on
5. Deutsches Arzneibuch. Bonn, Deutscher Apotheker Verlag, Govi- impurities in new drug substances (CPMP/ICH/2737/99)
Verlag-Pharmazeutischer Verlag, 2012 19. WHO Technical Report Series, Annex 7 WHO guidelines on trans-
6. Kommentar zum Europaischen Arzneibuch. Stuttgart fer of technology in pharmaceutical manufacturing No. 961, 2011.
Wissenschaftliche Verlagsgesellschaft, Eschborn Govi Verlag- http://apps.who.int/prequal/info_general/documents/TRS961/
Pharmazeutischer Verlag GmbH Eschborn, 2014 TRS961_Annex7.pdf. Accessed 10 Nov 2014
7. Boer Y, Bork-Kaptein MM (1998) Waar komt een te hoog gehalte 20. USP 37 Monograph <1224> on the Transfer of analytical
vandaan? Bereiding van suspensiezetpillen. Gemiddeld gehalte. procedures. The United States Pharmacopeial Convention,
Pharm Weekbl 133:606–612 Rockville, 2013
8. Hailey DM, Lea AR, Kendall CE (1982) Specifications of limits for 21. USP 37 Monograph <1226> on Verification of compendial
particulate contamination in pharmaceutical dosage forms. J Pharm procedures. The United States Pharmacopeial Convention,
Pharmacol 34:615–620 Rockville, 2013
9. Van der Veen J, Verbrugge P, van de Vaart FJ, Boom FA (1997) 22. European Medicines Agency (EMA): Scientific and Quality
Particulate matter determination in LVPs produced in Dutch hospi- Guidelines. http://www.ema.europa.eu
tal pharmacies, Part 1: Particle-counting accuracy. J Pharm Sci 23. European Commission: Opinion on diethylene glycol 2008 SCCP/
Techn 51:81–88 1181/08 http://ec.europa.eu/health/ph_risk/risk_en.htm
PRODUCTION
Documentation
33
Rik Wagenaar and Mark Santillo
Contents 33.9.5 Deviation/ Error/Out of Specification Reports . . . . . . . . . 750

33.9.6 Training Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
33.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
33.10 Documentation and Automation . . . . . . . . . . . . . . . . . . . . . . 750
33.2 Documentation Types for Preparation . . . . . . . . . . . . . . . 732
33.2.1 Documentation and Quality System . . . . . . . . . . . . . . . . . . . . 732 33.11 Management of Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
33.2.2 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732
33.2.3 Documentation of the Preparation . . . . . . . . . . . . . . . . . . . . . . 732 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
33.3 Standard Operating Procedures (SOPs) . . . . . . . . . . . . . 733

33.4 Batch Preparation Instructions and Records . . . . . . . 735 Abstract
33.4.1 Definition and Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 All processes and operations concerning the preparation
33.4.2 Drafting a Batch Preparation Instruction . . . . . . . . . . . . . . . 735
of a medicine are accompanied by documentation. The
33.5 Extemporaneous Preparation Instructions documents should promote uniform preparation methods
and Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
and should demonstrate the achieved quality. This
33.6 Analytical Instructions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744 requires not only a detailed description of the process,
33.7 Logbooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744 the preparation and the quality control, but also an accu-
rate recording of processes and operations. In this chapter
33.8 The Product File . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
33.8.1 Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744 the most important types of documents within the quality
33.8.2 Prescription Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746 system are discussed, such as procedures, preparation
33.8.3 User Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746 instructions, analytical instructions, preparation records
33.8.4 Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
and logbooks. Also the product file is discussed. In the
33.8.5 Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
33.8.6 Formulation and Method of Preparation . . . . . . . . . . . . . . . 747 product file all documents relating to a particular phar-
33.8.7 Process Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 macy preparation are brought together, including data on
33.8.8 Shelf Life Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 pharmacotherapy, the considerations which led to the
33.8.9 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
choice for a certain formulation, method of preparation
33.8.10 Product Quality Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
and quality requirements of the product. It provides back-
33.9 Other Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750 ground information on the product and contains an over-
33.9.1 Service Level Agreements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
33.9.2 Technical Agreements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750 view of the history of the preparation.
33.9.3 Permits to Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
33.9.4 Validation Procedures and Reports . . . . . . . . . . . . . . . . . . . . . 750 Keywords
Documentation Standard operation procedures Work
instructions Preparation instructions Logbooks Prod-
Based upon the chapter ‘Documentatie’ by Rik Wagenaar and Mieke de
Blois in the 2009 edition of ‘Recepteerkunde’. uct file
H.W.G. Wagenaar (*)
The Netherlands
33.1 Orientation
M. Santillo
Documentation forms an important part of the quality sys-
Regional Quality Assurance, South Devon Healthcare NHS Foundation
Trust, Torbay Hospital, Torquay, UK tem for the preparation of medicines. The documentation
e-mail: [email protected] should demonstrate the achieved quality and should promote

732 H.W.G. Wagenaar and M. Santillo
uniform preparation methods. For authorised medicines the

product documentation should follow the Notes for Guid-
ance for the design and GMP chapter 4 for preparation (see Quality
Sect. 35.5.7). This chapter is mainly directed at pharmacy Manual
preparation.
Procedures
Documentation should describe all major stages of the
process of pharmacy preparation: the decision to start prep- Preparation- and Operating
aration of a medicine, the drafted formulation, the produc- Instructions Analysis protocols
tion method, supporting data for the current preparation, the Records Logbooks
controls and tests during and after preparation and at release
of the product. In this chapter important documents are
Fig. 33.1 Structure of a documentation system
discussed, including instructions, procedures and records.
The focus is on the management of these documents and
on the way they are generally used. However, documenta- documents originates from the GMP guidelines [1]:
tion is bound to local rules and preferences. There are a procedures, instructions, records and logbooks can be distin-
number of ways of achieving the same objective, providing guished. These documents have a hierarchical relationship,
the general principles outlined are followed. However, the see Fig. 33.1.
system described in this chapter, has proven itself to be The purpose of the various documents is as follows:
useful and feasible in daily practice in pharmacies in the • Quality manual (see Sect. 35.6.1): the quality manual
Netherlands and the United Kingdom. describes the quality system of the pharmacy. It sets out
the structure of the organisation, the responsibilities, the
policy and the facilities of the pharmacy, such as rooms
33.2 Documentation Types for Preparation and equipment. It contains an overview of all procedures
in use. Some procedures may form a part of the quality
33.2.1 Documentation and Quality System manual themselves.
• Procedures (see Sect. 33.3): procedures are documents
Documentation is a part of the pharmaceutical quality sys- that describe all actions, controls, and other measures
tem (PQS) of the organisation, see Sect. 35.6.2. Chapter 4 of related to a particular activity. Procedures have a general
the GMP guidelines [1] states that proper documentation is structure. Often the term ‘standard operating procedures’
an essential part of quality control. Written information is (SOP) is used, although instructions or work instructions
less prone to errors than verbal information. Moreover, the are also commonly used terms. Instructions often provide
history of a prepared batch can be retrieved based on the more detailed descriptions of specific actions. In this
recorded information. chapter, the term Standard Operating Procedures (SOPs)
The quality manual is a central component of the docu- is preferred.
mentation section of the PQS. It usually refers to the • Records: a record is a paper or electronic copy of a piece
documents needed: descriptive documents, records to be filled of information or series of data, used by the operator to
in, documents describing particular details, documents report on the work carried out.
explaining their mutual relationship etcetera. To prevent • Logbooks (see Sect. 33.7): a logbook describes chrono-
errors and misunderstandings, all these documents should be logically the history of equipment or premises, such as
clear and unambiguous for the user. This requires a simple operation during use, maintenance, update, renewal and
language, with short, clear sentences. Text should be logical, repair.
and operations should be described chronologically. All • File: collection of information about a specific device or a
documents must be dated and authorised by the responsible specific product (see Sect. 33.8), including technical
person, usually the pharmacist. The documentation system descriptions, supporting literature, research etcetera.
should be up to date and the history of documents should be
recorded. Past versions should be archived and should remain
traceable after they have been superseded. It is important that
any decision made in the past remains traceable to provide
33.2.3 Documentation of the Preparation
background to the choices that have been made.
Regarding pharmacy preparations, three types of documents
can be distinguished:
33.2.2 Terminology • Preparation instructions (see Sect. 33.4), describing the
formulation, the method of preparation, the batch size, the
Documentation needs a uniform structure and uniform ter- packaging and labelling of a specific pharmacy preparation.
minology. The terminology for the various types of During preparation, all the actions taken are reported in a
33 Documentation 733
preparation record. Preparation instructions for stock from calibration of equipment, these results are collected in
preparations and extemporaneous preparations will be dis- an audit report, a record or a logbook, which is specific to the
tinctive in format, and there will also be differences between equipment being examined Sect. 33.7.
standard preparations and non-standard preparations . An example of a SOP is shown in Fig. 33.2. The figure
• Operating instructions, describing the operation, mainte- gives an impression of the possible lay-out of a SOP, but
nance and cleaning of a particular device or apparatus. other choices may be made depending on local preferences
Reporting occurs in a logbook (see Sect. 33.7), in which or needs. Items that are almost always required in a SOP are
the user records when the equipment has been used and mentioned underneath. The numbers correspond to the
cleaned. sections of Fig. 33.2.
• Analytical instructions (see Sect. 33.6), concern the
examination of a finished product, raw material or pack- Title (1)
aging. The results of analytical testing are presented in an A SOP bears a unique title that gives a brief description of
analytical report or certificate. the subject. A unique number may be useful. By choosing an
When several documents related to the same product are indication in letters and numbers a classification and
bundled, it is called a product file. The product file is basi- grouping can be made. Furthermore, an SOP number makes
cally a collection of information, instructions, records, it possible to refer to the respective procedure with a short
investigation results etcetera on a specific product. The notation, for example in Preparation Instructions.
product file is further discussed in Sect. 33.8.
Date and version number (2)
A SOP bears a date, usually the date of authorisation, in
combination with a version number. Whenever changes in a
33.3 Standard Operating Procedures (SOPs) SOP are made, the version number is incremented.
Written SOPs are essential documents to ensure a consistent Origin/reference (3)

process is followed and provide detailed guidelines for vari- The source or reason behind the SOP should be recorded and
ous activities. They serve as guidance documents and con- any references included.
tain generic information. SOPs can cover all parts of the
quality system, including the establishment and maintenance Author/responsible person (4)
thereof. Examples of required SOPs include: The source or reason behind the SOP should be recorded and
• Drafting, authorisation and implementation of SOPs any references included.
PRODUCTION
• Training, assessment and qualification of personnel
• Cleaning and maintenance of premises and equipment Authorisation (5)
• Preparation methods The SOP should be authorised and should bear the signature
• Release of preparations and function of the authorising person
• Handling of complaints and deviations
• Change management Principle/purpose (6)
Sometimes certain actions need to be described in more It may be helpful to start a SOP with a brief summary, for
detail, for example when describing a specific process in a example when a long or complex process is described. Such a
step by step manner. This kind of document is generally summary is put at the beginning of the text and may contain a
called a Work Instruction (WI). Examples are: brief statement on the purpose of the procedure and its scope.
• Calibration of balances;
• Preparation of specific dosage forms; Responsibilities
• Sampling for pharmaceutical analysis; The key responsibilities for the tasks outlined in the SOP may
• Microbiological monitoring of preparation areas. be listed, giving clarity as to the level of staff who carry
Thus, SOPs and WIs comprise general actions and operations responsibility at each level.
that apply to groups of products or equipment. The prepara-
tion of a specific medicine will be described in a Preparation Method (7)
Instruction (PI) (see Sect. 33.4), while maintenance of equip- The steps of the procedure preferably should be described as
ment is laid down in Operating Instructions. SOPs are not short sentences, with the imperative to create clarity. Where
suitable for the recording of control data. When the activities necessary, notes or important background information may
described in SOPs or instructions produce results or other be added. It is useful to number each specific point to enable
data, for example results of audits and investigations or data ease of referencing or referral.
SOP F08-4 1 Capsules with low dosage, preparation by solvent method
date 2 September 2014 drafted by ….

first issue 9 November 1993 revised by 4 ….
version number 2.2 authorisation 5 …..
source 3 [1] authorisation date 19 September 2014
6 Principle
This procedure provides a global way of preparation of capsules with a low dosage of active
substance (≤ 5 mg per capsule) by use of the solvent method. For details refer to [1].
8 Related documents
F08-1 Capsules, design composition
F08-2 Capsules, preparation for high dose (> 50 mg)
F08-3 Capsules, preparation for low dose (≤ 50 mg)
[….. ……]
7 Method
Design
Follow the general directions of SOP F08-1 'Capsules, design composition´ if it concerns a new
preparation. The solvent method is preferably used for mixtures with very unfavourable mixing ratios
(< 5 mg active substance). The method needs careful testing and validation.
- Choice of a suitable organic solvent.

In a suitable organic solvent the drug should dissolve easily. The solvent must ……
.
Active substance Solvent and Deposition and Diluent Reference

and dose: amount ratio:
……… ……. ………. ………… ……….
Determination of amount of diluent
[ ……………………………………………………………………………………………]
Dissolving the active substance
[ ……………………………………………………………………………………………]
Filling of the capsules
[ ……………………………………………………………………………………………]
In process controls
[ ……………………………………………………………………………………………]
Control checks
[ ……………………………………………………………………………………………]
References
[1]. [ .………………………………………………………………………………………]
3
Fig. 33.2 Example of a Standard Operation Procedure (SOP)

Related SOPs and documents (8) real time. Each raw material should have its batch number
This section should list other documents that are referenced recorded ahead of it being measured and the preparers
within the specific SOP including any related Work should record their initials as soon as the measurement has
Instructions. been completed to maintain the audit trail. The recording
activities for a stock preparation and a standardised extem-
Document history (9) poraneous preparation are not substantially different, but for
Although this may be kept elsewhere in the quality system it extemporaneous preparations a careful accounting of the
is often useful to include a version history of the SOP, preparation steps is particularly important, because any
summarising the changes made at each version. subsequent analysis of the product is unlikely.
The preparer has to follow all the specified instructions
closely and has to give a written justification for any
33.4 Batch Preparation Instructions process deviation, either as planned or unplanned
and Records deviations. It is important to follow the instructions
exactly, and not to make any unauthorised changes. Uncon-
33.4.1 Definition and Use trolled changes in batch sizes or quantities of material can
lead to serious defects in the final product. For any planned
Stock preparations are performed according to a deviation from the prescribed process the reason should be
standardised preparation instruction, an instruction that has known, and an authorisation by a pharmacist should be
been validated prior to use. This is called a Batch Prepara- given beforehand.
tion Instruction (BPI). Also for extemporaneous
preparations, a standardised preparation instruction – a BPI
A BPI should be clear and should describe a logical
– is preferred. However, often the operator has to follow a
sequence of actions and activities (also called unit
non-standardised preparation instruction that is less exten-
operations in manufacturing). For a number of issues
sive, where no prior validations have been performed, see
it may refer to general SOPs or WIs.
further Sect. 33.5.
A BPI is developed for a given batch size or a range of • For basic operations, the BPI may refer to a SOP, for
batch sizes of a standardised preparation. The formulation example for the process of the filling of capsules.
has been investigated in advance and the method of prepara- • For the use and cleaning of specific equipment the
tion has been validated. This means that data are collected BPI may refer to WIs.
and reviewed beforehand to ensure that each batch subse- • For controls the BPI may refer to a SOP, e.g. for
PRODUCTION
quently prepared will possess the required quality. The sampling.
preparation method as described in the BPI is therefore • For analytical testing, the BPI may refer to a sepa-
only valid for the specified minimum and maximum batch rate analysis instruction designed to test the prepa-
size. The selected batch range depends on the equipment and ration or the specific dosage form. When analysis is
materials used. Automated preparation documentation outsourced, the BPI may mention that a sample
systems calculate the quantities to be processed when the should be sent to the approved laboratory.
batch size is adjusted. In the manual mode, for each batch In the BPI only those quality specifications are
size within the batch range a separate BPI has to be created. included which can be tested during or immediately
Before the preparation of a specific product is started, after preparation. An overview of requirements and
whether for the first time or after a change, the responsible analytical tests for pharmacy preparations can be
pharmacist authorises the BPI and subsequently it is released found in Table 32.2.
for use.
The BPI forms the basis of any preparation process.
Before starting the preparation of a batch, a copy of the
BPI may be made to serve as preparation record during the
preparation. The operator uses it to record weighings and 33.4.2 Drafting a Batch Preparation Instruction
measurements during preparation, to record the batch details
of the starting materials and to record the results of in When a BPI is drafted, it is important to present a clear,
process controls and release controls. To distinguish compact collection of information. The text must be unam-
between the original BPI and the copy that is actually used biguous, legible and factually correct. Depending on the
for the preparation of the batch, the copy may be referred to scale of production, a BPI may consist of only one page
as Batch Preparation Record (BPR). for a standardised extemporaneous preparation or may con-
All the sections of the BPR have to be completed. It is tain multiple pages for stock preparations. The right combi-
very important that all the information recorded is done in nation of preparation process, in-process controls and
release controls should guarantee the quality of the Batch Size (2)
preparation. Subsequently, usually the batch size or batch range is
Obviously, the BPI should be kept clear for proper use mentioned. The latter means that the minimum and
and proper control. Therefore, it is important to mention maximum batch size are defined, resulting in a more flexible
only the issues that are directly related to the preparation BPI. The batch size can be specified as follows:
of the product. When drafting a BPI some editorial guidance • Number (for suppositories, capsules);
can be given: • Weight (for ointments, creams);
Sentence Structures: • Volume (for oral solutions, lotions);
• Choose the imperative. • Volume plus weight between brackets (for solutions with a
• Use short sentences, with proper punctuation. density unequal to 1);
• Describe, if possible, one operation (unit operation) per • Volume plus number of containers between brackets
sentence. (e.g. eye drops).
• Arrange the operations in chronological order. So for
example: ‘Dissolve X in Y. Triturate Z with this solution’ Origin/reference (3)
instead of ‘Triturate Z with a solution of X in Y’. Also, it may be useful to refer to the origin of the
Wording: formulation. This may be a formulary, a scientific
• Use familiar words. publication, information from a manufacturer (e.g. about
• Avoid composed words. products that have been withdrawn from the market), or a
• Avoid ‘heavy’ expressions, for example, rather ‘with’ reference to a proprietary formulation or one from a
colleague. It may be useful to mention a version number or
instead of ‘with the aid of’.
date of publication, to give a proper reference.
Sometimes it is possible to use a general exemplary BPI
belonging to a standard formulation (such as with FNA or
NRF). Such an exemplary BPI will be of a standard Authorisation and date of creation (4)
template and has to be adapted to the local pharmacy The person responsible for the content and implementation
situation. The description of the preparation method may of the BPI, usually the pharmacist, places his signature of
approval initials to authorise the document. By authorising
have to be adapted regarding the batch size and the avail-
it, the BPI is released for use. An unauthorised BPI should
able utensils and equipment in the specific pharmacy situ-
never be used. Automated systems are normally equipped
ation. For general preparation methods, e.g. for filling of
with a versioning option. In that case the pharmacist
capsules or for the folding of tubes, the general SOP that
authorises the BPI in the computer. Only when this has been
describes the appropriate preparation method should be done, can the BPI be used for preparation. When the BPI is
referenced. modified, the authorisation automatically expires and it
In larger preparation units, for example the hospital phar- cannot be used until the new version is authorised.
macy, often an automated system for the drafting of BPIs is Together with the authorisation usually the date of creation
used. Within such a system, it is usually possible to create or modification is mentioned. A version number on the BPI
one or more standard layouts, adjusted to the needs of the may serve the same purpose. In this way, it will be possible
specific organisation and adapted to the type of preparation to check if the latest version is used. In automated systems,
or the pharmaceutical form. the system usually records the version number and date of
The sections of the BPI are described in Fig. 33.3, which modification automatically.
shows an example of a Batch Preparation Instruction. The
items of the BPI are mentioned below. The numbers (if any) Batch number and Preparation date (5)
correspond to the sections of both Figs. 33.3 and 33.5. A BPI normally leaves some blank space, where the batch
number of the preparation and the date of its preparation can
Name, dosage form and strength of the preparation (1) be noted during preparation. For a standard extemporaneous
The name of the preparation is usually the title of the BPI. preparation the prescription number can be added for
The name of the preparation normally includes the strength traceability. In order to limit the amount of text, the
of the active substance. When the preparation contains more preparation date and batch number can be combined in one
than one active substance, it may be decided to assign a number. For example, when the date is mentioned as
specific name to the preparation. It may also be necessary to YYMMDD, an ascending numbering is obtained, which is
include the batch size (see below) in this title area where a simply traceable to the date. For larger scale production, an
variety of BPIs exist for a specific product formulation. extended batch number is needed for distinguishing different
1 Tretinoin cream 0.02% FNA 2 400.0g

Batch size Source 3 Version nr Autorisation 4
400.0 g FNA 2014 1-2014
Raw materials 7 Amount 8 Batch nr. Weighed/measured 9 Operator 10 Check
TRETINOIN 80.0 mg
ALCOHOL DENATURATED 95% 20.00 g
V/V (LOCAL STANDARD)
BUTYLHYDROXYTOLUENE 160.0 mg
CETOMACROGOL CREAM FNA 379.8 g
ALCOHOL DENATURATED 95% to 400.0 g
V/V (LOCAL STANDARD)
comments
Container Storage condition Shelf life

Coated aluminium tube 30 g refrigerated (2-8 °C) 14 12 months 13
Preparation – Avoid dusting of solid substances 11 In-process controls
• Turn off the light.
• Avoid using metal utensils.
• Dissolve the butylhydroxytoluene in the denaturated alcohol 95% V/V. Dissolved?
• Triturate with a glass rod the tretinoin in a glass beaker of at least 100 ml with
a few drops of the butylhydroxytoluene solution.
• Dissolve the tretinoin in this solution, if necessary with gentle warming and Temperature: °C
stirring. Dissolved?
• Cool down unto under 25 °C. Temperature: °C
• Tare a plastic mortar. Tare weight: g
• Weigh the Cetomacrogol cream FNA in the mortar.
• Add the tretinoin solution in portions and mix after each addition until
homogeneous.
• Weigh about 5 g denaturated alcohol 95% V/V in the glass beaker and swirl
gently.
• Add denaturated alcohol 95% V/V to the cream until 400.0 g. Total weight: g
• Mix until homogeneous. Homogeneous?
• Fill in the coated aluminium tubes. 12 yield: …tubes
• Take a sample for analysis if necessary.
PRODUCTION
Sampling Analysis
yes/no
Preparation review (according to Procedure S02-1)
• Appearance Consistency complies/doesn't comply: ….. 17
Homogeneity complies/doesn't comply: …..
No particles complies/doesn't comply: …..
• Packaging
• Labelling
• Analysis no / yes results:
Preparation data Release control

date of preparation 5 date of analysis 18
batch number signature analysis
yield 15
rejects release date 19
signature label final assessment
signature operator(s) 16 signature f or release
external use external use

Tretinoin cream 0.02% FNA
6 Date: dd/mm/yyyy Batch nr. copy of label used
Expiry date: mm/yyyy
Storage: 2-8 °C
Fig. 33.3 Example of a batch preparation instruction

preparations and to obtain a unique batch numbering. It is reason for this is to help the operator record the batch
common to add a number to the date, for example in the form numbers and signatures on the correct line of the BPR. In
of: 141015-001, 141015-002, 141015-003, etc. Also it is automated preparation systems, raw materials usually have
possible to use an alphabetical coding of the months, starting to be used in the listed order. Their sequence may depend on
with A for January, B for February and so on. For any system the equipment used or the batch size.
chosen, the important point is that the traceability of each The BPI should have space where the identity of the raw
batch is guaranteed. materials and packaging materials that have actually been
used may be recorded, for example by their batch numbers.
Reference label (6) This may be done either manually or by an automated
Normally, a BPI is provided with a reference label for the system with a barcode reader.
label to be used. On a paper BPI the reference label can be
stuck directly, in an automated system the label data may be Quantity (8)
recorded in the master label template. All the relevant data For each raw material that should be weighed or measured,
for the preparation should be included on the master label, the needed quantity is listed on the BPI. Excipients which
only variable data fields such as batch number and expiration are required on more than one occasion during preparation,
date should be left blank. According to [2] the following may be mentioned separately each time they are needed in
information should be included on the label: the required amount. Also the quantities of the required
• Name, dosage form and strength of the preparation packaging materials are listed, such as the number of
• Full qualitative composition and the quantity of the active suppository strips.
substance The quantities listed are given to the accuracy that they
• Batch number need to be measured (see Sect. 29.1).
• Expiry date It is advisable to specify the balance to be used in the BPI.
• Special storage conditions or handling precautions This ensures the use of a balance with sufficient accuracy
• Directions for use, warnings and precautions for the weighing process.
• Route of administration All amounts are mentioned followed by their units, for
See Sect. 37.3.2 for additional information on labelling for example grams (g) or milliliters (mL). Weighing is to be
the patient. preferred (see Sect. 29.1.2) but it may be simpler to work
It is useful to leave some space on the BPI where a copy of with volumes rather than weights. In that case adequate
the label that will be used for the batch concerned can be controls must be in place to ensure that the right volumes
attached. Ideally this should be next to the sample label. have been added. Generally weighing devices can give
print-outs of weighings made but volume devices cannot.
Raw materials and packaging materials (7)
Subsequently, the BPI provides a list of all active substances Weighed/measured (9)
and excipients, in a way that defines their identity and The list of raw materials on the BPI is usually followed by
quality unambiguously. For example, it should be clear if the spaces where the operator records the actual quantities
free active substance has to be used or the salt form, or, when which are weighed or measured, including the units. This
multiple hydrates exist, which hydrated form is required (see may be done manually, but the use of an automated system
Sect. 23.1).To define the quality of the raw materials it is coupled with an electronic balance provides a better
advisable to use their pharmacopoeial names wherever opportunity to capture the weighed quantities. With a
possible. Preferably, additional specifications (Functional manual system there should still be a printed record of any
related characteristics, FRCs) which are not mentioned in weighings made.
the monograph that distinguish between different qualities,
are added to the name of the raw material. Examples are the Initials and control (10)
particle size of a solid material, the viscosity of a liquid or a There is generally space where the preparer can place his
cellulose derivative, or the concentration of a solution. initials for each measurement or weighing. During
Sometimes a brand name reflects the quality better preparation, for each raw material the label on the container
(e.g. Witepsol H15 instead of Adeps solidus). If confusion is compared with the prescribed material on the BPI, then the
may still be possible (crystal water, salt forms), addition of source and the batch number are recorded, and the material
the chemical formula might be useful. is weighed or measured. The measured quantity is recorded,
It is also important to include a description of the containers, the raw material is processed and the preparer places his
including size and quantity and if necessary other quality initials. On the BPI model (Fig. 33.2) a column is reserved
characteristics. Raw materials and containers are mentioned for the initials of the operator, marked with the letter ‘O’.
in the same order in which the operator will use them. The There may also be space for the initials of a second
employee, who checks during preparation each weighing or controls, which require that the operator records a result
volume measurement. In automated system, the weights are before he is able to proceed to the next step. The nature and
controlled and printed automatically. The validation of the extent of the in-process controls are determined in
system is a prerequisite. Simple weighing systems cannot conjunction with the controls on the raw materials before,
monitor the volumes measured, which requires a check by a and in conjunction with the release controls which will
second employee. follow afterwards. Together these controls ensure the quality
Whatever process is used, the measurements and checks of the final product.
must be verifiable. Obviously, a print out of the balance may If the preparer has to perform a select sampling during
be sufficient. It can be attached to the preparation record by preparation, for example to check the content distribution of
the preparer, but it should be understood that this print out capsules or suppositories, the sampling method should be
alone does not prove which material was weighed. It may be described in the preparation text and not under the release
that a system such as barcode scanning needs to be used controls of the final product. Also the weighings used for a
alongside it if the second check at the time of preparation is weight control of capsules or suppositories should be
to be omitted. mentioned in the preparation text and are part of the
preparation process.
Preparation method (11)
The BPI has to provide a clear description of the preparation Equipment
method, including in process controls and line clearances. The required equipment may be listed at the beginning of the
All preparation operations are described step-by-step (as unit BPI, to make sure that all the required equipment is assembled
operations. To improve the readability each step best starts and ready for use. Where applicable, reference should be
on a new line. If not, all unit operations may be marked made to relevant operating instructions, for example for the
separately, to make them easily recognisable. In any case, use of an ointment mill. In the text of the BPI the equipment is
the essential points of the applied method of preparation, described at the place in the process where it is needed. Only
including all in process-controls as well as occupational if there are compelling reasons, the equipment may be listed
safety aspects have to be listed. separately, for example in an aseptic preparation where the
Also precautions should be stated to prevent any hazards operator should put all equipment in the laminar flow cabinet
such as fire or damage by corrosive properties of substances. or isolator before the preparation is started. It may be
advisable to leave some space on the preparation instruction
Packaging process; (12) for completion of batch numbers and serial numbers of
A description of the packaging process in a separate part of equipment and for signatures of operators at all key stages.
PRODUCTION
the preparation instruction may be added. Finally, it may be useful to mention the cleaning of the
equipment at the end of the description of the preparation
method, with referral to the procedure and the logbook where
In-process controls (13)
the use and cleaning has to be recorded.
In process controls that the operator runs during production
are mentioned separately on the BPI. In the BPI model a
Storage conditions (14)
separate section is reserved for these in-process controls.
When applicable these controls are described on the same The BPI may provide information on the storage conditions
line as the preparation step to which they apply. In that way of the preparation, for example at controlled room
the operator is instructed to perform the control immediately temperature (15–25 C or 15–30 C) or in the refrigerator
after this step. In the description of the preparation, the (2–8 C). Also other precautions may be mentioned, such as
control moments can be emphasised by mentioning them as storage protected from light. The specific location of storage
’check now . . .’ or ’record now . . . ". This should encourage may be mentioned on the BPI.
the operator to perform the control at that moment, and not at Storage period
the end of the preparation. When working in a specific The storage period or shelf life of the preparation is included
environment, such as laminar air flow (LAF) cabinet, the in the BPI. The shelf-life period of the formulated product
preparer cannot always interrupt his work to place his initials has to be determined in advance and standardised. The
on a paper record as this would represent poor aseptic terms for determining the storage period are described in
practice. In that particular case, a second employee may Sect. 22.7.
complete the BPR, and any required signatures can be
completed at the end of the process. However, there are also Label reconciliation
LAF cabinets with built-in display, where the preparer can A separate section is present to cover the label reconciliation
place his initials electronically. to account for the number of labels printed, used and
Automated systems may have obligatory in-process destroyed. The yield of labels is also discussed in Sect. 34.7.
Yield and rejects (15)

A separate section is present to cover the yield of the of dosage units is lower than the expected or required
product. The quantity of deliverable product (¼ net yield) is yield, then the reason for the rejected amount should
often less than the theoretical amount based on the processed be investigated and recorded (poor appearance, break-
quantities of active substances and raw materials. Recording age etc.). This may make it possible to take measures
of the gross yield, rejected units and net yield on the to prevent any similar failures in future. Laboratory
preparation record can also provide important information samples also need to be accounted for although this
about how the preparation process has been performed. should be in a separate line to the rejected products.
Therefore, the preparer should always fill in the sections ´ Theoretical yield (¼ Batch size) ¼ gross yield +
Yield and rejects´ on the BPR. Below the notions of ’gross expected preparation loss
yield´ and ’rejected units’ are defined in more detail. Gross yield ¼ net yield + rejects (including laboratory
samples)
The gross yield is the theoretical yield of the prepara- Net yield ¼ amount deliverable product
tion, minus the loss resulting from the preparation pro- Rejects ¼ loss after preparation
cess (e.g. residue on the equipment and utensils,
rejecting of suppositories, etc.). The gross yield is
expressed in a weight, a volume (e.g. oral solutions) Notes Finally, it may be useful that the BPI mentions rele-
or a number (e.g. suppositories). In preparations that are vant data and references that were used for designing the
packed in separate containers for the patient, the gross formulation and the preparation method (e.g. for suppositories
yield can also be expressed as a number of containers. the blank weight of the mold and the displacement factor).
For relatively simple preparations (e.g. oral solutions), Furthermore, for the results of quantitative measurements it
normally there is only a small amount of loss during may be useful to give standard values for comparison. When
preparation and the gross yield substantially performing in process controls, it is important that there are
corresponds to the theoretical yield, as listed under distinct limits within which a measurement result should lie.
"batch size". If there are more preparation steps A section on the BPI is reserved for this.
required (e.g., filtration) or if semi-solid preparations
or suppositories are concerned, the gross yield will Deviations A preparation record is intended to record the
always be lower than the theoretical yield. In that case preparation process in a standardised way, as far as possible.
the BPI should also specify the expected yield. However, there are always unforeseen circumstances which
In preparations that are filled into containers are not provided for in the preparation instruction. All
intended for the patient, immediately after preparation deviations, even if it concerns seemingly unimportant
(e.g. eye drops, creams) the gross yield is expressed in matters, should be recorded on the preparation record. The
number of completely filled containers. The net yield pharmacist must evaluate any deviation and has to decide on
may be even lower due to loss in incompletely filled further actions (see Sect. 35.6.13). He should ensure that the
containers. After preparation of a series of suppositories deviation is described clearly and precisely and any investi-
in molds, there will always be a number which must be gation required is completed ahead of release of the product.
rejected. A gross yield which is only a little lower than For that reason a section on the BPI may be needed where
the batch size may indicate that the units which should process deviations (either planned or unplanned) can be
have been rejected have not been. For preparations such listed and can be assessed during product release.
as capsules or divided powders, the gross yield (num-
ber) is always equal to the theoretical amount. The Signatures or initials (16)
preparation loss that occurs in these pharmaceutical The person responsible for the preparation process will
forms, manifests itself in a lower average weight than place a final signature before the product or batch is
the theoretical weight. This does not mean that a low fill transferred for final check. The final sign off will be
weight (and therefore a low dose) would be acceptable. placed by the person responsible for the quality of the
For these forms additional specifications are needed to product.
limit the preparation loss.
Rejected products are those which are lost after Quality Control (17)
preparation including: incompletely filled containers, A separate part of the BPI may be reserved to indicate which
samples for laboratory, breakage, failure from visual quality control tests are required. These controls may
inspection et cetera. The gross yield minus the reject comprise non-destructive tests, which can be performed
number gives the net yield. When the net yield of immediately after preparation, and analytical testing in a
preparation, the number of packages or the number laboratory. In the latter case, referral can be made to a
separate analysis instruction.
(continued)
The BPI may indicate a number of criteria that are involved mean weight that does not correspond to the expected
with the assessment of the final product in the case of a stock weight, Preferably the review should be performed by a
preparation. Some of these criteria have a general character, pharmacist, who has not been involved with the production
while other items are only applicable to a particular dosage nor the analytical process. As a result of his review, the
form or even to the specific preparation involved. The pharmacist may give a final decision on the preparation: the
required procedures may be referenced in the BPI. Standard batch is accepted or rejected. He notes down his conclusion
items are: on the BPR.
• Appearance, such as shape, colour and other external
characteristics. Release (see also Sect. 34.9) (19)
• Non-destructive tests: In addition, depending on the When the responsible pharmacist accepts the preparation for
dosage form, specific tests as uniformity of dosage units or release to be supplied to the patient, he places the release
deviation between theoretical and average weight may be date and his signature on the preparation record. For a stock
included. preparation, this is the formal way to release the batch so that
• Packaging and labelling: it may be necessary to indicate it may be removed from quarantine and can be supplied to
which packaging and labelling aspects should be checked. patients. In an industrial GMP environment this is the
• Analysis: here will be listed if samples should be sent to the responsibility of the Qualified Person (QP) (see Sect.
laboratory for analytical testing, and if so, in what quantity and 25.3.4).
with what frequency. For an extemporaneous preparation the responsible
How the quality control tests are carried out and to what extent pharmacist decides whether the preparation is suitable for
will depend on the type of preparation and on the specific release. After release, the preparation records are stored
processes in the pharmacy. In extemporaneous preparations or systematically for a period determined by local guidelines or
simple stock preparations in a community pharmacy, the national law [1].
operator may perform the non-destructive tests himself, such as
a check on the appearance or the weight distribution of capsules.
Analytical testing, at least in small community pharmacies, is
usually performed by an external pharmaceutical laboratory. In 33.5 Extemporaneous Preparation
extemporaneous preparations there is usually no possibility for Instructions and Records
analytical testing prior to release. Therefore, non-destructive
final inspections of the preparation are of great importance. With extemporaneous preparations a standard BPI is to be
Results of the performed tests may be recorded directly on the preferred. This situation – of a standard extemporaneous
BPR, thus forming an integral part of the preparation record.
PRODUCTION
preparation – has been described in Sect. 33.4.
However, in large-scale preparation quality control testing will But sometimes an extemporaneous preparation is
usually be separated from the preparation process, on the basis required where no standard formula and hence no BPI is
of an individual analysis instruction. In all cases the results of available. In that case the preparation instruction has to be
the investigated parameters should be documented, at least with
designed just before preparation can start.
"conforms" or "does not conform". Laboratory results can be
The preparation part of a non-standardised preparation
noted on the preparation record, but can also be reported on a
instruction (for instance referring to filling of capsules or
separate certificate of analysis record which may be attached to
triturating raw material with an ointment base) will prefera-
the preparation record.
bly be available as a standard instruction, probably even as a
template. Because of the individual character of these kinds
Review before release (see also Sect. 34.9.1) (18)
of preparations, it is not possible to perform a validation of
The last step before release of the finished preparation is an
the specific formulation and preparation method in advance:
overall check of the preparation and quality control record of
the preparation instruction has to be drafted on the basis of
the product. In order to be able to release the preparation, the
person responsible for preparation has to check if the BPR the prescribed formulation and the prescription assessment
has been fully completed. His review should comprise a which will refer to literature data. This requires additional
systematical check on all data, including correct weighings specialist knowledge and attention to detail in the design of
and measurements, in process controls, notes and deviations, the formulation.
if any, and the presence of printed information such as This knowledge is important because, in practice, it is
weighing prints or data on a sterilisation process. Also the rarely possible to perform an analytical release control on
results of non-destructive and analytical testing are part of extemporaneous preparations. Hence extra attention needs to
the review, if applicable. Furthermore, the review should be paid to controls during preparation. During the design of
involve a check on obvious mistakes, for example a yield the formulation, it should be determined what in process
that shows a large deviation from the theoretical yield or a controls and non-destructive release tests have to be
Fig. 33.4 Flowchart design and

authorisation of a preparation start:
instruction for non-standardised Prescription for a
non-standardised
preparations
pharmacy preparation
Is there
an existing BPI of Adapt the standardised Check amounts
a similar preparation? yes preparation instruction and preparation text
no
Define the
Define the Define the
pharmaceutical
formulation batch size
form
Choose a model Preparation Fill the Preparation

Check amounts
Instruction fit for the Instruction with amounts
and preparation text
pharmaceutical form and preparation text
authorisation of the
Preparation Instruction
by the pharmacist
Prepare the
non-standardised
preparation
performed. The controls and their results should be recorded, the advantage that the preparation will largely be in
to assure the quality of the final product. accordance with a standardised formulation, of which the
For drafting a preparation instruction for a non- design has been validated. There should be sufficient
standardised formulation, two routes can be followed, see evidence that the adjustments do not adversely affect the
Fig. 33.4. If a BPI is available for a closely related prepa- design quality and the alterations must be conducted and
ration, it may be possible to prepare the non-standardised approved in a controlled manner before the preparation is
extemporaneous preparation on this basis. The BPI can carried out.
be changed for another strength, for example, be modified If no BPI of a related formulation is available, a new
with respect to a particular excipient, or by a minor change preparation instruction has to be designed. When drafting
in the applied preparation process. The changes will inevita- such a preparation instruction, it is advisable to follow
bly turn the standardised preparation instruction into a broadly the same structure as pointed out in Sect. 33.4.2
non-standardised instruction, but working in this way has for drafting the BPI. A preparation instruction for an
a
………………….………………………………………………………………………………………………………………. (Name, dosage, strength) 1
Date: 4 Prescription Origin/reference: 3 Storage period: Expiry date:
nr.: 5
Amount to be Batch size: 2 Formulation/ calculations Operator Check

delivered: 8
Ingredient 7 To weigh/measure Batch nr. Weighed/ measured 9 Operator Check 10

Tare weight:
Packaging:
Safety measures: Preparation method: 11 12
In-process controls: 13
… … pH:
.…
b
Checks (procedure … )
Yield: 15 Rejects and cause:
… Packages of … ml/g
PRODUCTION
Creams, Ointments, Appearance: /n.a.
Suspensions: 17 Consistency: /n.a.
Homogeneity: /n.a.
Agglomerates: /n.a.
……………………….:
Solutions: Clarity: /n.a.

Colour: /n.a.
……………………….:
Powders : Fineness: /n.a.
Homogeneity: /n.a.
Packaging: Labeling: 6 Operator: 16
Final assessment: 18 Pharmacist: 19
Fig. 33.5 Example of a preparation instruction for non-standardised extemporaneous preparations, front (a) and backside (b). The numbers
correspond with the explanations in Sect. 33.4.2
extemporaneous preparation may differ from a BPI in num- analytical testing is conducted in the context of the validation
ber and size of the sections, because there is e.g. no time to of a new BPI, then the results should be in the validation part
validate the design of formulation and the method of prepa- of the product file for the product (Sect. 33.8.7).
ration. It should be kept in mind that the preparation is
intended for an individual patient and the risk assessment
is paramount (Sect. 2.2). 33.7 Logbooks
The composition and preparation method are usually
drafted directly on the document shortly before the actual For all major premises or equipment instruments and
preparation starts. It may be possible to refer to a procedure devices which may have critical influence on the preparation
describing a general preparation method. If available, refer- or analytical processes, a logbook should be kept. The logbook
ral can be made to a relevant procedure for the preparation of is the history of a piece of equipment or a facility and it aims at
a specific pharmaceutical form. traceability and verification. The investigation of any deviation
Furthermore, the document has to leave some space for may use the logbook as a vital source of information to enable
recording the process carried out, any deviations or issues the root cause to be traced. In addition, the logbook will
that came to light and for a final product review. include records as to whether equipment is maintained on
It may be helpful to develop standard models for such time, if rooms are cleaned on time etcetera.
preparation instructions, for instance for creams and It is important to get the balance between too many
ointments, for capsules or for suppositories. These models logbooks, that may lead to a disproportionate amount of
can be used for the drafting the preparation instruction. After administration and too few logbooks, that will lead to a
authorisation by a pharmacist, it can be used for recording lack of understanding of critical preparation processes.
the work during preparation. An example is shown in Logbooks describe in chronological order all the data on
Fig. 33.5 (numbers corresponding to the sections in the use of a particular device or equipment. All the
Sect. 33.4.2). The model has the following sections: associated preparations are recorded with date and identity
• The non-shaded sections on the front: these sections have of the operators.
to be filled in before starting preparation (the design). Also data are collected chronologically about mainte-
• The shaded sections on the front: these sections have to nance, updates, renovation, repairs and the like. This may
be filled in during preparation (preparation phase). actually be recorded on an equipment-maintenance card, as a
• The back side: here the results of the checks and final part of the logbook. On the maintenance card data are noted
evaluation are listed (evaluation phase). There is also of when and by whom the unit was cleaned, when and by
a small blank space, for example for calculations or whom repair or maintenance was done, also when and by
remarks. whom it was released for use again.
Where equipment is serviced by outside contractors it
will be useful to operate a ‘Permit to Work’ (see
33.6 Analytical Instructions Sect. 33.9.3) system which controls the access to the equip-
ment, the checking of the engineers report and the steps
A pharmacy with adequate laboratory facilities will be able to taken (e.g. cleaning) to put the equipment back into use.
perform analytical quality control tests in-house. In that case The same goes for cleaning and maintenance of premises,
the necessary analytical instructions are part of the documen- such as the LAF-cabinet or preparation areas. Logbooks
tation system. In other cases it may be necessary for a phar- must always be present at the place where they are needed,
macy to outsource its analytical testing to an external near the device or equipment, or near the workplace, so they
laboratory. Then it is necessary to have a copy of the analyti- can be consulted there during or subsequent to the work.
cal instructions, including the key acceptance criteria. In this Logbooks may need to be consulted as part of the product
scenario it is paramount that a Service Level Agreement release process in order to confirm the status of critical
(SLA) or Technical Agreement is in place between the phar- equipment.
macy and the laboratory (for SLA see Sect. 33.9.1).
Substances and finished products need to be analysed to
show that they meet the quality requirements of the pharma- 33.8 The Product File
ceutical preparation. The analytical instruction indicates which
parameters need to be measured and how these tests should be 33.8.1 Contents
performed. In practice the analytical instruction is often used
during analysis as a batch record. The results of analytical In the product file all documents relating to a particular
controls can be reported in a certificate of analysis, which pharmacy preparation are brought together, including data
gives a summary of the release specifications and the results on pharmacotherapy, the considerations which led to the
found. The results are an integral part of the documentation of choice for a certain formulation, preparation method and
a preparation, and thus should be kept with the BPR. If the quality requirements of the product. It provides background
information on the product and contains an overview of the may need to be reviewed or evaluated etcetera. In that aspect
history of the preparation. Many parts may show similarity the product file may be divided into two parts, first informa-
with a product dossier of licensed medicines. However, the tion about the product that should be available externally
guidelines for a product dossier of a licensed product are not (prescription assessment and user information) and then the
directly useful for pharmacy preparations. Therefore the details and backgrounds about its design and quality. The
pharmacist needs to develop his own procedure to cover way this is done in the Netherlands may serve as an exam-
the process. A product file should be available for every ple, leading to the following list of contents for a product
pharmacy preparation. file:
The European Resolution on quality and safety assurance • Contents (33.8.1)
requirements for medicinal products prepared in pharmacies • Prescription assessment (33.8.2)
for the special needs of patients [2] describes the following • User information (33.8.3)
list of topics to be covered in a product file, depth and • Pharmacotherapy (33.8.4)
interpretation depending on a risk assessment (see Sect. • Pharmacovigilance (33.8.5)
21.6.3): • Formulation and Method of preparation (33.8.6)
1. Added value and preparation process of the pharmacy • Product and Process Validation (33.8.7)
preparation • Stability investigation (33.8.8)
(a) Description of the final preparation process • History (33.8.9)
(b) Demonstration of the added value of the pharmacy • Product quality review (33.8.10)
preparation Of course these topics should be discussed in relation to
2. Composition the scale of the preparation and other items that affect the
(a) Function risk assessment. Commonly the product file for a non-
(b) Demonstration that the active pharmaceutical standardised extemporaneous preparation, may consist of
ingredients, excipients and containers meet relevant only a prescription assessment and a preparation record,
requirements, taking into account specific patient possibly with a cover sheet for archiving the other sections
needs may remain unfilled. If available, referral can be made to a
(c) Specifications and traceability of origin of the starting general file for the appropriate dosage form.
materials
(d) specifications of the primary packaging material, etc.
3. In-process controls and quality controls of the finished File for the Dosage Form
product It might be useful to develop general files for pharma-
PRODUCTION
(a) Product specific procedures ceutical dosage forms. In such files, all information is
(b) Records of prepared batches gathered about a particular dosage form, linked to the
4. In-process controls and quality control of finished method of preparation. A file for a dosage form has its
product value in extemporaneous preparations without a
(a) Sampling standardised preparation instruction. No product vali-
(b) Analytical methods dation can be performed but the preparation process of
(c) Acceptance criteria, etc. the dosage form can be validated though.
5. Results of test batches (namely, information on the devel- This process validation can be documented for each
opment, background and evaluation of the preparation dosage form in a file in which all the relevant data are
process, including testing) collected: preparation data for the model-preparation
6. Validation which was chosen for validation, information on the
(a) Of preparation process implementation and results of the validation studies,
(b) Of analytical methods and the conclusion of the study. In the conclusion the
7. Stability considerations future frequency of analysis of the preparations of the
(a) A plan for own stability studies specific dosage form is discussed, generally, in
(b) The evaluation of stability data, etc. retrospect.
8. Use of the product and information for the patient The relevant historical data regarding the dosage
The list of the European Resolution as mentioned above form are also collected in this file including any
is a good reference point, but it pays much attention to the problems encountered and lessons learnt from these.
technical quality of the product, while it tends to marginalise In this way, in the course of time, a clear picture of the
the information about the therapeutic qualities and the quality issues related to a particular type of preparation
design. However, the prescriber and the patient or his care- will come to light, and measures can be put in place to
giver may need these details: what are the benefits and risks correct for these.
of the product, how should it be administered, which risks
For a standardised preparation the product file may be It is advised to develop a procedure for the way in which
quite extensive. There is need for a more elaborate evalua- the name and strength of a preparation is given. The lists
tion of the topics discussed above, and the product file with standard terms of the EDQM for dosage forms, admin-
should also include information on the validation of the istration routes and containers are recommended. In
preparation and on the stability and shelf life of the prepara- Chaps. 4–14 these standards have been used.
tion. The product file of pharmacy preparations that are • The result may be in this case: Diclofenac sodium
distributed on a relatively large scale should be the most suppositories 12.5 mg, followed by a list of the
extensive. The various topics of the product file in its most excipients, for example hard fat and lactose
extensive form will be discussed in detail in the following
subsections. At the end of each section an example of 33.8.3.2 Information for the Prescriber
12.5 mg diclofenac suppositories is used, assuming that The product file should contain the information that the
diclofenac is not available in this strength as licensed prescriber may need at his decision about the treatment of
medicine. the patient. This information is related to the more elaborate
section Pharmacotherapy (see further) but will generally
only include the indication, adverse effects, contra-
33.8.2 Prescription Assessment indications, dosage and way of administration.
• In the case of diclofenac sodium suppositories 12.5 mg
Before a prescription with a request for a pharmacy prepara- the prescriber should know that these suppositories may
tion can be approved, it has to be decided whether there is a be given to children up to 12 years of age for pain and
specific clinical need for it. When defining the place in inflammations, and what may be the known side-effects
therapy, part of the assessment is the risk that is presented and/or contra-indications.
to the patient or a patient group both from receiving the
preparation and from not receiving the preparation because
it would not be available [3]. The risk should be estimated on 33.8.3.3 Information for the Patient
the basis of a documented risk assessment (see Sect. 2.2.3) The product file should also include information for the
and the outcome of the assessment is recorded in the product patient or his caregiver. In many countries national laws
file. prescribe what information should be given about pharmacy
• For a stock preparation of diclofenac sodium supposi- preparations. If available, a patient information leaflet on the
tories 12.5 mg, for example, the risk assessment should product is developed and included in the file. See Sects. 37.3
give information why it may be needed for children with and 37.4 for more information.
a specified indication of their illness, the unavailability of In some Countries general leaflets are developed for
a licensed product in this strength, choice of administra- patients about the particularities of pharmacy made
tion route and dosage form, an estimation of the risk of preparations. These may be supplied as well.
the use for children and balancing the benefits for the • For the diclofenac sodium suppositories 12.5 mg,
patient group against the risks of a (principally) limited understandable information for the patient about how to
design and preparation quality. use the product should be available, as well as informa-
• It is also necessary to list the prescribers and pharmacists tion about the dosage, the desired effect and the possible
who are responsible for this risk assessment and to indi- side effects of the product etcetera. (However, be aware
cate a frequency of reviewing the assessment for the that this an example. In some countries it is not permitted
indication that has been laid down. to claim a therapeutic effect for a pharmacy preparation,
this being reserved for licensed products).
33.8.3 User Information 33.8.3.4 Information Needed for Medication

Reviews
The user information on the product may contain informa- To perform a proper medication review, the pharmacist
tion about its composition and its use, including information needs additional therapeutic information such as contrain-
needed to perform a medication review. dications, interactions and intolerances, impact on driving,
dosing in pregnancy, kinetics (effect of reduced renal func-
33.8.3.1 Composition tion), metabolism, monitoring on polymorphism etcetera.
Patient and prescriber may need a short description of the • For the diclofenac sodium suppositories 12.5 mg infor-
pharmacy preparation, giving active substance, relevant mation may be obtained from international reference
excipients, strength, dosage form and administration route. works or national formularies, with additional informa-
See Sect. 37.3 for a comprehensive list. tion on these characteristics.
33.8.4 Pharmacotherapy • Storage conditions

• Specifications
As a part of the foundation of the quality of the product, the • Methods of analysis
product file should contain all the relevant According to the paradigm Quality by design (see Sect. 17.2)
pharmacotherapeutic information including biopharmaceu- a solid and scientific documentation of the design process
tical reasoning and literature, where possible with reference will improve understanding and hence the ability to deal
to relevant literature, national guidelines or local with deviations and changes.
agreements.
• Diclofenac sodium is a well-known non-steroidal anti 33.8.6.1 Formulation, Packaging and Labelling
inflammatory active substance, widely described in liter- The documentation about the formulation should show that
ature. For the diclofenac sodium suppositories 12.5 mg the intended formulation will result in a preparation with
good references will be available with regard to bioavail- sufficient technical quality. The choice of a formulation can
ability but also what is known from literature about the be based on literature sources or by referring to an existing
rectal availability of diclofenac sodium in general and formulation for a similar preparation. When a new formula-
what can be expected from the particular pharmacy tion is designed, the chosen formulation is explained here in
preparation. detail.
The section includes the specifications for the raw
materials and containers to be used. Preferably raw materials
33.8.5 Pharmacovigilance of a suitable pharmaceutical grade should be used (see Sect.
23.1.2), but this may not always be possible. All the
Pharmacovigilance is not regulated for pharmacy considerations that played a role in the choice of the raw
preparations and not easily performed. Usually there is no materials are recorded in this section, including the
possibility to test efficacy and safety before the product is excipients, preservatives, colourants and flavours. Amounts
administered to the patient. Therefore, it is advisable to and calculated doses are mentioned, and the need for specific
record all the therapeutic considerations in the product file properties (Functionally Related Characteristics) such as
(under Pharmacotherapy) and, if possible, to evaluate the purity, fineness or viscosity where this is essential for the
outcomes of the treatment. In this way a minimal form of final quality.
pharmacovigilance may be accomplished. For the packaging and labelling materials, preferably the
The preparation instruction of non-standardised functional requirements and specifications are listed. Also
preparations bears the name of the patient, which makes it recorded is the background about the necessary product
PRODUCTION
possible to connect the product to the documented informa- information for the patient.
tion about the preparation. This is particularly important General information about raw materials or packaging
when standardisation is being considered. Retrospective components that are used regularly may be collected and
analysis of the relevant patient records is then recorded centrally in a separate file, to which a reference can
recommended. Reporting unexpected effects to a central be added in the product file.
professional body is desirable. • For the diclofenac sodium suppositories 12.5 mg not only
• Any experience with the use of diclofenac sodium the choice of the composition (amounts and type of base
suppositories 12.5 mg will be collected in this part of or any other excipient) is explained, but also the quality
the file. requirements for the active substance and the excipients
are described in this part. For the quality requirements
reference may be made to the European Pharmacopoeia,
33.8.6 Formulation and Method of Preparation both for the active substance and for the excipients. Also
the size and quality of the suppository molds is
This section of the product file comprises all the details of described here.
the formulation and the preparation method and forms the
central part of the product file. In general, this section should 33.8.6.2 Method of Preparation
describe the details and considerations about: In addition to the formulation the method of preparation is
• Formulation described in the product file. The process is explained with
• Packaging all the preparation steps (unit operations) in chronological
• Labelling order, including the quantities of active substances and
• Preparation method excipients that apply to a particular batch size. Also the
• Stability and shelf-life safety of the preparation process and the safety of the
operator forms a part of this section. The reason for choices of diclofenac suppositories 12.5 mg are available, these
that have been made and in process controls that are required are presented here together with a conclusion about the
are given here. These topics are discussed in Sect. 21.6.3. shelf life and storage conditions.
When there is already an existing Preparation Instruction
then a referral can be made to this information in the product
33.8.6.4 Specifications
file. When the preparation is prepared on the basis of
The quality requirements are described in a separate section
in-house decisions and expertise, the considerations which
of the product file. These quality requirements include the
have led to the specific activities are recorded in the file,
specifications during preparation (in process controls),
including the specific work order, the choice of equipment,
immediately after preparation (release specifications) and
or the considerations which have led to the inclusion of
that at the end of shelf life of the product (shelf-life
certain in-process controls. The description of the prepara-
specifications). The specifications must be relevant to the
tion method must give the pharmacist an overview on the
respective dosage form and should be chosen in a such a way
process and should enable him to assess whether a modifica-
that they characterise the product quality within strict limits,
tion might have impact on the quality of the final product.
while simultaneously ensuring that sufficient margin is left
Also it might enable him to trace the critical preparation
so that small batch-dependent variations can be accepted.
steps where in-process controls might be in place.
For products described in a pharmacopoeia, the official
• Here a copy of the batch preparation record of the
specifications can and should be used for the product file,
diclofenac sodium 12.5 mg suppositories could be
with referral to the official source. The same applies to
included in the product file. Additional information may
preparations from standard formulations, in which quality
be given to explain the reasons for the choice of the
requirements are included. For in-house formulations, the
excipients, the melting temperature of the hard fat base,
quality requirements have to be set by an appropriately
the choice of the preparation method, the determination
competent person internally. Useful information can be
of overages, and of the number of suppositories that are
found in the formulation or validation studies. The results
expected to be rejected during production, etcetera.
of stability studies may be useful when setting the quality
requirements for the product, because the premise is that a
33.8.6.3 Stability and Storage Conditions
preparation should comply to the quality requirements
This section of the product file should give information
throughout the whole shelf life. An overview of the applica-
about the stability of the product and the choices that have
ble quality requirements, including supporting information,
led to its shelf life and the storage conditions. In most cases a
has to be included in the product file. In addition it should be
shelf life for the unopened package is defined, as well as for
specified how the packaging and labelling are checked, and
the container after opening. Also the storage temperature is
how and with what analytical method the product quality is
specified, and if applicable special conditions, for example
controlled. Additionally the validation of the analytical
‘protect from light’ or ‘in a well closed container’.
methods is included in this section of the product file.
If a standardised preparation instruction exists, for exam-
• For the diclofenac sodium suppositories 12.5 mg the
ple in a formulary, often information about the shelf life and
specifications of the product are outlined, together with
the storage can be found there. In other cases the shelf-life
information about the sources of these specifications. For
should be supported with data from in-house research. The
the specification on the content of active substance may
availability of data from the literature determines how exten-
be referred to national laws, for a specification on the
sively any in-house or commissioned stability research
uniformity of dosage units referral may be made of the
should be carried out.
European Pharmacopoeia, but for the appearance own
For infrequently prepared products the analysis of some
specifications may be used, for example “no holes or
expired batches may also provide useful support for the
cracks”.
shelf-life of a preparation. A more detailed product file
should include data from a thorough stability study. Stability
testing should ideally be performed prospectively, but it can 33.8.6.5 Methods of Analysis
also be performed concurrently by following the first batches The product file should contain information on how the
produced, this can be particularly useful if accelerated stor- finished product will be analysed. For a standardised prepa-
age at an elevated temperature is included in the study. The ration the controls are defined in the file, with reference to
product shelf life can be increased during the study as more the control methods or analytical techniques. If analysis is
data becomes available. The design of a stability study is performed internally, the analytical instruction should be
described in Sect. 22.5. included. When analysis is not performed on every batch,
• Here information from literature about the stability of the frequency of testing should be defined with the reasons
diclofenac sodium may be included. If any stability data for the choices that have been made.
• For diclofenac sodium suppositories 12.5 mg it should be 33.8.9 History

clear at least how sampling is performed, e.g. from the
start, the middle and the end of preparation, and which Historical data of prepared batches and their analytical
parameters should be tested: appearance, identity content, results are part of the product file. Although this information
uniformity of dosage units, disintegration. Also the fre- can be stored separately and a reference can be made in the
quency of testing is described, and preferably which product file. The historical data contain all the information
analytical techniques are used. relating to the preparation and its production during the past.
For a non-standardised preparation the control can only Here the records are stored regarding the preparation and the
take place by checking the outcome of the in-process analysis of all produced batches
controls. However, sometimes it is possible to produce an Old versions of BPI’s are archived in the product file with
excess of the product for analytical testing afterwards. In that a clear annotation that they have been superseded. On the
case a discussion regarding the frequency of testing may be BPI’s the changes and corrections which have been made in
given in this section. the course of time are recorded. Also the results of
re-validations that have been performed for example after a
change in the composition or in the manufacturing process
are recorded in the file including the reason for the change. It
33.8.7 Process Validation will give a good picture of how a specific preparation
method has changed in the course of time and with what
This part of the product file contains information about the
results, and hence will give a full history of the product
validation of the preparation process and the method of
analysis. It gives the rationale for the method of preparation,
with validation data and any changes that have been carried It may be practical to collect analytical results on an
out, and describes, where applicable, the background for the analysis card or an electronic system, to keep track of
quality specifications of the preparation. them. As more and more analytical results of a given
The process validation should show that the chosen for- preparation are collected, a clear picture can be gained
mulation, in combination with the chosen method of prepa- as to the quality of that product in the course of time.
ration, will lead to a product with a consistent quality. The By performing trend analysis on the historic results,
results of the validation are recorded on a separate validation intended or unintended deviations in the preparation
record. This record should contain information on the process can be traced. Also occasional errors can be
conditions during preparation and on the method of sam- easily detected. The results of such trend analysis are
PRODUCTION
pling for analysis, together with the date of drawing up the therefore also part of the product file and form a
corresponding BPI. Product Quality Review.
• For diclofenac sodium suppositories 12.5 mg a descrip-
tion may be given of the choices that have been made
concerning the production technique, the pouring temper-
ature, the homogeneity, the way of sampling, the ranges
33.8.10 Product Quality Review
for the batch size that have been chosen and how all these
have been tested.
A separate part of the product file includes the aftercare
around the preparation regarding an evaluation of all failures
or discrepancies. Information on complaints, deviations and
33.8.8 Shelf Life Investigation recalls is collected in this section, including the details of
how these were handled. Based on all the information in this
Normally a separate section of the product dossier discusses section, it is possible to perform evaluations such as Product
the stability of the preparation. All results of stability inves- Quality Reviews (see also Sect. 35.6.11) to look at the
tigation and data supporting the storage period are described robustness of the preparation and the need for change. Also
here. Also the preparation data on the batches which have this information may be useful to determine a frequency for
actually been tested for stability are kept here. how often the product has to be reviewed.
• For diclofenac sodium suppositories 12.5 mg all results Complaints, errors and recalls will provide useful infor-
from stability tests that have been performed are given mation for prioritising the improved design of a product,
here, together with the considerations and conclusions such as a change in the formulation or the preparation
that have led to the chosen storage period. method. Complaints and the resulting corrective actions
should be available in the product file, or be traceable from a equipment. At the end of the process the responsible phar-
central system. If the documentation of non-standardised macist needs to check the permit carefully to assure adequate
extemporaneous preparations is kept in files per dosage completion and also the equipment or facility before it is
form, then it is recommended that these data are collected signed back into use. Actions that may result from such work
in that file. may include recalibration of equipment, additional cleaning
The list of complaints, defects and recalls, together with or revalidation.
the historical data on the product may lead to a critical
evaluation of the file, and -if necessary- a possible adjust-
ment to the product. But even without a direct reason, a 33.9.4 Validation Procedures and Reports
product file needs to be updated regularly. The frequency
with which this should happen should be recorded in All validation exercises should be planned and well
the file. documented. Initially a validation master plan should be
For evaluation of the file, in response to deviations or produced to cover the validation exercise and should set
by routine review, it always should be considered whether out the details of the system or process to be validated, the
it is necessary to make changes to the product or prepara- validation to be carried out and the acceptance criteria. This
tion or analytical methodology. If a decision is reached to is the validation procedure and should be signed off by the
make a change, the impact of such a change needs to key staff ahead of the exercise being carried out. See also
be fully evaluated and ascertained (‘change control, see Sect. 34.10.
Sect. 35.6.10). Moreover, it has to be assured that
the change leads to the intended quality improvement.
The considerations, results of evaluations and support 33.9.5 Deviation/ Error/Out of Specification
for the change are documented in the product file or in Reports
the change control system and cross referenced in the
product file. All process deviations whether planned or unplanned,
together with errors and out of specification results should
be recorded with a controlled form or electronically onto a
33.9 Other Documents database system. Whether a paper system or an electronic
system this needs to facilitate the management of the inves-
33.9.1 Service Level Agreements tigation stage, including root cause analysis where neces-
sary, corrective and preventative actions and close out, as
Service Level Agreements are documents where a service or well as the data being available for trending (CAPA-system).
part of a service including equipment and facility mainte- This is an important part of any Pharmaceutical Quality
nance or monitoring is outsourced to a third party. They System, see Sect. 35.6.15.
outline the general level of service to be provided including
timescales and details of reporting arrangements and often
financial information regarding the costs to be incurred. 33.9.6 Training Records
It will be useful to keep training records of all employees

33.9.2 Technical Agreements concerned with the preparation and analytical processes in
the pharmacy, to show their knowledge and experience with
A Technical Agreement is an essential adjunct to the SLA it the work. This topic is discussed in Sect. 25.5.2.
includes the key responsibilities including the provision of
information between the parties for example where there are
deviations or planned changes to processes. 33.10 Documentation and Automation
Computer automation is an integral part of any pharmacy.

33.9.3 Permits to Work For maintaining the documentation system in the pharmacy,
there are a large number of systems available, ranging
A template permit to work should be produced by the phar- from the publicly available Windows programs such as
macy and this can be adapted to specific circumstances. The Word, Excel and Access to specialised quality software for
document needs to be raised whenever persons have to enter Quality Management Systems. Several programs are avail-
the pharmacy for maintenance or monitoring of facilities or able for the control and monitoring of equipment; sometimes
these are already built in into the equipment. An inventory – Who is responsible for the correct and timely introduction
thereof and a weighing of pros and cons is beyond scope of of new or amended documents
this book. – Who and by when should updated or new documents be
read and understood
– Who identifies missing documents, and who is responsi-
Computers and automated systems can be used in
ble for the drafting thereof
various ways in the small-scale preparation of medici-
– Who is responsible for correcting document
nal products. Examples include:
non-conformances raised at audit or through investigative
• Search and retrieval of information about
procedures following incidents and errors
preparations in professional databases
The aim is to ensure that all documents controlled within
• Creation, maintenance and management of
the documentation system are reviewed at least every
standardised procedures and instructions
3 years, the frequency may need to be increased for certain
• Processing the results of in-process and final prod-
documents. In order to ensure that all documents are
uct analysis controls
reviewed in time there should be a database or list of
• Registration and control of identity of raw materials
documents together with their issue and review by dates, in
and their weighted amounts
this way the documentation system can be kept up to date.
• Management and printing of labels
Automated systems can be a practical tool to help with this.
• Registration of monitoring actions
• Performing trend analysis
• Control and monitoring of equipment (sterilisers, Besides the periodic review and updating of
water treatment, refrigerators) documents, it may also be necessary to amend
• The management and control of documents documents for the following reasons:
• Inspections and audits (internal or external) or
supervision by the pharmacist
If computer systems are applied to support the small scale
• Complaints or errors
preparation in a pharmacy, they have to be validated in the
• Comments from employees
same way as all preparation equipment or preparation pro-
• Changes in personnel
cesses do, see Sect. 34.15. All forms of automation ultimately
• Change in the equipment or the batch size
may have an impact on the quality of the product. Therefore it
• Change in a formulary or specification
is advisable to validate all systems used in advance and to
• Modification of a BPI
validate any changes ahead of their introduction.
PRODUCTION
• External testing results
• Changes in official regulations
33.11 Management of Documents

Only by continuous maintenance the documentation sys-
tem can retain its value and play its critical role within the
A system for the documentation of the pharmacy preparation
quality system of the pharmacy.
will only retain its value if it is continuously updated. In
addition, the contents of frequently used documents, such as
procedures, should be known broadly by all employees
References
involved in the relevant processes. Having read and under-
stood the procedure, the employees should sign or place their 1. Eudralex – Volume 4 – EU guidelines to good manufacturing prac-
initials on a cover sheet or training document to indicate this. tice. European Commission, Brussels
In the pharmacy the following should be clearly defined 2. Resolution CM/ResAP (2011) 1 on quality and safety assurance
– Who stores the documents and maintains the archives requirements for medicinal products prepared in pharmacies for the
special needs of patients. Council of Europe, Strasbourg, 19 Jan 2011
– Who assesses and approves changes in documents 3. Pharmaceutical preparations. European Pharmacopoeia, 8th edn.
(including “change control”) Council of Europe, Strasbourg, France 2014, 04/2013:2619
Production, Quality Control and Validation
34
Rogier Lange and Lilli Møller Andersen
Contents 34.14.2 Process Validation in Practice . . . . . . . . . . . . . . . . . . . . . . . . . . 762

34.14.3 Extemporaneous Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . 764
34.1 Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754
34.15 Qualification of Premises, Installations, Equipment
34.2 Quality of Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 and Automated Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
34.3 Prevention of Contamination 34.16 Cleaning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
and Cross-contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755 34.16.1 Good Cleaning Practice and Cleaning Validation . . . . . 766
34.3.1 Technical Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755 34.16.2 Premises, Workbenches and Worktops . . . . . . . . . . . . . . . . . 766
34.3.2 Organisational Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755 34.16.3 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
34.4 Material Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756 34.16.4 Utensils and Clothing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
34.5 Batch Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
34.6 In-process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756

34.7 Label and Yield Reconciliation . . . . . . . . . . . . . . . . . . . . . . . 757
34.8 Quarantine Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
Abstract
34.9 Quality Control and Release . . . . . . . . . . . . . . . . . . . . . . . . . . 758 The quality of pharmaceutical preparations is the result of
34.9.1 Batch Documentation Review . . . . . . . . . . . . . . . . . . . . . . . . . . 758 the design and the execution of the manufacturing pro-
34.9.2 Quality Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
34.9.3 Release Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 cess. The Good Manufacturing Practice (GMP) principles
and guidelines are about incorporating quality into all
34.10 Validation: General Principles and Terminology . . 759
aspects of the manufacturing process. This chapter covers
34.10.1 Validation and Qualification . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
34.10.2 Prospective, Concurrent and Retrospective Validation 760 the design, execution, monitoring and validation of the
34.10.3 Re-validation and Requalification . . . . . . . . . . . . . . . . . . . . . . 760 process, as well as the quality control and release of the
34.10.4 Organisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760 product.
34.11 Validation Master Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760 Preparations differ in size and complexity. The scale
34.12 Validation Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
can range from a tailor-made preparation for one patient
to production for many thousands of patients. The com-
34.13 Validation Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
plexity can range from reconstitution to complex
34.14 Process Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761 preparations from active pharmaceutical substances and
34.14.1 General Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761 excipients. For all kind of preparations it is essential to
minimise the risk of mix-up or cross-contamination by
applying technical measures and an appropriate working
discipline. All preparation steps must be controlled and
traceable. A watertight procedure for quarantine, final
Based on the chapter Productie by Rogier Lange and Rik Wagenaar in
quality control and release has to be in place. Further-
the 2009 edition of Recepteerkunde.
more, in order to guarantee the quality and safety of a
R. Lange (*)
product the preparation and cleaning processes have to be
Meander Medisch Centrum, Amersfoort, The Netherlands
e-mail: [email protected] validated, including the qualification of premises and
equipment. These validation activities have to be planned
L. Møller Andersen
Region Hovedstadens Apotek, Herlev, Denmark and executed in accordance with quality risk management
e-mail: [email protected] principles.

754 R. Lange and L. Møller Andersen
Keywords and processes should be formally documented and the

Production Quality control In-process controls impact on the validated status or control strategy assessed.
Reconciliation Validation Qualification Cleaning Decisions on the scope and extent of validation and qualifi-
Quarantine cation should be based on a justified and documented risk
assessment.
Personnel issues, premises and equipment, which may
affect the described processes, are discussed elsewhere
34.1 Orientation (Chaps. 25, 27 and 28 respectively), as well as the design
of the medicine (Chap. 15) and the documentation of the
This chapter is about preparation of medicines and quality preparation process (Chap. 33).
control. The text is mainly based on Chaps. 5, 6 and Annex
15 of the GMP [1–3]. We have chosen to clarify a selected
number of subjects from these GMP chapters and to give 34.2 Quality of Production
some practical examples. The main topics discussed are
briefly introduced below. Preparations differ in size and complexity. The scale may
Preparations can be divided into stock preparations and range from a tailor-made preparation for one patient to a
extemporaneous preparations. In this chapter the focus is (semi-)industrial production for thousands of patients. The
mainly on stock preparations. The principles described are complexity may range from the reconstitution of an
equally applicable to extemporaneous preparations. How- authorised medicine to complex preparations from active
ever, the required extent of quality control and validation substances and excipients. In this chapter we focus mainly
might be less in extemporaneous preparations due to the few on stock preparations. The principles described are equally
affected patients and the need to deliver urgently (see also applicable to simpler preparations such as extemporaneous
Sect. 21.6.3). preparations and even for reconstitution [4]. However, the
Product quality is the result of the quality of design, extent of quality control and validation should be justified by
documentation and execution of the preparation or risk assessment [5, 6 and Chap. 21].
manufacturing process. Production operations must follow The main elements to guarantee the quality of the prepa-
clearly defined procedures and must comply with the ration process are:
principles of GMP in order to obtain products of the requisite • The use of qualified and validated premises, systems and
quality. GMP means incorporating quality into all aspects of equipment
the process (see Sect. 35.5.7). • The application of a validated preparation process
First of all, measures to prevent (cross-)contamination • A validated program for cleaning of premises, equipment,
and mix-ups must be in place. These measures can be tech- utensils and clothing
nical or organisational. Other methods to guarantee a safe • Minimisation of the risk of mix-up or cross-
process comprise adequate documentation including contamination
in-process controls and yield and label reconciliation. All • A clear description of all operations in preparation
processes should be controlled and supervised. instructions, operating instructions and procedures (see
Quality Control is concerned with sampling, Chap. 33)
specifications and testing as well as the organisation, docu- • Continuous education and training of employees (Sect.
mentation and release procedures, which ensure that 25.5.2)
materials and products are not released for use, until their • A clear indication of identity and/or status of materials,
quality has been judged satisfactory. Quality Control must premises and equipment in all phases of the production
be involved in all decisions that may concern the quality of process
the product. The independence of Quality Control from • The control and recording of all essential preparation
Production is fundamental. steps, so they are traceable
Batch documentation review and analytical testing are • The use of deviations, errors, complaints, changes, audit
decisive for the release of the products. To ensure a safe results and periodic evaluation or re-validation of prepa-
release process a watertight quarantine procedure must ration processes for continuous optimisation of the pro-
be used. duction process or the necessary conditions or both (see
An important part of this chapter is dedicated to valida- also Sect. 35.6)
tion and qualification. It is a GMP requirement that critical • A comprehensive procedure for quarantine, final inspec-
aspects of operations are controlled through qualification tion and release
and validation during the lifecycle of the processes and These essential elements are elaborated in the following
products. Any planned changes to the facilities, equipment sections or are cross-referred.
34 Production, Quality Control and Validation 755
Products that are prescribed sporadically or with a vari- of areas, equipment and utensils (Sect. 34.16) is also
able composition or with a very limited shelf life are carried intended to prevent cross-contamination.
out as extemporaneous preparations. Preferably a
standardised preparation instruction is used, because this is
the best guarantee for a reproducible preparation. Often only 34.3.2 Organisational Measures
the batch size is varied, because the required amount may
differ for each patient. For example, the needed amount of a It cannot be stressed enough that humans are a key risk
cutaneous preparation depends on the body area to be factor for contamination and cross-contamination. The
treated, the nature of the preparation and the duration of work discipline should aim to avoid mix-up of materials at
treatment. each stage of the preparation process. The golden rule is:
If no standardised preparation instruction is available, a never work on different products in the same room simulta-
non-standardised preparation instruction has to be drafted ad neously or subsequently, unless any risk of confusion is
hoc. Because hereby the possibility of errors is relatively excluded. An example of achieving this is the practice of
large, it is preferred to have available a template for each performing only one preparation per workplace and that this
type of preparation in which only the active substances and workplace is released before starting a new preparation; this
the amount have to be applied. For instance, templates for is also called line clearance. It is advisable to organise the
preparation instructions for capsules or suppositories could work in such a way that once started, preparations can be
be developed (see Sect. 33.5). Of course, the appropriateness completed undisturbed and uninterrupted.
of the templates has to be demonstrated, including the under- A logical method is needed to avoid mix-ups. An exam-
pinning of the preparation method. ple is the weighing process of different ingredients, where all
Many preparations for individual patients concern recon- steps (putting out, identification, opening container,
stitution of licensed products. Examples are dissolving and weighing and replacing of the container) always take place
diluting a powder for injection or creating an antibiotic in the same logical order. The weighed ingredients must
suspension. Again, quality is incorporated by standardising preferably be processed immediately. If this is not possible,
the instructions applied. encode them and keep them together so that it is clear for
The quality of preparation and manufacturing processes which preparation they are intended (see Sect. 34.4).
is based on a combination of technical and organisational Another example is the implementation of a line clear-
measures, instructions, in-process controls, reconciliation, ance of a labelling process. At the end of the process all
quality control (QC) and documentation. An automated sys- printed labels not attached to the product, must carefully be
tem is recommended for the process support. removed and destroyed. Before a new product is labelled,
PRODUCTION
the correct line clearance must be verified.
A good working discipline is essential to prevent cross
contamination. This requires careful planning, but a system
34.3 Prevention of Contamination for identification as well. In stock preparations the identity of
and Cross-contamination the product in operation must be fixed to premises, equip-
ment and vessels. For this purpose labels can be used, or a
34.3.1 Technical Measures form that is part of the preparation record. Logbooks can
also play an important role in the securing of the history of
Contamination is the pollution of raw materials, product or use of rooms and equipment (see Sect. 33.7). If a room or
equipment with dust or microorganisms or both. Cross- equipment has been cleaned according to the applicable
contamination is pollution with substances from other procedure, the status indication “clean” has to be applied.
preparations. Measures to prevent (cross) contamination In extemporaneous preparation, the identification of
include the use of dedicated and well-designed facilities premises, equipment and vessels is not necessary because
and equipment (e.g. closed systems), the use of disposables, of the very short processing time. A clean workspace and
maintaining adequate ventilation in rooms and pressure clean materials are satisfactory.
differences between rooms, as well as the partitioning of The working methods need attention. During weighing
areas where different activities can take place. The and processing of ingredients, dusting has to be prevented.
partitioning of rooms, which can be achieved by placing Manufacturing processes and cleaning operations must be
walls or partitions on workbenches, makes the likelihood run so that no remnants of preparations can end up else-
of mix-ups smaller as well. Other technical measures, such where. If this happens even so, for example in a calamity, a
as the installation of barriers, the use of different colours in proper cleaning procedure has to be followed before the
the floor covering, mainly support the maintaining of a room or equipment or both can be released for the next
proper work discipline. Performing a valid cleaning process preparation. See also Sect. 26.9.1.
34.3.2.1 Supervision For example, how to deal with germ-free packaging

Despite the presence of well-trained staff and clear materials when the overpouch is removed has to be defined.
documents, deviation from the procedures and agreements If it is not yet clear whether materials can be used in the
may occur inadvertently. This requires supervision of future, the material has to be marked clearly with “quaran-
working behaviour (see Sect. 25.5). The immediate supe- tine” and stored separately.
rior, such as a team leader, may perform this. Also a The way rejected materials and products should be
stepwise supervision system can be considered, in which removed safely has to be described in a procedure. In addi-
both experienced pharmacy technicians, the team leader tion a procedure on the permissibility of reprocessing (when
and pharmacists play a role. In all cases it is helpful to an intermediate or bulk product does not meet the
make checklists to record all control operations that are part requirements) has to be in place. Reprocessing should be
of the supervision carried out. Examples of items on such a minimised and performed only in close collaboration with
checklist are the control of completing logbooks and the quality control laboratory and documented carefully.
cleaning verification. Reprocessing of previously delivered and returned products
must be excluded.
34.4 Material Handling 34.5 Batch Documentation
In connection with the traceability of all materials used, it is The documentation that guides a preparation, called batch
important to have clear procedures about the routing and preparation instruction and batch preparation record, has two
encoding of these materials. Herein should be specified that functions: the documentation of all operations to be carried
all materials are put into quarantine upon entry, then be out during the entire process (from weighing of ingredients
sampled, tested and finally released. In all these steps, to the release) and the traceability of all used materials,
the status of the article must be clear. Until release the premises and equipment (see Sect. 33.4). It is possible to
status is “in quarantine”. It is worthwhile to mark refer to the instructions and procedures available for the
containers with “sampled” on the packing of raw materials preparation concerned. Due to the potential impact on the
upon sampling and to note the date of sampling for quality of the product and the consequences for the quality
ingredients with a short shelf life after opening. Upon control all deviations from the intended process and the
release a label is placed on the package with identifying conclusion must be recorded. As part of the continuous
items, an analysis number and the expiry date. The analy- quality improvement, it is also useful to record suggestions
sis number may be printed in the form of a barcode as for improving the preparation instructions on the preparation
well. This makes identification when weighing or measur- record (see Sect. 33.4).
ing the ingredients easy, because in the analysis number The weight or volume measurement or both of
the identity, status and expiry date of the article are ingredients must be verified independently, both the
incorporated. Only released ingredients shall be used for weighing/measurement as well as the control have to be
preparation. Packaging materials and labels are processed recorded. If an automated system is used for these
the same way as all pharmaceutical ingredients. recordings, it has to be validated (see Sect. 33.10).
Also during the preparation process, it is important that
materials have been identified and that the status of the
process phase is unambiguous. If ingredients are not directly 34.6 In-process Controls
further processed after weighing or volume measurement,
the preparation for which they are intended has to be In-process controls, also called IPC’s, are important parts of
indicated unambiguously. the preparation instruction (Sect. 33.4.2). These are controls
The storage conditions and allowed storage period of bulk in the preparation process, which are incorporated in order to
and intermediate product should be mentioned in the product ensure that critical process steps (unit operations) have been
dossier and, if needed, the product should be stored under performed correctly (see also Sect. 15.7). There are quanti-
security control. At relevant points in the process the quar- tative or numerical IPC’s, where results are logged (e.g. pH
antine status is marked and monitored. An example is an value) and qualitative or alphanumeric IPC’s, where an
intermediate or bulk product that is not directly processed observation is described (e.g. colour) or ticked off (with
further. Unambiguous procedures for dealing with surplus initials) (e.g. if a solution is clear). Some IPC’s relate to
and discarded materials must be in place. Surplus materials the product (e.g. homogeneity), some to the process (e.g. a
may be kept in storage again only if these procedures mixing time) – but all IPC’s can be related to the initial risk
are met. assessment and the determined critical control points.
As unnecessary IPC’s may reduce the awareness and disci- called reconciliation, justification of the processing of all
pline of the personnel it is important to consider carefully printed labels takes place, including the throwing away of
whether IPC’s are really necessary in order to control the quality the remaining labels. The reconciliation has to include all
of the product. An example is the preparation of an all-in-one labels used or destroyed including any labels used for the
parenteral nutrition admixture wherein the aqueous part has to quality control samples and for documentation in the batch
be checked for clarity, because precipitates or particulate matter record or the logbook or both. The number of rejected labels
cannot be seen after the fat emulsion is added. Another reason (for example, due to poor printing quality) has to be recorded
for the use of an IPC is to control critical process steps when no and justified as well.
final quality control of the product is possible. An example of The yield must be recorded in an unambiguous manner. It
this is the control of the application of nitrogen for making should be clear how many units have been produced, but also
ampoules oxygen-free after the filling process, because the how many are not used (e.g. due to fracture) or rejected
laboratory is unable to measure the oxygen content in each (e.g. at visual inspection) in various stages of the process.
ampoule. This IPC is based upon the conclusions from the If the final net yield deviates significantly from the theoreti-
validation of the oxygen replacement process. cal yield according to predefined limits, the reason has to be
The results of the IPC’s are useful data for performing clarified. See example in Table 34.1.
trend analysis and the validation of preparation and Table 34.1 shows that the ampoules are packed in boxes
manufacturing processes. of 12 ampoules. At first glance the reconciliation seems to
fit. On closer inspection, there are some deviations: it seems
that 10 ampoules are not labeled and there are two boxes
labeled too much (4,116 ampoules correspond to 343 boxes).
34.7 Label and Yield Reconciliation There is nothing else than to check whether the line clear-
ance has been performed, to inspect the produced batch (are
Labelling and packaging operations are an essential part of all boxes filled?) and to count the ampoules and boxes again.
the process. These operations can be recorded in a separate A non-conclusive reconciliation can be based on counting
packaging instruction. However, in pharmacies, given the and/or writing errors. The relatively low yield may be
limited batch sizes and the short process time, it is common explained satisfactorily. However, verification of sufficient
to include these operations in the batch preparation instruc- inspection of the ampoules (glass particles present?) is
tion (Sect. 33.4.2). needed. Also additional particle counts can be considered
In general, roll-feed labels are preferable to cut-labels in because of the reported trouble in the sealing of the
order to prevent mix-ups. With the label accountability, also ampoules.
PRODUCTION
Table 34.1 Label and yield reconciliation of a batch of ampoules
On product On secondary packaging Initials
Label reconciliation Used Printed Used Printed
Created labels 4,200 365
Labels on product/box 4,116 345
Labels on lab samples 10 1
Labels on quarantine forms 2 2
Labels on batch record 1 1
Labels rejected 2
Labels unused 69 16
Total 4,200 4,200 365 365
Yield reconciliation Loss Yield Initials
Theoretical yield 4,750
Yield after preparation 4,165*
Loss during inspection 27
Loss during labelling 2
Laboratory samples 10
Final yield 4,126
Total 4,165 4,165
*Cause of additional loss: failure of ampoule filling machine at sealing ampoules
34.8 Quarantine Management print-out of filter testing device, sterilisation indi-

cator and sterilisation report, attached?
To prevent the delivery of unapproved products a watertight • Are raw data for critical processes within
quarantine policy is very important. Materials with a quar- specifications?
antine status must be separated from released materials in a • Are the correct labels used and are the printed data
totally safe way. correct and complete?
The following items must have the quarantine status: • Is the label and yield reconciliation, including line-
• Unreleased starting materials clearance, performed correctly?
• Intermediate and bulk products which are not directly • Are deviations, if any, adequately documented and
further processed concluded?
• Filled units that have not yet been labelled If there are deviations from the desired process that
• Products not yet analysed or released or both need extra attention during quality control, this is
• Starting materials or products where doubt about quality noted on the protocol. An example is a too long
is raised after release of the batch in question sterilisation process, in which case special attention
It is preferable that these items are placed in a lockable must be paid during analysis to the presence of possi-
quarantine location. An alternative is storing in lockable bly formed degradation products.
cabinets or quarantine-carts. The access to the quarantine
locations should be limited to a small number of people.
If storage in a closed quarantine location is not possible,
for example a bulk product in a production vessel that is not
directly filled and labelled, the quarantine status is stated
34.9.2 Quality Control
with a striking and well attached plate or label.
The quarantine status is indicated and also recorded on
The Quality Control (QC) department has to operate
the batch documentation, including the number of items
according to Good Quality Control Laboratory Practice
placed in quarantine and the additional number of samples
(GQCLP) standards [2]. All QC methods have to be
that may be taken.
validated and verified before application. The instruments
used for QC are qualified and calibrated before QC testing is
performed. There is a procedure in place for the investiga-
34.9 Quality Control and Release tion of Out Of Specification (OOS) and Out Of Trend (OOT)
results. The reference standards used should be certified,
34.9.1 Batch Documentation Review qualified and verified. Documentation and traceability are
important such as in production. All raw data should be
Final inspection is an essential element in controlling the retained.
quality of pharmaceutical preparations. In the first place, the During quality control the laboratory checks whether the
final control comprises of the control of the batch documen- product meets all specifications. The control of the end
tation. In a larger organisation, such as a hospital, this is product includes a number of non-destructive tests, such as
often the task of the production pharmacist. checking the yield or the weight distribution or a visual
control of packaging and labelling. Subsequently the
required analytical and microbiological tests are carried
The final inspection of the batch preparation record out. The assessment of the finished product includes produc-
should comprise of the following checks: tion conditions, the results of IPC testing, the documentation
• Are all raw and packaging materials properly review and compliance of the final product with the
identified and is the correct amount of each sub- specifications.
stance processed? An important part of the quality control is the sampling
• Are all items of the preparation record completed policy (number of samples, method of sampling, select or
correctly? random samples or both see Sect. 20.4). The selected
• Are all initials put? samples must be taken in those places where the risk of
• Are all IPC’s within limits and are any deviations is greatest (worst case procedure, see for
discrepancies handled correctly? instance 11.5 for sampling suspension-type suppositories
• Is the necessary documentary evidence, such as after serial filling). In addition, samples are taken for sta-
print-out of pH meter, packaging of used filter, bility testing (reference and retention samples) and
validation.
(continued)
QC is not restricted to laboratory operations, but should

be involved in all decisions related to product quality (see principle is based on the recognition that a comprehen-
Sect. 35.6). As an example, QC participates in the investiga- sive set of in-process tests and controls may provide
tion of complaints about product quality. QC is involved in greater quality assurance that the finished product
the assessment and the monitoring of the stability of the meets the specifications than finished product testing.
products as well. The QC department has to approve the Parametric release might be applicable for the routine
IPC methods used in production. In all situations, the inde- release of finished products without carrying out a
pendency of QC from the production department is sterility test and can be authorised if the data
fundamental. demonstrating correct processing of the batch provides
When the pharmacy doesn´t have own facilities for sufficient assurance, on its own, that the process
conducting pharmaceutical analysis, these QC activities designed and validated to ensure the sterility of the
can be outsourced [4]. product has been performed. At present parametric
release may only be applied for products terminally
sterilised in their final container.
34.9.3 Release Policy Parametric release of products with a market
authorisation has to be authorised by the competent
The final release of products comprises a major responsibil- authorities. Authorisation is based on a strict set of
ity, which must be independent of production. In pharma- requirements described in annex 17 of the EU GMP
ceutical industry release is performed by a qualified person [7]. The principle of parametric release is also used in
(QP), in pharmacies often by a pharmacist. Investigational the release of terminally sterilised products in hospital
medicinal products (IMPs) always have to be released by a pharmacy (see Sect. 30.9). The requirements men-
notified QP (Sect. 25.3.4). tioned in GMP annex 17 have to be described in a
The extent of the final inspection and release policy procedure. One of the requirements is a risk assess-
depends on the type of preparation. Thus, for extemporaneous ment of the process (see box in Sect. 34.14.1).
preparations an independent control of the preparation record
and a few non-destructive inspections of the product will
suffice. If no abnormalities are observed, an authorised phar-
macist can perform the product release. In some countries a
delegated person may release the extemporaneous product 34.10 Validation: General Principles
conditionally; afterwards, within a defined time frame, the and Terminology
PRODUCTION
authorised pharmacist releases the product formally.
In some situations, for example with very short-lived 34.10.1 Validation and Qualification
radiopharmaceuticals, conditional release before all QC
tests are performed is necessary. As a consequence, process The GMP (Annex 15) requires that the producer controls the
validation is important. An immediate recall procedure must critical properties of the product and of the critical steps in
take place, when product quality is found to be insufficient. the process [3]. This means that the quality of the design of
Stock preparations usually undergo an extensive analyti- the product, the preparation or manufacturing process, the
cal control (see Sect. 34.9.2) and remain in quarantine until equipment and automated systems used have to be assured.
the QC is fully completed (see Sect. 34.9). The release is The organisation must demonstrate that processes, equip-
based on the assessment of the document control in combi- ment, systems, installations and analysis perform reliably
nation with the analytical quality controls. During release, and reproducibly under all possible conditions. This is usu-
final reconciliation takes place. For certain preparations ally called validation.
(e.g. aseptic preparations) also the results of monitoring of According to GMP, validation is the action of proving, in
production conditions are included. accordance with the principles of GMP, that any procedure,
process, equipment, material, activity or system actually
leads to the expected results. Qualification is the action of
Parametric Release proving that any equipment works correctly and actually
Parametric release is a system of release that gives the leads to the expected results. The word validation is some-
assurance that the product is of the intended quality times widened to incorporate the concept of qualification.
based on information collected during the preparation Because of these somewhat vague and overlapping
process and on the compliance with specific GMP definitions, in this chapter the term qualification is used in
requirements related to parametric release [7]. The the case of equipment and persons and the term validation
when assessing processes or methods.
(continued)
34.10.2 Prospective, Concurrent proposed change on all related equipment, systems and
and Retrospective Validation processes. A standardised risk assessment procedure may
be helpful to determine the extent of re-validation activities.
As a rule, qualification of equipment and building-related It is usually not necessary to entirely repeat the initial vali-
installations takes place before putting into operation (¼ dation. Guided by the quality requirements of the product
prospective). Validation of preparation and manufacturing and the nature of the changes a decision is made which parts
processes is done preferably prospective as well, when of the initial validation have to be repeated.
designing a new process. However, in some situations quali-
fication or validation has to be performed simultaneously
with the application of the equipment or process; this is 34.10.4 Organisation
called concurrent qualification or validation. Concurrent
qualification or validation should only be applied to simple In general, the head of the production department and the
equipment or processes, where there is very little chance that head of the QC department have management responsibility
the outcome would be negative and products would have to for the validation program. Quality staff may play a signifi-
be destroyed. cant supporting role in supporting validation activities. The
It is also possible to perform a qualification of equipment final responsibility for validation is described in the valida-
or validation of a production process that is already operation master plan (see Sect. 34.11). Validation activities
tional, but has not been previously validated. This so-called should only be performed by suitably trained personnel
retrospective validation consists of collecting, evaluating who follow approved validation procedures.
and assessing data from the past. Retrospective validation Despite its complexity, validation provides benefits.
is only possible if no significant changes in the method of Besides the increased control of processes, validation
preparation or equipment have occurred during the measur- provides more insight into the critical factors, which can
ing period, and if sufficient, reliable data are available. If that result in increased patient safety, fewer errors and less
is not the case, additional prospective validations have to be rejections. The PIC/S has published a recommendation
performed. regarding validation, which may be used as reference mate-
When changes occur, it has to be ascertained that the rial [5]. However, the latest version is from 2007 and recent
product still meets the specifications and whether developments are not included.
re-validation is necessary to prove this. Therefore, an effec- In the following sections the principles and different
tive change control procedure has to be in place. forms of validation and qualification are elaborated.
34.10.3 Re-validation and Requalification 34.11 Validation Master Plan
A one-time validation or qualification does not exist whether Validation has to be planned, implemented and maintained
regarding equipment or process. The minimum requirement in the total life cycle of products, premises, equipment and
is that the status of validation and qualification has to be systems. A systematic approach targeted at local conditions
evaluated on a regularly basis. The evaluation frequency has is mandatory and it is recommended to document this
to be pre-defined in accordance with a risk-based approach. approach in a so-called validation master plan (VMP) [3,
The evaluation has to include a systematic going through 8]. According to Annex 15 of the GMP validation master
any changes, deviations or trends in performance e.g. as plan contains the following subjects:
indicated from test results. If the evaluation leads to the • Validation policy
conclusion that the “validated state” is changed a targeted • Organisational structure of validation activities
re-validation has to be done. If there is no indication or need • Summary of facilities, systems, equipment and processes
for re-validation the evaluation is documented in a report, to be validated
which has to be approved by the same functions as the initial • Documentation format: templates for protocols and
validation or qualification. For sterilisation processes reports
re-validation is mandatory every year. Beyond the regular • Planning and scheduling
re-validation an important reason for re-validation is an • Change control
essential change in the equipment, the process or the product • Reference to existing documents
range. The validation policy indicates the necessity of the valida-
All proposed changes must go through the change control tion work and the responsibility of the management, so that
procedure (see Sect. 35.6.10) to determine the impact of the the preconditions for implementation can be met.
In the VMP the organisation of the validation and the • Conditions for and contents of re-validation
tasks of the members of the validation team (see below) are • Test plans
laid down. What to validate and to what extent is decided The results of the validation are archived in a validation file.
after the execution of a risk assessment. The most frequently A validation file of equipment may consist of the following
used methods for risk assessment are described in ICH Q9 chapters: URS, functional/technical specification, DQ, IQ,
[9] (see also Chap. 21). OQ, PQ, re-validation(s) (see Sect. 34.15).
Through prioritisation, the sequence of the qualification
and validation activities is formulated. For each device or
process acceptance criteria have to be set based on a risk
34.13 Validation Team
assessment including critical aspects for the total product
range. Tests in relation to acceptance criteria are described
For successful validation a multidisciplinary approach,
in test plans. Tests have to be reported and the approved
involving production, quality control, quality assurance and
report might be the base for future change control. Ideally,
technical service, is mandatory. The GMP places the respon-
protocols and reports with a fixed layout are used.
sibility for validation at the head of production and the head
Qualification and validation can be outsourced. However,
of quality control.
the responsibility remains in-house so the contract-taker has
Extensive and complex validations can be addressed by
to be approved according to current GMP requirements for
establishing a validation team. The validation team may
outsourced activities [10]. For example, the following quali-
consist of the pharmacists who are responsible for produc-
fication and validation items can be outsourced: LAF
tion, quality control and quality management, and a phar-
cabinets, safety cabinets, HVAC-systems, sterilisers, rinsing
macy technician, an analyst, a quality manager and an
machines and devices for performing filter integrity testing.
employee of the technical department. If necessary, an addi-
When tasks of qualification and validation are outsourced,
tional person can be added to the team for specific expertise.
internal approval of protocols, raw data and reports have to
In larger projects, the validation team can act more decisively
take place according to internal procedures.
by working with a steering committee (e.g. pharmacists and
Activities should be planned in a logical way for effi-
quality manager) and dedicated working groups per valida-
ciently achieving a validated state. After listing and
tion topic. In the formation of a validation team it is impor-
prioritising the activities a validation plan (including costs
tant to incorporate thorough knowledge of the process to
and need for resources) and a timetable are formulated and
ensure the best possible assessment of quality risks and to set
presented to the management. A logical planning begins
the right priorities.
with the validation of the analytical methods because they
PRODUCTION
underpin the conclusions of the process validation. Also
before initiation of process validation of production pro-
cesses the qualification of the relevant equipment has to be 34.14 Process Validation
finalised. For example, before validating aseptic processes,
qualification of the HVAC-installation has to be finished. 34.14.1 General Aspects
Process validation aims to show that the producer controls

34.12 Validation Documentation (the critical steps of) the process so the preparation method
consistently leads to the intended result [11]. The structure
Documentation is an important part of validation. Prior to and the critical steps of the process have to be determined
the validation protocols need to be set up, in which the using process analysis and risk assessment (see Chap. 21).
execution is described. The person responsible for the vali- The effects of small or large deviations in the preparation
dation checks and authorises the protocols together with process have to be determined in order to define the neces-
other disciplines; then they can be used. sary limits during routine production, the so-called design
Validation protocols and reports may include the follow- space (see Sect. 17.6).
ing sections: In most cases, a preparation process is not designed from
• Introduction scratch. Typically, the process, whether or not after acquisi-
• Functions and tasks (for executing activities, for evaluation from the literature or from a colleague, is developed
tion the results and for release) further and recorded in procedures and instructions. A useful
• Execution tool in the development and validation of the preparation
• Acceptance criteria process is process analysis. Hereto, the entire process is
• Results divided into small steps (unit operations, see Sect. 17.6),
• Conclusion which are performed after each other. It must be clear how
Table 34.2 Process analysis: preparation of injections in ampoules

Process step Conditions/Requirements the probability of occurrence and how likely it is that
1. Machine set Proper settings the error is not detected in time is assessed. Each of
Correct mounting of the filling pump these three factors is scored, for example between
2. Weighing ingredients Controlled conditions 1 and 5, and the product of the outcomes is calculated.
Qualified balances The resulting number is called the Risk Priority Num-
3. Preparation of Qualified room ber (RPN). The RPN is a relative number. It is a way to
solution Clothing/hygiene according to procedure identify the principal risks of the process and the focus
Production vessel clean items of validation.
WFI from qualified installation An example of a process step with a relatively low
Proper mixing time risk is the used water for injections (WFI). As a possi-
pH adjustment is correct ble error WFI with a too high bioburden is considered.
Adequate oxygen removal
The severity is 2 (bacterial filtration and terminal
Analysis of sample meets requirements
sterilisation of the finished product), the probability
4. Filtration Right filter and correct placement
of occurrence is 1 (WFI is continuously kept at a
Filter integrity test passed using qualified
device temperature of above 80 C and circulated), and the
5. Pump and filter rinsing Method/time according instruction risk of non-detection is 3 (continuous monitoring of
6. Placing filling needle According to instruction temperature and conductivity, regular determination
and nitrogen needle of the bioburden), and. RPN ¼ 2 1 3 ¼ 6.
(if needed) An example of a process step with a relatively high
7. Filling/closing Qualified filling and closing machine risk is the incorrect loading of the steriliser. Here the
ampoules
severity is 5 (insufficient heat penetration in certain
8. Volume control Correctly adjusted
9. Visual inspection Absence of particles determined by qualified
units by incorrect loading), the probability of occur-
employees rence is 2 (a load instruction is in place) and the risk of
10. Cleaning According to validated cleaning procedure non-detection 3 (only one person is loading and
unloading and controls the load), so, RPN ¼ 2 3
5 ¼ 30. This process step needs more attention
than the other example.
each step has to be performed and which conditions has to be
met. See example in Table 34.2 The correctness of each
process step has to be checked, for example by means of
in-process controls. Also, the influence of external
circumstances or factors on the different process steps has
34.14.2 Process Validation in Practice
to be verified.
A useful tool in the further development of a process is a
Process validation is basically a facility-based activity spe-
risk assessment [9, see also Chap. 21]. On the basis of the
cific for each product or group of products [11]. The base for
severity of certain errors in the process steps, the probability
validation of a preparation process consists of the qualifica-
of occurrence and the timely detectability of a mistake, the
tion or validation of the components of that process:
preparation process can be provided with appropriate
• Building-related installations
instructions and in process controls (see example below).
• Equipment
A detailed evaluation of a process is not only necessary
• Utilities
for the optimisation of a preparation process, but also for the
• Automated systems
validation.
• Process validation of unit-operations
• Cleaning methods
A risk assessment is the basis for parametric release • Analytical methods
of sterilisation processes, replacing the sterility test. Furthermore it must be assured that relevant documentation
One of the requirements of GMP Annex 17 for apply- is up to date and available. If data from Product Quality
ing parametric release is the implementation of a risk- Review (PQR, see Sect. 35.6.11) and stability testing are
analysis of the sterility assurance system [7]. All pro- available they should be evaluated in order to identify any
cess steps in which errors can occur are listed (see critical aspect of the processes. If not available related qual-
Sect. 21.4). Then the severity of any possible error, ity indicators, such as test results, deviations and complaints
should be evaluated.
(continued)
It is very important to keep the correct order when As an example, the process of the preparation of
validating (see Sect. 34.11). This shows that process valida- parenteral solutions in ampoules and its validation are
tion is a complicated experience. Later in this section the elaborated. In Table 34.2, the process from weighing the
validation of the process ‘preparing injectables’ is ingredients to sterilisation of the ampoules is displayed
elaborated. stepwise. During the validation of this process there is refer-
When all components of a preparation process are quali- ral to the following “external” factors that need to be quali-
fied and validated separately, the largest part of the validation fied or calibrated:
process is complete. The prerequisites are described in a • Premises (air control, microbiological monitoring)
protocol and test plans for the final validation are enclosed. • Water production
In general process validation includes preparation of three • Balances
consecutive batches with extended sampling. Acceptance • pH meter
criteria typically include: no OOS, no OOT and critical IPC • Oxygen meter
within specified limits. Samples may be collected from criti- • Filter integrity testing equipment
cal control points during the manufacture. However, when Usually, existing processes are validated retrospectively.
unit operations have been validated, often only samples of the Here a representative period is considered in which the
finished product (after packaging and labelling) are tested. A process took place without adjustments, e.g. 3 years.
conclusion about the preparation process as a whole is An important part of the retrospective validation is the
reported in a Validation report, which has to be approved by collection of all batch preparation and analysis records of the
the heads of Production, QC and QA and afterwards will be a preparations in the period examined. This is done in a sys-
base for change control in relation to the process. tematic way by ascertaining that all preparations are
performed in accordance with the applicable procedures
and instructions, all in-process controls met the requirements
Due to the large amount of products in a (hospital)
and all discrepancies (e.g. less yield than normal) are ade-
pharmacy validating the preparation process sepa-
quately explained. All preliminary and final analytical
rately for each product, is not feasible. The preparation
results are taken from the analysis records. To support the
of a group of products can be validated if the used
data collected the analytical validation is used.
production process is standardised. An example is
If any product is properly prepared and if all in-process
performing media fills to simulate and validate aseptic
controls and final quality controls meet the requirements, the
handling (see Sect. 31.6.2). Another example is the
retrospective process validation may yield no surprises.
validation of a mixing process by using an ingredient
Nonetheless, the evaluation of processes often provides use-
PRODUCTION
with poor mixing properties. This is called a worst-
ful information. The process is reviewed in the same way
case scenario. It is necessary to argue for each product
and by the same person. This allows trends to be discovered
whether the general process validation is applicable
which are not noticed in the assessment of individual
and to record this in the product dossier.
products. It may also become clear that certain aspects of
the process are still too little known. This is a motivation for
In the validation master plan is laid down which pro- additional research.
cesses have to be validated and which priorities have been The conclusion of a process validation is based on the
set (see Sect. 34.11). measured quality of all process components studied.
Processes with a high degree of reproducibility, for exam- In the validation report a recommendation is entered at
ple filling injection liquids in ampoules with a machine, are what time the process must be re-validated. Re-validation is
generally easier to validate than processes with many man- indicated if significant changes in the process are introduced.
ual steps or stages, such as mixing a semisolid dermatologi- The change control procedure (see Sect. 35.6.10) provides
cal preparation manually in a mortar, or the small-scale for this. It is also necessary to define a maximum period
preparation of capsules. For processes with many manual within which re-validation should be performed, so that the
steps the knowledge and skills of the preparer plays a crucial influence of small or creeping changes on the quality of the
role, and the emphasis is on the qualification of the employee process is visible in the course of time. An example of a
and the execution of in-process controls. These give essen- creeping change is a decrease in the working discipline that
tial information about the correctness of that step or the can occur with changes in the personnel. During
process up to that point. re-validation it is checked whether there have been changes
Preferably, process validation is carried out prospec- in (the performance of) one of the process steps, for example
tively. The process is performed an agreed number of in response to recommendations in the initial validation
times (often three) and is taken into use only after a positive report. Also handling of deviations and reported complaints
evaluation. about products have to be addressed.
The design of the re-validation largely follows that of the • Suppositories: content, mean weight, content uniformity,
initial process validation. However, if no significant changes appearance, microbial purity.
have occurred and evaluation of data does not indicate • Suspensions: content, resuspendability, homogeneity,
the presence of OOT, re-validation may be limited to appearance, particle size.
paperwork. How to choose model preparations:
• Active substance should be rather troublesome to process
but doesn’t need to be practically relevant (for instance
34.14.3 Extemporaneous Preparations acetylsalicylic acid in suppositories; hydrocortisone ace-
tate to be dispersed in a cream base; salicylic acid to be
The preparation instruction of standardised individual dispersed in white soft paraffin).
preparations is validated beforehand. For non-standardised • Analysis should be feasible and if possible easy to
preparations this is not the case, and therefore it is advisable perform.
to validate the preparation template of the relevant dosage How to sample:
forms. By choosing a model preparation for each combina- • Define the sample size. Generally 1 sample is sufficient
tion of dosage form and method of preparation the validation for homogeneous preparations and 6 for divided dosage
can be performed. It is not necessary to prepare the model forms.
preparation in daily practice. An example is the validation of • Define the sampling method, for instance:
the manual preparation of suspension suppositories. – Capsules: per filled portion 3 from the corners and
Suppositories with acetylsalicylic acid 100 mg can serve as 3 from the center
a model preparation, because the equal distribution of the – Cutaneous preparations: 6 spread across the batch
active ingredient in this product is difficult (see Sect. 11.5.2). – Solutions: 1 or 2 random samples
By scheduling the model preparations in a periodic cycle, – Suppositories poured in series: first and last one plus
this validation can be coupled to the permanent qualification 4 in between
of personnel. – Suspensions: take 2-3 samples after shaking, spread
Additionally it is useful to analyse individual across the batch
preparations from the daily practice at a fixed frequency,
for example by the preparation of an excess.
A practical approach for the validation of non-
standardised extemporaneous preparations may be: 34.15 Qualification of Premises, Installations,
• List all non-standardised extemporaneous preparations Equipment and Automated Systems
performed in a sufficiently long period.
• Group them according to their dosage form. See also Chap. 27. Building-related installations (including
• Per dosage form: list all applied methods of preparation utilities), preparation equipment and automated systems
(such as capsule filling after dry mixing or using the have to be qualified for use according to predetermined
solvent method). specifications based on specific user requirements (URS).
• Specify all utensils used. For the qualification of equipment and installations specific
• Determine important factors for risk analysis: high fre- guidelines are given in annex 15 of the GMP. Annex 11 of
quency of preparation, critical preparation method the GMP states that computerised systems should be
(e.g. dispersing), critical quality requirement validated [12, 13]. Detailed instructions for the validation
(e.g. content uniformity). of computer systems can be found in the document Good
• Based on the combination of dosage form/preparation Automated Manufacturing Practice Guide for Validation of
methods/utensils and on risk analysis, decide on way Automated Systems in Pharmaceutical Manufacture
and frequency of validation. (GAMP) [14]. This guidance has been designed by the
• Decide which validations have to be performed generally International Society for Pharmaceutical Engineering.
and which have to be operator-specific. When, for example, a new machine is purchased, the
Parameters to be analysed (this list is meant as a following order of the qualification process might be used
guidance): although other terminology may also be used:
• Capsules: content, uniformity of weight, content unifor- • Determine user and regulatory requirements for the
mity, appearance, disintegration time, dissolution rate. intended use of the machine (User Requirement Specifi-
• Cutaneous preparations: content, homogeneity, appear- cation, URS).
ance, particle size, chemical purity, microbial purity. • Draft functional and technical requirements (Functional
• Solutions: content, appearance, homogeneity (especially Requirement Specification, FRS and Technical Require-
with viscous solvents), chemical purity, microbial purity. ment Specification, TRS).
• Usually the previous two steps are accompanied by a risk Usually, after delivery SAT is performed to check the
assessment to determine which requirements are manda- correction of the deviations identified at the FAT and to
tory and which are nice to have. detect any damage caused during delivery. Conclusion of
• Qualify the design (custom-made) or justify the purchase SAT tests may have major legal and economical impact as
(Design Qualification, DQ). handover of the equipment may be linked to finalisation
• Carry out a factory acceptance test (FAT) and a site of this step.
acceptance test (SAT), if applicable. After delivery of the equipment the IQ is performed. In
• Perform the installation qualification (IQ). fact, this is a check to see whether the equipment is delivered
• Perform the operational qualification (OQ). and installed according to the specifications. Also, a check on
• Perform the performance qualification (PQ). the completeness of the documentation, such as operating,
Depending on the associated risk, some of the above men- maintenance and cleaning instructions, calibration require-
tioned steps may be skipped or combined or extended. ments and reports of critical meters, is carried out. It should
The user enters the (legislative) requirements and his also include technical drawings (‘as-built’ drawings) and
wishes concerning the equipment in the URS (see Sect. diagrams (Piping & Instrumentations Diagrams (P & IDs)).
21.5.2 for a URS based on risk assessment). Then he tries During the OQ the operation of the equipment is tested
to find a supplier who can supply a machine or installation and measured effectively. The aim is to show that the system
that meets the URS. After the URS the FRS has to be drafted. works as shown in the functional specification, according to
The FRS results from the translation of the wishes of the user pre-established acceptance criteria. The OQ includes tests
(what should it be able to do?) to the functionality and design for the system operation, calibration, operation of alarms and
of a device or installation (how are the requirements met?). the simulation of emergency situations. Also a SOP and a
The functional requirements describe what the equipment maintenance plan have to be drafted in this stage.
should be able to do and how it should look, such as the size The IQ- and OQ-tests may be performed by, or in coop-
or the materials to be used. Sometimes technical eration with the supplier; the formal qualification is the
requirements are laid down in a separate document, the responsibility of the user.
TRS. On the basis of these specifications a vendor may The final step in the validation process is the PQ, which is
then, if necessary, design the machine or installation. The the verification of the suitability of the installation for the
more carefully the user prepares the URS and FRS, the better intended purpose in the production process. Often quality
the quality of next steps are. control of the finished product is involved in carrying out the
The next step is the Design Qualification (DQ), in which PQ. An example is the measurement of the homogeneity of a
the purchase is justified and the design (when it is custom- mixture that is produced by a mixing machine. The PQ is
PRODUCTION
made) of the equipment is approved, including drawings and performed by the user. When all the above-mentioned steps
documentation. It is important to prepare the first edition of are completed, the equipment is qualified and can be used in
the URS before agreement with the supplier and to finalise it a preparation process.
in connection with the DQ at the latest. The different phases of the validation process can be
For very large and expensive projects it is worthwhile to shown in a V-model (Fig. 34.1), which shows the mutual
include FAT. If possible staff from the pharmacy should relationships. Each step in the validation process reverts to a
participate in FAT tests in order to become familiar with step prior to the purchase. This model was developed with a
the equipment and in order to detect failures as soon view to software validation, but may well be applied to
as possible – this can save a lot of time and money. equipment and installations.
Fig. 34.1 V-model for

qualification and validation
dust. Dust from prior activities that is not removed through

34.16 Cleaning the HVAC system is accumulated, mainly, on the floor. To
remove non-dusty dirt (e.g. spilled and dried liquids) damp
34.16.1 Good Cleaning Practice and Cleaning cleaning is suitable, preferably with disposable mops on
Validation wipers. The required frequency of cleaning can be different
for floors, walls, counter tops and ceilings. Affected
Proper cleaning of premises, equipment and utensils is places such as door handles, push buttons and switches
essential to prevent microbiological and cross contamination should be explicitly addressed. For the cleaning of small
(see Sect. 34.3). The purpose of cleaning validation is to surfaces disposable low-dust wipes may be used.
demonstrate that the correct cleaning processes are applied, Microfibre towels are suitable as well; they can be re-used
that the frequency is adequate and that cleaning leads to the after washing at minimal 70 C and centrifuging at
desired result, namely the prevention of cross-contamination 1,000 rpm. The advantage is cleaning without moisture
during preparation [8, 15]. In general, cleaning validation is and detergents. The disadvantage is that they have to be
necessary before use of new or changed facilities or equip- used within a day after they are washed and centrifuged
ment, in the context of corrective and preventive actions because of microbiological reasons.
(CAPA, see Sect. 35.6.15) after non-conformities or moni- Cleaning materials should not be moved from a less clean
toring trends and if cleaning procedures or materials are environment to a clean room. The use of dedicated cleaning
changed. materials for each manufacturing area is preferred.
Cleaning validation begins by describing all cleaning There is an important difference between cleaning and
activities and to standardise these when possible. The influ- disinfection. Cleaning is removing dirt and other unwanted
ence of the human factor in cleaning processes cannot be substances. Disinfection is aimed at reducing germs on
overestimated. Cleaning activities can be divided into surfaces (e.g. worktops) and is effective only when the
cleaning of premises, equipment and utensils. surfaces are cleaned beforehand (see also Sect. 31.4). In
practice, the right order is: first cleaning and then, where
necessary (for example, the work surface of a laminar flow
34.16.2 Premises, Workbenches and Worktops cabinet), disinfection.
Monitoring of the cleaning is performed by visual inspec-
Own staff may clean the premises, workbenches and tion (note this in the logbook), but also by microbiological
worktops, but outsourcing is possible. In both cases, it is monitoring and wipe tests. Microbiological monitoring
important to record what is being cleaned, with which tools provides insight into the microbiological contamination
and products and in what frequency. Supervision and control of critical points in rooms. Since microorganisms are
forms and logbooks are useful to determine whether these often attached to dust particles, microbiological monitor-
activities are performed in accordance with the agreements. ing also gives an indication of the particle contamination.
In the case of outsourcing, it is necessary to agree on a By sampling before and after cleaning the quality of the
service level agreement (see Sects. 36.4 and 32.9.1). It is cleaning can be measured. At high risk processes, e.g.
also important that only people with proven background preparation of antineoplastics or radiopharmaceuticals,
knowledge on hygiene perform cleaning. periodic surface sampling (wipe tests) is performed to
Cleaning and disinfection of qualified areas such as clean check the cleaning (see Sect. 26.5.4). These wipe tests
rooms (see Sect. 31.4), require intensive training, a special have to ensure the safety of employees, but the results of
attitude and a thoughtful system. This is necessary to ensure the wipe tests also provide an insight into the quality of the
that the persons performing the cleaning do not cause the cleaning.
opposite. The validation of the cleaning of rooms is required for
Wet cleaning can constitute a problem with the moisture surfaces that may come into contact with the product. It
regulation. As the walls, floors and ceilings of clean rooms can be executed retrospectively by checking whether all
are basically airtight, introduced moisture has to be removed scheduled cleaning activities are performed in accordance
through condensation in the Heating Ventilation Air Condi- with the agreements and whether correct actions have
tioning (HVAC) system (see Sect. 27.5.1). This is not only been taken with any deviations. Furthermore, the results
energetically unfavourable, but it takes too long. This is a of the microbiological monitoring, wipe testing and vali-
risk, because a too damp room promotes the growth of dation of air quality gives quantitative information on the
microorganisms. quality of the cleaning processes. By setting limits,
Cleaning with a clean room vacuum cleaner (vacuum conclusions can be drawn about the effectiveness of
cleaner fitted with a HEPA filter) is preferred to remove cleaning activities.
34.16.3 Equipment Furthermore, the analytical methods to assess the rinse

and wipe samples have to be validated. Also, the recovery of
The operating instructions of equipment provide information the test substance during sampling has to be established.
as to how it is cleaned. After cleaning, each apparatus must The amount of an active substance that may be present in
be visually checked for residues of the product or detergent the next product must meet established criteria, such as the
(if applicable). The spots of the equipment to be visually strictest of the following three conditions [8]:
checked must be well defined, based upon experiments with, • Up to 0.1 % of the normal dose of each product may be
for instance, contamination with riboflavin (see further). detectable in the maximum dose of the next product.
However, this is not sufficient, because not all residues are • Up to 10 ppm of each product may be detectable in the
visible and some equipment cannot be inspected entirely. next product.
Cleaning validation is required only for surfaces of mul- • No residual should be visually perceptible.
tipurpose equipment that come in direct contact with the To assess acceptance criteria for cleaning validation, limits
product. When using dedicated equipment only verification for the maximum allowable carryover of product residues
of the cleaning process is necessary. Attention should be must be calculated, based on the pharmacological or toxico-
paid to so-called hot spots: difficult-to-clean locations, logical properties of the substances studied and their permit-
which if improperly cleaned would lead to contamination. ted daily exposure (see Sect. 26.7.2). A risk assessment may
Sampling should be performed through wipe tests and by be useful to support choices and decisions.
collecting flushing liquid. Hot spots can be detected by UV If allergens, steroids or antineoplastics are prepared, these
light when a model substance such as riboflavine is used in must not be detectable above the detection limit of the analyt-
the test procedure. The suitability of the sampling procedure ical method used [8], but see also Sects. 26.5.4 and 26.8.
has to be proven. In the analysis of rinse water, it is impor- The detection limit of model substances should be low
tant that the cleaning has been carried out in the correct enough to meet the established requirements.
manner. When cleaning a production vessel, the rinsing of Finally, the dirty hold time and the clean hold time have to
the inside of the lid could be forgotten. If the rinse water is be established [17]. When a vessel is not cleaned immedi-
clean nothing can be concluded about the cleanliness of the ately after use, the remnants may dry in so the vessel may not
production vessel. As an example, in a kitchen one will not be cleanable using the normal procedure. The dirty hold time
decide upon the cleanliness of a pan only from the clarity of is the time for the cleaning to be completed to be sure that the
the rinse water. Because a wipe test is conclusive about local validated cleaning procedure is still effective. The clean hold
cleaning, both methods should be carried out [8, 16]. time is the time that the equipment may be considered clean
For many devices, the microbiological purity is of after performing cleaning and sanitisation (if applicable) and
PRODUCTION
importance for the quality of the products prepared can be safely used for the next production.
with it. This equipment must be designed and constructed
‘sanitary’. This means that all parts that may come into
contact with the product must be cleanable and that after 34.16.4 Utensils and Clothing
cleaning, no moisture remains. A chemical cleaning (often
an alkaline detergent, followed by an acid agent Tools or utensils used for manufacturing include glassware,
for neutralising) combined with rinsing leads to a strong mortars and spoons. Because the cleanliness of these items
bacterial reduction. Microbiological controls, including and of clothing and clogs directly or indirectly may influence
the determination of total bacterial count in a subsequent the quality of the product, the cleaning of tools and clothing
preparation, provide information about the cleaning has to be validated.
procedure. Utensils and clogs can be cleaned and disinfected manu-
For the validation of the cleaning of equipment existing ally or mechanically. A manual cleaning is difficult to vali-
products or model substances can be used. When validating date. Only the end result can be assessed by visual inspection
a solution a model substance is chosen of which the solubil- and by analysing random wipe and rinse samples. To avoid
ity is similar to the worst-soluble substance in the prepara- unnecessary validation activities, the use of disposables can
tion, since this is the most difficult to remove (worst-case be considered.
approach). Per device or preparation method the nature of Mechanical cleaning is more reproducible and therefore
the model substance(s) (organic, inorganic, or both) is better to validate. A disinfection step can be introduced by
substantiated. Because the pH may affect the solubility of increasing the temperature to above 80 C by the end of the
active substances and excipients this must be taken into cleaning phase, so the cleaned articles are germ-free after the
account in the design of the flushing procedure and the procedure. The process can be monitored by measuring the
choice of the model substance. temperature, the use of detergents and the conductivity of the
process water. In addition, tools are available that can dem- preparation of medicinal products in healthcare establishments.
onstrate the cleaning effect of the process (e.g. Tosi® test). PE 010-4. 2014, pp 1–56. http://www.picscheme.org/publication.
php?p¼guides. Accessed 4 Sept 2014
Random sampling for visual, analytical and microbiological 5. Council of Europe. Resolution CM/ResAP(2011)1 on quality and
checks of the final result may yield additional substantiation safety requirements for medicinal products prepared in pharmacies
of the quality of the cleaning and disinfection process. Sepa- for the special needs of patients. 2011. https://wcd.coe.int/
rate attention must be paid to the drying and storage of ViewDoc.jsp?id¼1734101&Site¼CM. Accessed 14 July 2014;
Accessed 4 Sept 2014
utensils, because recontamination must be avoided. 6. Bouwman Y, Andersen LM (2012) GMP and preparation in hospi-
tal pharmacies. Eur J Hosp Pharm Sci Pract 19(5):469–473
7. European Commission. Eudralex volume 4 EU guidelines to
The Tosi® test is a validated cleaning indicator, good manufacturing practice medicinal products for human and
which is made up of a grooved stainless steel plate veterinary use – Annex 17: Parametric release. 2001, pp 1–5.
on which a strong adhesive red colored substance has http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/v4an17_en.
pdf. Accessed 4 Sept 2014
been applied. This plate is mounted at a very narrow
8. Pharmaceutical Inspection Convention Pharmaceutical Inspection
angle in a transparent plastic container. At the end of Co-operation Scheme. Recommendations on validation master
the cleaning process, the plate must be fully free of the plan – installation and operational qualification – non-sterile
red test substance. If not, the cleaning process has been process validation – cleaning validation. PI 006-3. 2007. http://
www.picscheme.org/publication.php?p¼guides. Accessed 4 Sept
insufficient.
2014
9. European Medicines Agency. Quality Risk Management (ICH Q9)
(2011) http://www.ema.europa.eu/docs/en_GB/document_library/
Garments can be thrown away after use (disposable clean Scientific_guideline/2009/09/WC500002873.pdf. Accessed 4 Sept
room overalls), or reused after cleaning. If clothes are used 2014
that are cleaned in house, validation of this process will not 10. European Commission. Eudralex volume 4 EU guidelines to good
be easy. Therefore, the use of clothing cleaned and packaged manufacturing practice medicinal products for human and veteri-
nary use – Chapter 7: Outsourced activities. 2012, pp 1–4. http://ec.
by specialised and, preferably, certified companies is europa.eu/health/files/eudralex/vol-4/vol4-chap7_2012-06_en.pdf.
preferred. Accessed 4 Sept 2014
11. Amer G (2000) An overview of process validation (PV). Pharma-
ceutical Engineering 20(5):62–76
12. European Commission. Eudralex volume 4 EU guidelines to good
References manufacturing practice medicinal products for human and veteri-
nary use – Annex 11: Computerised systems. 2010, pp 1–5. http://
1. European Commission. Eudralex volume 4 EU guidelines to good ec.europa.eu/health/files/eudralex/vol-4/annex11_01-2011_en.pdf.
manufacturing practice medicinal products for human and veteri- Accessed 4 Sept 2014
nary use – Chapter 5: Production. 2014, pp 1–11. http://ec.europa. 13. Pharmaceutical Inspection Convention Pharmaceutical Inspection
eu/health/files/eudralex/vol-4/2014-08_gmp_chap5.pdf. Accessed Co-operation Scheme. Good practices for computerised systems in
4 Sept 2014 regulated “GxP” environments. PI 011-3. 2007, pp 1–54. http://
2. European Commission. Eudralex volume 4 EU guidelines to good www.picscheme.org/publication.php?p¼guides. Accessed 4 Sept
manufacturing practice medicinal products for human and veteri- 2014
nary use – Chapter 6: Quality control. 2014, pp 1–7. http://ec. 14. International Society for Pharmaceutical Engineering. Good
europa.eu/health/files/eudralex/vol-4/2014-03_gmp_chapter_6.pdf. Automated Manufacturing Practice (GAMP) 5 Guide. 2008
Accessed 4 Sept 2014 15. Ghosh A, Dey S (2010) Overview of cleaning validation in phar-
3. European Commission. Eudralex volume 4 EU guidelines to good maceutical industry. IJPQA 2(2):26–30
manufacturing practice medicinal products for human and veteri- 16. Yang P, Burson K, Feder D, Macdonald F (2005) Method develop-
nary use – Annex 15: Qualification and validation. 2014, pp 1–17. ment of swab sampling for cleaning validation of a residual active
http://ec.europa.eu/health/files/gmp/2014-02_pc_draft_gmp_annex. pharmaceutical ingredient. Pharmaceutical Technology 2005 Jan,
pdf. Accessed 4 Sept 2014 84–94
4. Pharmaceutical Inspection Convention Pharmaceutical Inspection 17. Fugate T (2007) Hold time studies: a lost parameter for cleaning
Co-operation Scheme. PIC/S Guide to good practices for the validation. J Valid Technol 13(3):206–209
Pharmaceutical Quality Systems
35
Contents 35.6.10 Change Management, Change Control . . . . . . . . . . . . . . . . . 784

35.6.11 Product Quality Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
35.1 The Purpose of a Quality Management System . . . . . 770 35.6.12 Internal Audits, Inspection, External Audits . . . . . . . . . . . 785
35.2 Structure of the Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 35.6.13 Non-conformities (Deviations and Complaints) . . . . . . . 787
35.6.14 Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
35.3 Pharmaceutical Quality Development . . . . . . . . . . . . . . . 771 35.6.15 Root Cause Analysis and Corrective and Preventive
35.4 Product Life Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 Action System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
35.4.1 Product Life Cycle Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 35.7 Structuring a PQS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
35.4.2 Pharmacotherapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773 35.7.1 Desire for Structuring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
35.4.3 Design of Formulation and Method of Preparation . . . . 774 35.7.2 ISO 9001/EN 15224 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
35.4.4 Preparation or Manufacturing Process . . . . . . . . . . . . . . . . . 774 35.7.3 Pharmaceutical Quality System of GMP Chapter 1 . . . 791
35.4.5 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774 35.7.4 ICH Q10 as a Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
35.5 Pharmaceutical Legislation and Guidelines . . . . . . . . . 775 35.7.5 Seven Pillars Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
35.5.1 PQS, Legislation and Guidelines . . . . . . . . . . . . . . . . . . . . . . . 775 35.7.6 Suitability of Structures for PQS in Pharmacies . . . . . . . 794
35.5.2 European Directives, Regulations and Guidelines . . . . . 775 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
35.5.3 Pharmaceutical Preparations Ph. Eur. . . . . . . . . . . . . . . . . . . 776
35.5.4 Resolution on Pharmacy Preparation (Council
of Europe) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
35.5.5 PIC/S GPP Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777 Abstract
35.5.6 Professional Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778 A quality management system (QMS) is an important tool
35.5.7 Good Manufacturing Practice (GMP) . . . . . . . . . . . . . . . . . . 779 for process control and continual improvement. After a
35.5.8 Site Master File . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
brief section about development of the quality principle
35.5.9 ICH Guidelines Q8, Q9 and Q10 . . . . . . . . . . . . . . . . . . . . . . . 779
35.5.10 Investigational Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 in the preparation of medicines over the years, this chap-
ter lists the processes in preparation and in the manufac-
35.6 Elements of a PQS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
35.6.1 Quality Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 ture of medicines that have to be controlled. A medicine,
35.6.2 Documentation and Knowledge Management . . . . . . . . . 782 whether developed in a pharmacy or in industry, starts
35.6.3 Management Responsibility and Commitment . . . . . . . . 782 with defining the needs of the patient. Then the formula-
35.6.4 Management Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783 tion and the method of preparation are designed to meet
35.6.5 Quality Policy, Quality Plans, Quality Objectives . . . . . 783
35.6.6 Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783 product specifications. The next step of the product life
35.6.7 Product Realisation, Product Design . . . . . . . . . . . . . . . . . . . 784 cycle is the production, including quality control and
35.6.8 Quality Risk Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 release.
35.6.9 Quality Characteristics and Quality Requirements . . . . 784 In practice pharmaceutical quality management
systems (PQSs) may follow the structure of quality
standards for medicines, mainly GMP, PIC/S-GPP, and
Based upon the chapter Kwaliteitszorg by Mieke de Blois en Yvonne Q10 to which GMP is referring. These standards are
Bouwman-Boer in the 2009 edition of Recepteerkunde.
described as well as standards that are more applicable
Y. Bouwman-Boer (*) to preparation in the pharmacy i.e. the Ph. Eur. mono-
graph Pharmaceutical Preparations, the Council of
e-mail: [email protected] Europe (CoE) Resolution and USP Compounding
Standards. If a PQS has to cover the complete life cycle
L. Møller Andersen
Region Hovedstadens Apotek, Herlev, Denmark of the product, preparation in pharmacies or even all
e-mail: [email protected] pharmacy activities then a more universal structure such

as 7 Pillars or ISO 9001 may be used, more precisely the

EN 15224 as it applies to health care.
Any of these structures or models contains similar
elements. These are dealt with including: Quality Man-
ual, Management review, Change management, act plan
Complaints, Deviations and Recall.
Keywords
QMS Quality PQS GMP Q10 ISO 9001 EN check do
15224 Regulation 7 pillars Standard
35.1 The Purpose of a Quality Management

System Fig. 35.1 Deming’s circle or PDCA-cycle for quality improvement
The processes of design and preparation of medicines quality system and be compliant with the standards relevant
need to be controlled, monitored and continually improved to the type of product being made.”
in order to deliver products with the intended quality now
and into the future. This may be accomplished in a con-
Definitions of some frequently used quality terms are
trolled and structured way: using a quality management
as follows:
system (QMS), which for pharmaceutical preparations is
more commonly called a Pharmaceutical Quality System
Quality The degree to which a set of
(PQS). The implementation of a PQS supports the operations
inherent characteristics of a prod-
in the highly regulated field of medicinal products. This
uct or service fulfils requirements.
field is characterised by high-level professional standards
Requirements may be prescribed
and comprehensive requirements to transparency and
by law, but may also reflect needs
documentation.
and expectations of organisations,
A QMS is common to all types of organisations and
customers and other stakeholders,
products and generally intends to achieve:
in short: of society.
• A system, that allows the delivery of products or services
Quality All activities of the management
of the right quality
management of an organisation meant to
• A state of control through shared standards and effective
achieve and demonstrate the
monitoring and control systems
intended quality level as well as
• Facilitation of development and continual improvements
further improvement. These
All QMSs circle around the query: how does every-
activities require a joint contribu-
thing that happens within an organisation affect the final
tion from all concerned.
quality?
Quality manage- A set of interrelated or interacting
The concept of managing the processes – maintaining
ment system elements that organisations use to
them and continually improving them as well – is visualised
direct and control how quality
by Deming’s quality circle, also called the PDCA-cycle:
policies are implemented and
Plan, Do, Check, Act (see Fig. 35.1).
quality objectives are achieved.
The Deming cycle entails: make a plan for an improve-
Quality control The operational measures that are
ment, do it, check whether the desired result is obtained, and
(QC) taken to meet the specified
act from now on in this way. Continuous monitoring of the
requirements. This includes the
result, if necessary followed by (further) adjustment, allows
activities for maintaining the
for a structured quality improvement. In the pharmaceutical
quality management system,
area a QMS (PQS) is also necessary for the demonstration of
such as analysis of the product,
compliance with regulatory requirements and professional
procedures for change control,
standards. Thus, the Ph. Eur. monograph Pharmaceutical
deviations and complaints, inter-
Preparations (see Sect. 35.5.3) states: “Manufacture/prepa-
nal and external auditing.
ration must take place within the framework of a suitable
35 Pharmaceutical Quality Systems 771
35.2 Structure of the Chapter 35.3 Pharmaceutical Quality Development
For pharmaceutical manufacturing it is quite common to This section shows how ideas about guaranteeing pharma-
refer immediately to GMP guidelines (see Sect. 35.5.7) if ceutical product quality have developed over time.
considering a PQS. Section 35.3 accounts for the historical In the early days of the 1960s through to the late 1970s,
background of that approach. There are a few reasons how- quality activities in relation to the production of medicines,
ever for this chapter to put the PQS in a broader perspective, as of other products, mainly focussed on product control: on
such as that of the International Standards Organisation detection and subsequent restoration or elimination of
(ISO, see Sect. 35.7.2): flawed products. Organoleptical controls were utilised as a
• The general ISO approach of quality is more conceptual and pharmaceutical key competence and laboratory testing
applies, thus connects, to all other enterprises in society. played a key role. The quality management of products
• GMP is absorbing by and by the ISO concepts. was based on professional standards, knowledge and experi-
• Pharmacies, as opposed to manufacturers of medical ence. However, even though the professionalism was high,
products, are part of health care organisations, which quality varied. Documentation of decisions and production
have clinical processes as their principal activity. data was poor and knowledge management challenging. As
Pharmacy preparation is essentially a clinical process if it is shortcomings in processes do not always become apparent
meant (see Sect. 3.2) to provide patients with the medicines and as not all shortcomings in the product quality are detect-
they need and which are not available as licensed medicines. able, it was understood that end product testing was not
ISO, especially its particularisation to health care EN 15224, sufficient. Quality had to be built into the products.
can be applied to healthcare organisations. So it can be Building quality into the product has always been an
applied to pharmacies as well. The EN 15224 consideration important process for pharmacy preparations in order to
that ‘pharmaceuticals to be regulated elsewhere’ applies to obtain confidence about the finished product. The analytical
licensed medicines but not to pharmacy preparations. quality control of the product may be limited because of the
GMP is principally directed at and very specialised in the limited access to analytical resources (or even lack thereof)
manufacturing of licensed medicinal products. GMP lacks or because of the immediate need for the product, and often
therefore some principles that are necessary for a PQS for the ‘batch’ only comprises of one preparation. The entire
pharmacies. process from the request by the doctor, design of formulation
Section 35.3 gives the development of pharmaceutical and preparation was for a long time in the hands of one
quality thinking. Section 35.4 describes the Product Life expert: the pharmacist that worked secundum artem (liter-
PRODUCTION
Cycle for pharmacy preparations as well as for licensed ally: following artisanal rules). Due to the involvement with
medicines. A PQS has to cover the life cycle of a medicine. all stages of the process this pharmacist encountered no
Section 35.5 is about Legislation and Quality Standards, barriers to implement necessary processes immediately.
for pharmacy preparation and for manufacturing. These give Later the secundum artem concept developed more and
the quality objectives as well as some guidance how to create more into quality thinking. Pharmacy preparation still puts
a PQS. great emphasis on in-process controls and the individual
Section 35.6 describes a large series of PQS elements, pharmacist being acquainted with all stages of the process.
each of them with examples from pharmaceutical For industrial production, in addition to product control,
preparations. The extent of their use in the manufacturing process control was introduced. This occurred mainly with
situation or in pharmacies depends on the outcome of risk the introduction of Good Manufacturing Practices (GMP)
assessments. As elements they should principally be adhered regulation but also with pharmacopoeial requirements.
to in both situations.
Section 35.7 tries to put all elements of a PQS into a
The GMP directives were composed in the 1960s
structure, a visualisation that helps to keep an overview.
in the United States and a GMP guide was issued
In many hospital pharmacies the structure of a PQS for the
as the Orange Guide in the UK in 1971. In 1989
production department will probably be found in its Quality
the GMP directives were introduced in Europe. They
Manual that contains all SOPs, well structured in chapters,
can be considered as a collection of instructions,
presumably those of GMP. If however characteristics such as
warnings and recommendations that intends to mini-
benefit/risk ratio, timeliness, availability or patient empower-
mise all risks for the product and thereby guaranteeing
ment have to be added, a hospital pharmacy may be better off
constant yield and quality. It serves patient and
with a structure that uses the ISO 9001–EN 15224. Such a
manufacturer.
structure may be useful as well if the PQS for production has
to be merged with the PQS for the whole pharmacy. (continued)
and innovation are required to meet the ever-increasing

Worldwide the International Conference on demands of customers and the achievements of competitors.
Harmonisation of Technical Requirements for Regis- From about 2000 especially the pharmaceutical industry
tration of Pharmaceuticals for Human Use (ICH, see pays more attention to the importance of the quality of
also Sect. 35.5.9) is involved in further development of design of the formulation and preparation method. The con-
GMPs. The ICH is a collaboration of the pharmaceuti- cept of Quality by design was introduced. With small-scale
cal industry and registration authorities from Europe, preparation in pharmacies, the design phase has always been
the United States, and Japan. The initial objective of part of preparation as design and preparation of a medicine
this organisation in the 1990s was harmonisation of were, together, including the prescription assessment.
the technical regulations and requirements for the reg- In recent years focus is on Quality Leadership: the need
istration of medicinal products, to accomplish that of commitment from senior management to quality.
registration in different countries could be obtained Besides quality, also the costs of a product are of impor-
as fast, efficiently, and cost-effectively as possible. tance for an organisation. Manufacturing industry utilises
Since the beginning of the twenty-first century, the the terminology Lean Management to promote an approach
objective has shifted more towards international that leads to a both qualitatively sound and cost-effective
harmonisation in general. product. Some key elements in Lean Management are:
The concept of the Qualified Person (QP, see also • Constant and persisting focus on the needs of the
Sect. 25.3.4), giving the final responsibility for release customer
to an appointed individual with a required set of skills, • A systematic elimination of any waste (in relation to
was introduced in manufacturing through the EU value for the customer)
GMP. The QP responsibility includes all aspects in • A standard approach to elimination of variations and
relation to quality of the released products as well as continuous improvements
conformance with regulatory requirements as appro-
priate. Even today the QP concept is a keystone in EU
GMP, and to be seen as a significant difference in 35.4 Product Life Cycle
GMP understanding compared with other regions.
With the development ICH Q10 (see Sects. 35.5.9 and
Process control is defined as taking measures to monitor 35.7.4) as a standard for a pharmaceutical quality system,
and, if necessary, adjust processes that lead to the end the process approach (maintenance as well as improvement)
product. Quality of products can still not be guaranteed but was emphasised. Q10 states as well that a PQS should cover
a production based on professional standards aims to build the whole product life cycle. This section describes the
quality into every step of the preparation process. product life cycle of medicines, for preparation in
Subsequently, system control was introduced, through pharmacies as well as for industrial production. A medicine
defining preconditions for the prime processes, such as whether developed in a pharmacy or in industry is designed
well-trained personnel, adequate premises and equipment. to meet the needs of the patient and starts with clarifying that
Continuous improvement was going to be supported by, need. The product life cycle consists of a series of processes
among others, Root Case Analyses and Systems for Correc- that need to be controlled and continually improved in order
tive and Preventive Actions (CAPA). The need was to deliver products with the intended quality.
recognised of structured decisions based on Quality Risk
Management (see Chap. 21).
The concept of Supply chain management was subse- 35.4.1 Product Life Cycle Approach
quently developed. All parties in the supply chain cooperate
on quality for the end user. Generally the product life cycle consists of four main
Ultimately, all processes, including all personnel, deter- processes:
mine the quality of the product and associated services. For • Pharmacotherapeutics
everything that happens within an organisation, the senior • Formulation
management asks the question: “How does this affect the • Preparation process
final quality?” This approach is called total quality manage- • Storage & Distribution
ment, and quality improvement is pivotal in maintaining a This description will usually do for pharmacy preparations.
quality system. Ideally, a learning organisation is created, Pharmacy preparation sees that the patient’s need is com-
founded on the rationale that continuous quality improvement bined with a knowledge of pharmacotherapy with a known
active substance. The assumption of a positive benefit/risk The following sections discuss the Product Life Cycle in
ratio regarding this pharmacotherapy leads to a request, more detail, mainly based on the four main processes for
commonly a physician’s prescription, for the active sub- preparation in pharmacies.
stance in a suitable dosage form. Next a formulation, a
way of preparation and packaging have to be designed,
specifications set and assays developed. The actual prepara- 35.4.2 Pharmacotherapeutics
tion has to be started. If more patients need this medicine, the
preparation has to become predictable and reliable to deliver Pharmacotherapeutics for pharmacy preparation is about
more preparations or even batches with a constant quality prescription assessment, information of physician and
and yield. Quality control has to be defined, as well as patient, and pharmacovigilance. The therapeutic quality of
release, storage, distribution and transport. The actual use the product is the outcome of a benefit/risk balance. It
of the preparation by the patient should lead to any form of accounts for efficacy and effectiveness, patient friendliness
feedback about effectiveness and safety, patient friendliness and the contribution to the safety of healthcare processes
and fitness for the healthcare process that it serves. The life (see Sect. 2.2). The benefit risk balance at the start of the life
cycle of a pharmacy preparation will end with a discontinu- cycle is assumed to be positive, which has to be proven to a
ation, usually because of a new licensed medicine with a reasonable extent before the patient gets the medicine. For
better benefit/risk ratio. Sometimes its life cycle ends due to pharmacy preparation a review of literature, medical opinion
e.g. unavailability of substances or packaging materials or to and sound thinking usually provides the start. The benefit
stability problems. risk assessment is the duty of care of all health professionals
The life cycle of a licensed medicine follows this involved, as it is put in the Ethical guidance and
sequence as well, although it is much more regulated and considerations of the Ph Eur monograph Pharmaceutical
with formally separated processes, due to larger batches and Preparations (see Sect. 35.5.3). The CoE Resolution on
widespread use. Pharmacy Preparation (Sect. 35.5.4) also mentions this
For industrial production the Product Life Cycle for new duty: the pharmacist has to prove the ‘added value’ com-
and existing products is characteristically defined by ICH pared to licensed medicines. Documentation of these profes-
Q10 as a sequence of four groups of technical activities, with sional decisions is essential for building up knowledge,
subgroups: communication between healthcare professionals and from
Pharmaceutical Development a liability point of view. Forms for this type of documenta-
• Active substance development tion are given in Sect. 2.2.
• Formulation development (including container/closure
PRODUCTION
system)
For the application for a marketing authorisation clin-
• Manufacture of investigational products
ical trials have to be performed. An official European
• Delivery system development (where relevant)
body, the European Medicines Agency (EMA),
• Manufacturing process development and scale-up
assesses the therapeutic benefit risk ratio.
• Analytical method development
An EMA project on benefit-risk methodology is
Technology transfer
being performed. Some approaches of the assessment
• New product transfers during development through
method have been published [1].
manufacturing
If the medicine is used for other indications its
• Transfers within or between manufacturing and testing
benefit risk balance will be different and should be
sites for marketed products
assessed again. If not the medicine is used ‘off-label’.
Commercial manufacturing
• Acquisition and control of materials
• Provision of facilities, utilities, and equipment After the introduction or start of use of any medicine, the
• Production (including packaging and labelling) benefit risk ratio may be changed, because of:
• Quality control and assurance • Unknown adverse reactions
• Release • Unexpected problems with product stability e.g. the
• Storage detection of toxic degradation products
• Distribution (excluding wholesaler activities) • New indications
Product discontinuation • Development of better therapeutic alternatives
• Retention of documentation • Unexpected differences between groups of patients
• Sample retention These possible changes necessitate monitoring: pharma-
• Continued product assessment and reporting covigilance. Pharmacovigilance has been defined by the
World Health Organisation as the science and activities needs of the patient, the pharmacist should document the
relating to the detection, assessment, understanding and rationale for that decision in the product file (see Sect. 33.8).
prevention of adverse effects or any other medicine-related For the documentation of the decisions about the design and
problem [2]. For the monitoring of the pharmacotherapy the risk assessment, some checklists and forms are available,
of licensed medicines, the qualified person for pharma- see Sect. 2.2. The process of formulation design may be laid
covigilance (QPPV see also Sect. 25.4.4) has to handle down in SOPs for different dosage forms.
complaints and reports of suspected adverse events. Moni- For licensed medicines the description of the design has
toring occurs by a regulated system of pharmacovigilance. to be given by the manufacturer in the registration dossier.
Patients, caregivers and health care personnel may be Notices to applicants contain instructions for a registration
questioned, and regular product reviews are created, includ- dossier, which can be used in consultation with national
ing the analysis of complaints and of literature. This moni- professionals and the EMA. Furthermore, scientific
toring may lead to a conclusion that the active substance recommendations from the Committee for Medicinal
is not beneficial any more, the dosage form should be Products for human use (CHMP), Reflection papers, and
changed, indications added, volume or packaging improved Scientific guidelines (see Sect. 35.5.1: Volume 3 of the
etcetera. Rules) are available. So-called European Assessment
Pharmacovigilance for pharmacy preparations has not yet Reports (EPARs) of specific licensed medicines can be
been developed very well. However in some countries the quite informative about design backgrounds. They are
competent authority expects pharmacies to have pharmacov- published at the EMA website. The national registration
igilance procedures. authority or the EMA (pan-European) have to approve the
The information about the therapeutic qualities of quality of the design.
licensed medicines is part of the product dossier to obtain
and keep a marketing authorisation. For pharmacy
preparations information about therapeutic quality and
35.4.4 Preparation or Manufacturing Process
about its monitoring can be part of the product file (see
Sect. 33.8).
The production process is the most visible and most exten-
sive part of the Product Life Cycle. Several pharmaceutical
quality systems in use support ’just’ the preparation process.
35.4.3 Design of Formulation and Method
These PQSs may extend from the involvement of senior
of Preparation
management, handling complaints, change management,
maintenance of facilities and documentation, self-inspection
The formulation has to meet the needs of the patient with
to analysis and knowledge management. These elements are
active substances, excipients, dosage form and package, it
elaborated in Sect. 35.6. Structures to group these elements
has to meet (regulatory or professionally set) product
in a logical way are discussed in Sect. 35.7.
specifications and it should support a sound production
process (see Chap. 17 Product design). The preparation’s
stability plays a large role, its shelf life has to be predicted
and analysed (see Chap. 22 Stability) and instructions 35.4.5 Distribution
for use have to be developed (see Chap. 37 Instructions
for use). A PQS usually covers the distribution process as well. GMP
A good and well-organised documentation of the design (see Sect. 35.5.7) specifies the distribution being part of the
process can be very supportive and time-saving on many PQS in Chap. 1 Pharmaceutical Quality System:
moments in the product’s life cycle. It will help when pro- • Records of manufacture including distribution which
cess deviations need to be explained or changes need to enable the complete history of a batch to be traced are
be made. retained in a comprehensible and accessible form.
For the design of pharmacy preparations the phar- • The distribution of the products minimises any risk to
macist refers to knowledge sources, such as this textbook. their quality and takes account of Good Distribution
Chaps. 4–14 describe the essentials of the design processes Practice.
for most dosage forms. • A system is available to recall any batch of product, from
For the specifications of the active substances, excipients sale or supply.
and dosage forms the pharmacist can refer to the Ph. Eur. If it Information on storage of medicines, transport and distribu-
is necessary to deviate from these requirements to meet the tion is dealt with in Chap. 36 Logistics.
dealt with in Sect. 35.5.10 with focus on the tasks of hospital

35.5 Pharmaceutical Legislation pharmacists.
and Guidelines
35.5.1 PQS, Legislation and Guidelines

35.5.2 European Directives, Regulations
The quality characteristics of medicinal products and quality and Guidelines
objectives of a preparing pharmacy or manufacturer are
generally and sometimes in detail covered by European European legislation on medicines for human use consists of
and national legislation and guidelines. A quality system several directives and regulations, further referred to as
for medicinal products will therefore have to connect with ‘Rules’. They are clustered in Volumes, to be found at
the appropriate legislation and professional guidelines that [3]. The main series that are relevant for the production of
are meant to support their quality. medicines are in Volume 1 and 4.
Legislation is aimed at the protection of the citizen, and In Volume 1, EU pharmaceutical legislation for medici-
are nowadays often supranational. The professionals, for nal products for human use, the main directive is Directive
instance the national pharmaceutical society, may have 2001/83/EC on the Community Code relating to medicinal
defined standards for the implementation of or products for human use. It is directed at licensed medicines.
complementing the regulations. Pharmacy preparations are however mentioned in Article 40:
This section deals at first with the basic European legisla- However, such authorisation shall not be required for prepara-
tion on medicines. Then follows the monograph Pharmaceu- tion, dividing up, changes in packaging or presentation where
tical Preparations of the Ph. Eur. This is legally binding for these processes are carried out, solely for retail supply, by
pharmacists in dispensing pharmacies or by persons legally
preparation in pharmacies as well as for industrial licensed in the Member States to carry out such processes.
manufacturing and it covers three parts of the product life
cycle: pharmacotherapeutics, product design and prepara- Directive 2001/83/EC points with Article 47 2nd para-
tion process. It states the need for a PQS by: “Manufac- graph at the Commission Directive 2003/94/EC laying down
ture/preparation must take place within the framework of a the principles and guidelines of good manufacturing practice
suitable quality system and be compliant with the standards (see Sect. 35.5.7) in respect of medicinal products for human
relevant to the type of product being made.” use and investigational medicinal products for human use. In
With regard to preparation in pharmacies three other the introduction on GMP it is stated that
guidelines are relevant: the Council of Europe (CoE) Reso- The principles of GMP and the detailed guidelines are applica-
PRODUCTION
lution on Pharmacy Preparation, the Pharmaceutical Inspec- ble to all operations which require the authorisations (..). They
tion Convention and Pharmaceutical Inspection are also relevant for pharmaceutical manufacturing processes,
such as that undertaken in hospitals.
Co-operation Scheme (PIC/S) – Good Preparation Practice
(GPP) Guide, and the professional guideline USP The definition of pharmaceutical manufacturing pro-
Compounding standards. Some other European professional cesses is however not given.
guidelines are mentioned as well, which however are not Articles 48 49, 51 are about the Qualified Person that has
easily accessible due to their language. to be at disposal of any Manufacturer’s Authorisation Holder
For licensed medicines the GMP guidelines are legally (see further Sect. 25.3.4).
binding, insofar that other practices are allowed on the This basic legislation is supported by a series of
condition that the same principles are fulfilled. They give guidelines:
many details on production and a PQS. The EU GMP (see • Volume 2 – Notice to applicants and regulatory
Sect. 35.5.7) states that a manufacturer should establish, guidelines for medicinal products for human use and
document and implement a “comprehensively designed and specific rules for medicinal products for paediatric use,
correctly implemented QMS incorporating Good orphan, herbal medicinal products and advanced
Manufacturing Practice and Quality Risk Management”. therapies (mentioned in Sect. 35.4.3)
The GMP principles apply as well to preparation in • Volume 3 – Scientific guidelines for medicinal products
pharmacies. The global International Conference on for human use (mentioned in Sect. 35.4.3)
Harmonisation (ICH) guidelines Q8, Q9 and Q10 are mainly • Volume 4 – Guidelines for good manufacturing practices
in use in industrial production. The regulatory function of for medicinal products for human and veterinary use (see
the Qualified Person, with functional connections to a PQS, Sect. 35.5.7)
is dealt with in Sect. 35.5.7 and Chap. 25 Human Resources. • Volume 8 – Maximum residue limits (mentioned in Sect.
Regulations about Investigational Medicines are shortly 22.4.2)
• Volume 9 – Guidelines for pharmacovigilance for medic- The exemptions from the formal licensing requirement allow
inal products for human and veterinary use (mentioned in the supply of unlicensed products to meet the special needs of
individual patients. However, when deciding to use an unli-
Sect. 35.4.2) censed preparation all health professionals involved (e.g. the
• Volume 10 – Guidelines for clinical trials (see prescribing practitioners or the preparing pharmacists or both)
Sect. 35.5.10) have, within their area of responsibilities, a duty of care to the
Guidelines are meant to guide the implementation of legis- patient receiving the pharmaceutical preparation.
In considering the preparation of an unlicensed pharmaceuti-
lation, as it is stated for instance: “Volume 4 contains guid- cal preparation, a suitable level of risk assessment is undertaken.
ance for the interpretation of the principles and guidelines The risk assessment identifies:
of good manufacturing practices for medicinal products – the criticality of different parameters (e.g. quality of active
for human and veterinary use laid down in Commission substances, excipients and containers; design of the prepara-
tion process; extent and significance of testing; stability of
Directives 91/356/EEC, as amended by Directive 2003/94/ the preparation) to the quality of the preparation; and
EC, and 91/412/EEC respectively.” – the risk that the preparation may present to a particular
patient group.
Based on the risk assessment, the person responsible for
the preparation must ensure, with a suitable level of assurance,
35.5.3 Pharmaceutical Preparations Ph. Eur. that the pharmaceutical preparation is, throughout its shelf life,
of an appropriate quality and suitable and fit for its purpose.
For stock preparations, storage conditions and shelf life have
This monograph [4] had its first edition in 2011. It applies to
to be justified on the basis of, for example, analytical data or
all pharmaceutical preparations: licensed medicines as well professional judgement, which may be based on literature
as pharmacy preparations; or in other words: to licensed as references.
well as unlicensed medicines.
These guidance points at three processes that are part of
Pharmaceutical Preparations Ph. Eur. monograph
pharmacy preparation’s life cycle: pharmacotherapeutics,
contains the sections:
product design and preparation process. Therefore to be in
• Introduction
accordance with this Ph. Eur. monograph, the corresponding
• Definition
quality system should cover all three processes, including
• Ethical considerations and guidance in the preparation of
responsibilities, to be most useful. The monograph gives
unlicensed pharmaceutical preparations
further guidance to the process of formulation design.
• Production
– Formulation
– Active substances and excipients The ethical considerations of the monograph may, for
– Microbiological quality instance, be specified by the following paragraph, to
– Containers be included in the PQS of a specific hospital pharmacy
– Stability (see Sect. 35.7.6):
• Tests The duty of care for the pharmacist implies that he
– Appearance considers the consequences for his patient(s) of not
– Identity and purity tests preparing a preparation that is required by the physi-
– Uniformity cian and the patient. He may consider the availability
– Reference standards of a specific medicine to be more important than the
• Assay degree of quality assured by a licensed preparation.
• Labelling and storage The pharmacist should balance the safety of the prod-
• Glossary uct (therapeutic qualities including toxicity and
– Formulation adverse events, design quality and product quality)
– Licensed pharmaceutical preparation and the unavailability of the medicine. This balancing
– Manufacture (see Sect. 2.2) refers to an individual patient in case of
– Preparation (of an unlicensed pharmaceutical an individual preparation or to a defined indication or
preparation) patient groups in case of a stock preparation.
– Reconstitution
– Risk assessment
– Unlicensed pharmaceutical preparation
Especially the Ethical considerations are important for a
PQS for pharmacy preparation: 35.5.4 Resolution on Pharmacy Preparation
(Council of Europe)
The underlying principle of legislation for pharmaceutical
preparations is that, subject to specific exemptions, no pharma-
ceutical preparation may be placed on the market without an The full title of this resolution is: Resolution CM/ResAP
appropriate marketing authorisation. (2011)1 on quality and safety assurance requirements for
medicinal products prepared in pharmacies for the special 35.5.5 PIC/S GPP Guide
needs of patients [5]. The aim of this resolution is “to set a
standard for national requirements for quality and safety The Guide to good practices for the preparation of medicinal
assurance for pharmacy preparation in community and hos- products in healthcare establishments (PIC/S-GPP Guide)
pital pharmacies.” It mentions many levels of pharmacy [6] was published in 2008. It states: “the basic requirements
preparation: from industrial manufacturing of unlicensed presented in this Guide apply to the preparation of medicinal
medicines to extemporaneous preparation for a single products normally performed by healthcare establishments
patient and reconstitution on the wards. for direct supply to patients.”
For the quality management system of the preparation
process, reference is made to the GMP and the PIC/s GPP,
The PIC/S is a global organisation that is committed to
the PIC/S seen as ‘GMP light’ (see Sect. 35.5.5). The choice
harmonisation and mutual recognition of the
between these should be determined by a risk assessment
inspections of various countries. It publishes inspec-
that has to include the scale of preparation.
tion guides, which can serve as guidance to inspections
by National Authorities. One of these guides is the
The Resolution states: “All pharmacy-prepared medic- GMP guide:
inal products should be prepared using an appropriate PE 009-10 Guide to good manufacturing practice
quality assurance system. Before preparation, a risk for medicinal products – Part I (2013); Part II
assessment should always be carried out in order to (2013); Annexes (2013). The content of this guide
define the level of the quality assurance system which resembles, more or less, European GMP, except for a
should be applied to the preparation of the medicinal few definitions.
product. It is recommended that the PIC/S GPP Guide Furthermore, PIC/S publishes recommendations
be used for an appropriate quality system for “low-risk regarding various GMP topics. Examples are
preparations” and that the GMP Guide be used as a • Recommendations on general aspects of validation
reference for “high-risk preparations”. The application (PI 006-3)
of other guidelines with an equivalent quality level is • Recommendations on the validation of aseptic pro-
possible, depending on the national legislation or cesses (PI 007-4).
guidance.”
It is considered as a GMP for pharmacy preparation, has a
If the pharmacist however has to assess which products GMP-like structure and starts from the same principles. It is
PRODUCTION
are ‘less critical’ he may as well use the GMP principles as easier to read than the GMP because details not referring to
starting point. These principles are valid for any sort of pharmacy preparation are left out. Deviations from GMP
preparation; they just have to be detailed and specified (for instance in Annex 1 on Sterile Preparation) are however
(by a risk assessment, see Sect. 21.6.3) for any pharmacy not explained. It was developed before the CoE Resolution
preparation situation. (Sect. 35.5.4), which refers to it, or the Ph. Eur. monograph
For the quality management of therapeutic assessment (Sect. 35.5.3). The Resolution limits the use of PIC/S GPP to
of the physician’s request and formulation design (two ‘less critical products’.
other processes of pharmacy preparation’s life cycle), no The PIC/S GPP Guide approaches pharmacy preparation
reference is made other than to professional responsibility from an industrial production process perspective, only mar-
and education. In this way, the Resolution (and thus its ginally acknowledging specific qualities of the preparation
example model for a risk assessment) is rather unbalanced, process in pharmacies. Only a differentiation based on scale
because too much is focussed on the preparation process is made: between extemporaneous and stock production.
itself. GPP touches upon the processes: assessment of the
The Resolution seems valuable as a starting point for physician’s prescription or formulation design in the Docu-
further standards, and will play its role in complicated mentation paragraph: “a pharmaceutical assessment of ther-
legal discussions about how to regulate large-scale prepara- apeutic rationale, safety data, toxicity, biopharmaceutical
tion of unlicensed medicines. However because its risk aspects, stability and product design should be carried out,
assessment procedure is not covering therapeutic qualities before preparation takes place.” No further details are
and formulation design, it may not lead to the best way to established however.
assure the quality of patient medication. The Ph. Eur. mono- So from a quality system viewpoint the PIC/S GPP can
graph (Sect. 35.5.3) puts the different aspects in better only be used for quality of the preparation process, not for
balance. prescription assessment or design of formulation.
35.5.6 Professional Guidelines 35.5.6.2 USP Compounding Standards

USP being a private company, USP standards can be consid-
35.5.6.1 European Professional Guidelines ered as professional guidelines. Their ‘compounding
The results of an enquiry in 2009 by EDQM [7] highlight standards’ [13] consist of the following chapters:
that most European countries have professional guidelines <797> Pharmaceutical Compounding—Sterile
for pharmacy preparation. Most of them only give a global Preparations
description. Only some of them include the therapeutic <795> Pharmaceutical Compounding—Non sterile
rationale and pharmacovigilance. This situation might have Preparations
been improved in the meantime. <1160> Pharmaceutical Calculations in Prescription
Professional guidelines to be mentioned: Compounding
• Referenzsystem Qualität für Spitalapotheken (in German <1163> Quality Assurance in Pharmaceutical
and French) [8], a Swiss PQS for hospital pharmacies. It Compounding
is compatible with the ISO 9001 methodology, see also <1176> Prescription Balances & Volumetric Apparatus
Sect. 35.7.6. The General Chapter <1163> Quality Assurance in
• ADKA guidelines from the German Society of German Pharmaceutical Compounding [14] describes a quality
Hospital Pharmacists (ADKA) (in German): assurance program as “a system of steps and actions that
– Preparation and quality control in hospital pharmacy must be taken to ensure the maintenance of proper standards
(2005) [9]. in compounded preparations”. It consists of following
– Aseptic preparation and quality control of ready-to- sections:
administer parenterals (2012) [10]. • Training
• GMP-H(ospital pharmacy) from the Dutch Society of • Standard operating procedures
Hospital Pharmacists NVZA, The Netherlands • Documentation
(in Dutch), contains the interpretation of GMP guidelines • Verification
and Addenda on Formulation and Preparation method • Testing
design, Extemporaneous preparation, Aseptic handling • Cleaning, disinfecting and safety
and Occupational Health and Safety [11]. • Containers, packaging, repackaging, labelling and
• UK Guideline on the Quality Assurance of Aseptic Prep- storage
aration Services by the Regional Quality Control • Outsourcing
Pharmacist’s Committee [12]. • Responsible personnel
The accessibility of these professional guidelines for the Through the section Standard operating procedures several
international reader may be limited because of the language. processes are mentioned, though not further detailed, such as:
• Compounding methods
• Environmental quality and maintenance
As none of the European regulations or models yet
• Equipment maintenance, calibration and operation
cover the complete process of pharmacy preparation,
• Formulation development
European professional guidelines may still be very
• Quality assurance and continuous quality monitoring
welcome as an elaboration of the Ph. Eur. monograph.
etcetera
Such guidelines should cover as said all main pro-
Through chapters <795> and <797>, many of these
cesses and pay attention to specific preparation pro-
sections and SOPs can be detailed. For instance chapter
cesses in pharmacies such as:
795 [15] has among others the following sections:
• Adapting licensed medicines (see Sect. 5.5.1)
• Categories of Compounding, giving criteria for
• Aseptic handling (see Chap. 31)
classifying preparations into simple, moderate or com-
• Extemporaneous preparation from raw materials
plex, or in other words to enable risk assessment for
(see Sect. 33.5)
whether or not to compound a specific medicine
• Preparation in non-dedicated rooms (see chapter
• Responsibilities of the compounder, also containing ten
Premises)
general principles of compounding
• Conditional release (see Sect. 34.9.3)
• Compounding process, giving all steps from the prescrip-
• Validation of small batches (see Sect. 34.14.3)
tion assessment until instruction of the patient or caregiver
• Compounding facilities
• Compounding equipment aspects a manufacturer should take into account when

• Component selection, handling, and storage implementing the principle.
• Stability criteria and beyond-use dating Some detailed GMP guidelines may only be applicable to
• Packaging and drug preparation containers specific (industrial) production processes. GMP principles
• Compounding documentation are however generally valid, also for pharmacy
• Quality control preparation [17].
• Patient counselling EU GMP contains no guidelines about the design phase,
• Training because that part of development of medicines belongs to the
This Standard has no clear relation to EU GMP but gives authorisation process. Volume 3 of the Rules gives some
attention to three processes of pharmacy preparation: pre- directions for the design (see also Sect. 35.4.3).
scription assessment, design of formulation and preparation
process. It might be useful for structuring a quality system 35.5.7.2 Other GMPs
for pharmacy preparation (see Sect. 35.7.6). Other GMPs that may be relevant for European pharmacists
are the US-GMP created by the FDA [18] and the
WHO-GMP [19]. The latter may act as a basis for countries
35.5.7 Good Manufacturing Practice (GMP) that lack own GMP legislation. There is a global
harmonisation activity of GMPs through the Pharmaceutical
35.5.7.1 EU GMP Inspection Convention and Pharmaceutical Inspection
EU GMP guidelines are located in Volume 4 of the Rules Co-operation Scheme [20].
[16]. This Volume is also called the current GMP (c-GMP).
Compliance with c-GMP is a prerequisite for a
manufacturing authorisation. Compliance is assessed by 35.5.8 Site Master File
the Competent Authority.
Volume 4 consists mainly of the basic legislation, three A Site Master File (SMF) gives a concise overview of the
Parts and Annexes: current manufacturer’s situation and is required as a public
• Part I – Basic Requirements for Medicinal Products – document for the Inspectorate to give to other Agencies,
discusses the requirements with which the production of when requested. It is mentioned in Part III of EU-GMP
a licensed medicinal product should comply. (see Sect. 35.5.7). It includes some identical elements as
• Part II – Basic Requirements for Active Substances used the Quality manual (Sect. 35.6.1). Table 35.2 shows the
abbreviated contents.
PRODUCTION
as Starting Materials – deals with the requirements for
active substances that are used as starting materials in The site master file describes both practical aspects, such
medicinal products. These substances are referred to as as the address and the location of buildings, and quality
active pharmaceutical ingredients (APIs). aspects. For elaborate contents reference is made to the
• Part III – GMP related documents – contains documents relevant PIC/S inspection guide [21]. The sequence of
such as Site Master File (Sect. 35.5.8) and ICH Q10 aspects is the same as in the GMP and also matches the
(Sect. 35.5.9). The aim of Part III is “to clarify regulatory form that a manufacturer should fill to obtain a
expectations and it should be viewed as a source of manufacturing licence.
information on current best practices.”
• Annexes, elaborating on topics mentioned in the chapters
of Part I. 35.5.9 ICH Guidelines Q8, Q9 and Q10
GMP contains instructions on the setup of the quality man-
agement system (Chap. 1), on preconditions such as the ICH Guidelines are the result of global harmonisation in
premises, and on the actual production process at a detailed medicines manufacturing. Q8, Q9 and Q10 are getting
level, as seen in Chap. 5 Production, and Annex 1 Manufac- internalised in regional or national regulations and quality
ture of Sterile Medicinal Products. Table 35.1 depicts the standards. Although created for the production of licensed
detailed contents of Parts and Annexes of EU c-GMP. The medicines, they can be helpful for structuring PQS for phar-
chapters and annexes of the GMP are regularly revised and macy preparation as well.
complemented.
The chapters of part I of the GMP are headed by the main 35.5.9.1 ICH Q8
principle for the part of the production process with which ICH guideline Q8 (Pharmaceutical development) is also
the chapter deals. The body of the chapters describes the called Quality by Design (QbD) and it guides how to build
Table 35.1 Contents of c-GMP in force at July 2014 Table 35.2 Abbreviated Site Master File Structure
Introduction Site master file – content
Commission Directive 2003/94/EC, of 8 October 2003, laying down 1 General information on the manufacturer
the principles and guidelines of good manufacturing practice in respect Contact information
of medicinal products for human use and investigational medicinal Authorised pharmaceutical manufacturing activities of the site
products for human use
Any other manufacturing activities carried out on the site
Chapters part I
2 Quality management system of the manufacturer
1 Pharmaceutical quality system
The quality management system of the manufacturer
2 Personnel
Release procedure of finished products
3 Premises and equipment
Management of suppliers and contractors
4 Documentation
Quality Risk Management (QRM)
5 Production
Product quality reviews
6 Quality control
3 Personnel
7 Outsourced activities
Organisation chart showing the arrangements for quality
8 Complaints and product recall management, production and quality control including senior
9 Self inspection management and Qualified Person(s)
Chapters part II Number of employees and their functions
1 Basic requirements for active substances used as starting materials 4 Premises and equipment
Chapters part III Premises (site, buildings, lay outs and flow charts of production
Site master file areas, warehouses and storage areas)
Q9 quality risk management Equipment (for production and laboratory, cleaning and
Q10 note for guidance on pharmaceutical quality system sanitation, GMP critical computer systems)
MRA batch certificate 5 Documentation
Template for the ‘written confirmation’ for active substances 6 Production
exported to the European Union for medicinal products for human Type of products
use Process validation
Annexes Material management and warehousing
1 Manufacture of sterile medicinal products 7 Quality control (in terms of physical, chemical, and microbiological
2 Manufacture of biological active substances and medicinal and biological testing)
products for human use 8 Distribution, complaints, product defects and recalls
3 Manufacture of radiopharmaceuticals Distribution
4 Manufacture of veterinary medicinal products other than Complaints, product defects and recalls
immunological veterinary medicinal products 9 Self Inspections (self inspection system, criteria used for selection
5 Manufacture of immunological veterinary medicinal products of the areas to be covered)
6 Manufacture of medicinal gases Appendices with lists, charts and schemes
7 Manufacture of herbal medicinal products
8 Sampling of starting and packaging materials
9 Manufacture of liquids, creams and ointments importance of meeting patient requirements. A control strat-
10 Manufacture of pressurised metered dose aerosol preparations for egy needs to be defined and in-process controls planned
inhalation correspondingly in connection with the design of the prepa-
11 Computerised systems ration. Quality by design is further dealt with in Chap. 17
12 Use of ionising radiation in the manufacture of medicinal products Product design.
13 Manufacture of investigational medicinal products Q8 may contribute to a structure for the PQS part on the
14 Manufacture of products derived from human blood or human design of pharmacy preparations (see Sect. 35.7.6), for its
plasma
contents are grouped as:
15 Qualification and validation
• Components of the drug product (active substance,
16 Certification by a qualified person and batch release
excipients)
17 Parametric release
19 Reference and retention samples
• Medicinal product (formulation development, overages,
Glossary
physico-chemical and biological properties)
• Manufacturing process development
• Container closure system
quality into the design of the formulation and the preparation • Microbiological attributes
process. QbD starts when the need for a therapeutic product • Compatibility
emerges, for example, due to a particular clinical problem Q8 is adopted as a Note for Guidance, so for creating an
(‘target product quality profile’) and thereby stresses the application for authorisation, by the EMA/CHMP [22].
35.5.9.2 ICH Q9 Qualified Person. So a hospital pharmacy needs a QP (see

ICH Q9 Quality Risk Management provides principles and Sect. 25.3.4) for this functionality.
examples of tools for quality risk management that can be Every IMP has to be accompanied by an Investigational
applied to different aspects of pharmaceutical quality, most Medicinal Product Dossier (IMPD). Drafting an IMPD is
of them directed to complex manufacturing situations. It is less laborious than a full dossier but requires pharmaceutical
included in Part III of current GMP (see Sect. 35.5.7). It is expertise and knowledge of the mentioned elaborated
further dealt with in Chap. 21 Quality Risk Management. regulations. In hospitals, medical researchers are generally
not trained in drafting an IMPD independently, but
pharmacists are. A hastily drafted research may prove use-
35.5.9.3 ICH Q10
less when the quality characteristics and controls of the
Although the ICH guideline Q10 strictly speaking only aims
product have not been thoroughly investigated or
to serve as a model for a PQS, in practice it serves as a
documented. Pharmacists are also faced with judgement of
standard for it as well, by mentioning many elements that are
IMPDs and the extent of GMP compliance of a trial
considered necessary. Q10 is included in part III of current
preparation.
GMP (see Sect. 35.5.7).
Most hospital pharmacists don’t produce IMPs but have
The ICH Q10 guideline is developed as a PQS model for
to supervise the clinical investigations with IMPs in the
the whole life cycle of an industrially made product. It
hospital.
therefore starts with the design phase of the product and
ends with product discontinuation. It does not include how-
ever the very first step: the therapeutic issues (prescription
35.6 Elements of a PQS
assessment, benefit/risk balance) which are relevant for
pharmacy preparations.
This section is about common elements of a PQS, with focus
on pharmacy preparation as a process and community and
hospital pharmacies as the organisations. For industrial pro-
35.5.10 Investigational Medicines duction the same principles are valid but more elaborate
literature exists. Most elements are common to any Quality
Investigational Medicinal Products (IMPs) are not Management System and are for instance described and
medicines and the subjects are not patients. The purpose of structured in ISO 9001 (see Sect. 35.7.2). Some elements
IMPs is not to treat a disease but to experiment with a are closely related and are therefore seen as pharmaceutical
product to discover if it would treat a disease. quality subsystems. They are combined in one subsection,
PRODUCTION
The legislation on Investigational Medicinal Products for instance internal audits, inspection and external audits
(IMPs) is described in Volume 10 of the Rules [23]. It
consists of six chapters, each containing several documents
that are regularly updated: 35.6.1 Quality Manual
1. Application and Application Form
2. Safety Reporting A quality manual is a written representation of the quality
3. Quality of the Investigational Medicinal Product management system. The making of a quality manual in the
4. Inspections pharmacy usually starts with the establishment of work
5. Additional Information instructions and operating procedures, such as preparation
6. Legislation protocols, analysis protocols and clothing instructions. The
GMP annex 13 Investigational Medicinal Products applies description of more general activities, such as the assess-
GMP to the manufacture of IMPs. Separate legislation for ment of a request for a preparation, installing new equip-
IMPs as compared with medicines warrant their specific ment, or handling of a complaint is usually done in a later
position. The formulation of the product may change during phase. However, especially those descriptions contribute to
the trial. Blinding is often required which introduces the the structure of the manual and are the starting point for
risk of mix-up. The preparation or reconstitution process improvements and risk assessments.
is not routine yet. Extra securities on the preparation are A quality manual contains at least a description of:
necessary not only to protect the subject, but also to prevent • The quality policy.
differences between batches or improperly documented • The scope of the PQS.
batches. • The PQS processes, as well as their sequences, linkages
Production of Investigational Medicinal Products needs a and interdependencies. Process maps and flow charts can
manufacturing license. This brings about compliance with be useful tools for clarifying pharmaceutical quality sys-
GMP, for the dosage forms involved and the availability of a tem processes in a visual manner.
• The organisation (organisational chart, management purposes of a QMS: the support of development and
responsibilities). improvement, and of QbD by supporting the understanding.
• The facilities, such as premises and equipment.
• Furthermore, procedures and work instructions can be a 35.6.2.2 Knowledge Management
part of the manual. Knowledge management is seen by ICH Q10 (see
The establishment of a quality manual can cover: Sect. 35.7.4) as an “enabler” of a QMS. The description by
• A part of or a department of the organisation Q10 includes much of what is defined under documentation
• A standard that should be adhered to (see above), such as: “(. . ..) of development activities using
• The entire organisation scientific approaches provide knowledge for product and
A disadvantage of a manual for each department is, when process understanding. Sources of knowledge include, but
multiple departments of the same (pharmacy) organisation are not limited to prior knowledge (public domain or inter-
are described in this way, this usually leads to double nally documented); pharmaceutical development studies;
descriptions and indistinctness about relationships between technology transfer activities; process validation studies
departments. over the product life cycle; manufacturing experience;
Establishment of a quality manual according to the innovation; continual improvement; and change manage-
requirements of a standard has the disadvantage that the ment activities.”
manual usually does not complies when the organisation For pharmacy preparation external sources are very
should also adhere with another standard. Actually, a PQS, important, such as formularies, standards and reference
and thus a quality manual, including the preparation works. Keeping up with updates of those sources is essential
activities as well as the clinical processes of a pharmacy is and needs its own procedures. Some sources or institutions,
not easy to structure. See further Sect. 35.7 for possible such as EDQM, already offer the possibility of getting
solutions and Sect. 35.7.5 for a practice advice when work- notices by mail, but this is not yet the case with, for instance,
ing with the 7 Pillars model. GMP guidelines.
The descriptions in the quality manual should be concise
to keep the manual manageable. When the descriptions are
too extensive and detailed, it is difficult to obtain a uniform
35.6.3 Management Responsibility
document in the available time. Moreover, its maintenance
and Commitment
requires much more time.
GMP defines in Chap. 1 the responsibilities of Senior Man-
agement in a Quality System. It states that “Senior manage-
35.6.2 Documentation and Knowledge ment has the ultimate responsibility to ensure an effective
Management Pharmaceutical Quality System is in place, adequately
resourced and that roles, responsibilities, and authorities
35.6.2.1 Documentation are defined, communicated and implemented throughout
Documentation is the total of written quality manual, the organisation. Senior management’s leadership and active
procedures, instructions, dossiers, records, etcetera. Docu- participation in the Pharmaceutical Quality System is essen-
mentation provides knowledge and work agreements, which tial. This leadership should ensure the support and commit-
thereby becomes transferable between employees. It ment of staff at all levels and sites within the organisation to
supports uniformity of procedures, which reduces the chance the Pharmaceutical Quality System.”
on deviations in processes and thus in the end product. For These responsibilities are further elaborated on in Q10 by
documentation, and especially for its maintenance, stating that Senior management has the ultimate responsibil-
agreements should be made to prevent the current practice ity to achieve the quality objectives. Management should
from deviating from the documented system before revision. participate in the design, implementation, monitoring and
See also Chap. 33 Documentation. maintenance of an effective pharmaceutical quality system,
Many documents, often dossiers or files, will contain define individual and collective roles, responsibilities,
knowledge and explanation about backgrounds of the design authorities and inter-relationships of all organisational
of the formulation and the preparation method, or of units related to the pharmaceutical quality system.
procedures. As soon as a PQS has been created all changes In terms of an industry whose sole purpose is the manu-
in the system should be documented: through change-logs. facture of pharmaceuticals it is obvious that Senior Manage-
These will contain knowledge that can be very useful for ment is at Board level of the organisation. This is not so
future actions and decisions. It serves one of the principal obvious in the case of hospitals where the focus of top
management may be concentrated elsewhere. Nevertheless • Evaluation of the state of facilities, equipment and
the Board is where decisions on finances, staff numbers and systems
premises will be made. The Board will also hold a ‘Corpo- • Review of the (local) PQS: inspections from authorities,
rate liability’ for everything that happens in the organisation. internal audits, needs for corrective actions in relation to
There will be a delegation of some roles and responsibilities documents in the PQS systems, issues related to
to Department level. Nevertheless the Board must be outsourced activities
informed of the principals of the QMS implemented in the • Quality related projects and changes
pharmacy to fulfil their responsibilities. Contacts for recalls In a hospital pharmacy QMR meetings may be held 1–2
etc. are often delegated to the Pharmacy Department. The times a year. Participants may be Senior management
involvement of the Board in the Pharmacy systems will together with management representatives from Production,
ensure a commitment and understanding necessary for the Laboratories and other relevant departments. If a QP is part
future improvement of the pharmacy. of the organisation this person may host the meetings.
The EU Directive [3] introduced the concept of an indi- Minutes from the meetings are available for participants
vidual taking responsibility for releasing a batch of product and also for inspectors on request.
to market. This position, unique to Europe, is defined by the
Qualified Person. This individual has to take decisions inde-
pendent from the Board. The role is further elaborated on in
35.6.5 Quality Policy, Quality Plans, Quality
the Guide to GMP (see also Sect. 25.3.4). This role is only
Objectives
defined for products with a Marketing Authorisation and
Investigational Medical Products. However the function is
Quality policy is the choice of an organisation regarding
equally applicable to preparations made by the pharmacist.
quality management, usually described in terms of concrete,
Pharmacies should nominate a person, independent of the
measurable and time-dependent objectives. The quality pol-
preparation function, to be responsible for the release of the
icy, which the senior management drafts in general terms
preparation.
and for a prolonged period of time, should always be
accompanied with a quality plan and quality objectives.
These are valid for a limited period of time, for example
for a year. When this period ends, the management should
35.6.4 Management Review
perform an evaluation, which results in new quality plans
and quality objectives. To be able to perform an evaluation,
A management review reflects the governance of the
PRODUCTION
the quality objectives should be Specific, Measurable,
senior management and it reports on suitability and effec-
Acceptable, Realistic and Time bound (SMART).
tiveness of the QMS. It also shows how senior management
has dealt with reviews of the performances of processes.
Management reviews should provide assurance that process For pharmacy preparation quality policy may be
performance and product quality are managed over the life formulated such as: “in the next five years, both the
cycle. quality and the efficacy of the preparations will be
Depending on the size and complexity of the company, improved.”
management review can be a series of reviews at various The accompanying quality year plan could then
levels of management and should include a timely and state: “this year, non-standardised dermatological
effective communication and escalation process to raise preparations will be reduced by 20 %, either by
appropriate quality issues to senior levels of management standardisation or by providing alternatives.”
for review [24]. They are very valuable especially when
looking at trends for several ongoing years. Some persistent
problems or slowly developing negative trends may require
senior management actions.
An example of items to be discussed when having a 35.6.6 Resources
Quality Management Review (QMR):
• Status regarding actions from last Management Review In a quality management system ‘resources’ apply to human
• Presentation and discussion of key performance resources, financial resources, materials, premises and
indicators in relation to product quality, such as recalls, equipment.
complaints and adverse events, non-conformities, out of The description of organisation, processes, premises and
specifications (OOSs), any conclusions from product equipment is necessary to get an overview and is usually the
quality reviews, rejections first that is done when a quality management system is
drafted. New employees can be informed this way and are 35.6.8 Quality Risk Management
trained to work according to the same procedures.
A hierarchic overview of departments and functionaries Quality Risk Management (QRM) is seen as a systematic
(organisational chart, see Sect. 25.2.4) is the basis for the process for the assessment, control, communication and
description of human resources of an organisation. Tasks, review of risks to the quality of the medicinal product.
responsibilities, competences and required qualifications are Risk management is, whether explicitly or not, used in
specified in a function description. An employee description almost all phases of quality management processes. It is
entails the true competences and qualifications of an dealt with in a separate chapter in this book (Chap. 21).
employee, including the development of the employee by ICH Q10 sees QRM as an ‘enabler’ for the PQS.
training and other activities. (see Sect. 25.5.1).
Premises, equipment and systems most often are
described in a Validation Master Plan (VMP, see Sect. 35.6.9 Quality Characteristics and Quality
34.11) part of the PQS and are consequently subject to Requirements
change control. The VMP has to include a summary of the
facilities, systems, equipment, processes on site and the The intended quality level is determined by quality
current validation status. A Site Master File (see standards, see Sect. 35.5. Those are point of departure and
Sect. 35.5.8) includes more detailed description of facilities, will be supplemented continuously by results from the
equipment and systems. If a Site Master File is available the handling of non-conformities (see Sect. 35.6.13) and from
VMP may simply refer hereto and only add policy and validation (see Sect. 34.10) as well as from the change
instructions related to the validation activities. management process (Sect. 35.6.10).
For pharmaceutical preparations the Ph. Eur. (see
Sect. 35.5.3) considers the following quality characteristics
required to obtain a product that has “an appropriate product
35.6.7 Product Realisation, Product Design quality, is suitable and fit for its purpose”:
• Efficiency, effectiveness, safety
The design of a new medicine (or health care service) has to • Quality of active substances, excipients and containers
be planned and controlled. It is reasonable to lay down the • Good design of the preparation process
elements of that process in the PQS. • Significant testing
The element Product Realisation of ISO 9001/EN 15224 • Stability of the preparation
(see Sect. 35.7.2) specifies: From the viewpoint of health care by pharmacies some
• Design and development stages additional quality characteristics may be taken into account:
• Approaches for risk assessment in each stage availability, continuity of care, timeliness. Those
• Review, verification and validation that are appropriate to characteristics are mentioned by ISO 9001/EN 15224 (see
each design and development stage Sect. 35.7.2) and identified as ‘inherent characteristics’ for
• Responsibilities and authorities for design and the quality of healthcare services. They may however con-
development flict with the usual characteristics for product quality.
In pharmacy preparation the very first step of Product Conflicts are easy to be imagined between for instance:
realisation is the prescription assessment for an individual • Timeliness and significant testing, or
patient or the benefit/risk assessment (and definition of • Availability and good design of the preparation process
indications) for a stock preparation. See Sect. 2.2 for the Which characteristics are most important in particular
performance of this step and for the assignment of situations has to be the professional decision of the pharma-
responsibilities. cist who performs a risk assessment (see Sect. 2.2). Keeping
ISO 9001/EN 15224 further points to sub-elements a record of those decisions is essential.
such as: Quality requirements can be seen as elaborations of qual-
• Quality characteristics (for setting specifications) (see ity characteristics. They are dealt with in Chap. 32.
Sect. 35.6.9)
• Change management (see Sect. 35.6.10)
• Product quality review (see Sect. 35.6.11) 35.6.10 Change Management, Change Control
The design of a product does not end as soon as the first
batch has been produced or the first version of a service has Change management includes the evaluation of proposed
been provided. It continues during the whole life cycle, thus changes, the attendance of the implementation and the eval-
includes the discontinuation of the product or the healthcare uation of it. The importance of change control for the PQS is
service. More about that process in Chap. 17 Product design. reflected in GMP Chap. 1 (see Sect. 35.7.3) and also in other
GMP sections such as Annex 15, as well as in ICH Q10 35.6.12 Internal Audits, Inspection, External
Sect. 3.1.3. Audits
GMP 1 states: “A Pharmaceutical Quality System appro-
priate for the manufacture of medicinal products should This combination of elements is seen as a pharmaceutical
ensure that: (. . ...) (xiii) After implementation of any change, quality subsystem. Auditing gives the opportunity for feed-
an evaluation is undertaken to confirm the quality objectives back, adjustment, and thereby optimisation. Auditing is the
were achieved and that there was no unintended deleterious ‘check’ phase in the PDCA-cycle (see Fig. 35.1); it
impact on product quality”. contributes to the cyclic character of quality management:
Change management with pharmacy preparation also a situation of continuous improvement. The relevant types of
includes any change of therapeutic risk/benefit ratio (see auditing are: the internal audit, management review and
Sect. 35.4.2), of formulation or of specifications. certification/accreditation. Management review has been
The basic understanding is that every change potentially discussed in Sect. 35.6.4. Inspection is dealt with as a type
increases the risk for errors and unexpected consequences, of external auditing.
so an increased risk for patients. If the handling of changes is
structured (Change control) the risks of changes will be
35.6.12.1 Internal Audit
diminished. Change management also supports the involve-
During an internal audit or self-inspection, trained
ment of the right professionals.
employees of the organisation check the functioning of the
It should not be forgotten that also changes in the PQS
quality system. They may use structured questions and
have to be subject for change control.
checklists with which they compare the information in the
quality manual and connected procedures with the actual
situation. An experienced auditor will also use a more intui-
35.6.11 Product Quality Review tive approach for instance getting information about (lack
of) cooperation between sections or departments, exploring
The quality of the design has to be monitored, with help of a peculiarities or interviewing staff. When discrepancies are
regular review of results of analysis, complaints, recalls found, they will usually be classified as critical, important or
etcetera. In order to frame that activity into the PQS, the minor. Subsequently corrective or preventive measures (see
term ‘Product quality review’ is used. GMP Chap. 1 Sect. 35.6.15) should be taken to adapt the actual methods or
emphasises the importance of product evaluation: an annual the documentation in order to make them match again.
evaluation of product quality for every product, and a risk Internal audits can be performed according GMP Chap. 9
analysis as well. A Product Quality Review has “the objec-
PRODUCTION
Self Inspection. This chapter points at examination of per-
tive of verifying the consistency of the existing process, the sonnel matters, premises, equipment, documentation, pro-
appropriateness of current specifications for both starting duction, quality control, distribution of the products,
materials and finished product, to highlight any trends and arrangements for dealing with complaints and recalls, and
to identify product and process improvements”. . . ... self-inspection.
Well-known elements of a Product quality review are Common elements of the production processes that are
(see also GMP Chap. 1): eligible for internal audits may be:
• Trend analyses • Involvement of the senior management
• Stability monitoring • Training of staff
• Retrospective validation • Facilities (gases, water, air, premises, maintenance,
• Supply chain traceability of active substances cleaning)
• Critical in-process controls and finished product results • Reporting within the organisation
• Deviations or non-conformities and the effectiveness of • Organisation of decision-making
the subsequent corrective and preventive actions • Corporate culture to recognise commitment of employees
• Quality-related returns, complaints and recalls • Design of procedures and demonstrability of following
• Qualification status of relevant equipment and utilities, them correctly
e.g. HVAC, water, compressed gases, etc. • Progress in handling of deviations
Product quality reviews may be grouped by product type, • Consistency of computer systems
e.g. solid dosage forms, liquid dosage forms, sterile • Follow-up of improvements, which in the case of prior
products, etc. where scientifically justified. This is an appro- audits have been required
priate approach for a quality review of non-standardised Internal audits are usually conducted according to a
pharmacy preparations, see also Sect. 34.14.3. prearranged programme, which should leave room for
ad-hoc audits due to complaints or due to the implementa-

tion of a large change. General monitoring entails inspections without a
The frequency of internal audits should be the highest for specific cause. They are performed to gain insight
the most critical processes. A risk assessment, focussed on into the general quality level and quality control of
the risk for the patient, can be used to put processes in an pharmacies, including the preparation unit. For gen-
order of criticality. In hospital pharmacies the preparation of eral inspections a set of performance indicators is
parenterals is generally seen as having the highest risk. For a used. A performance indicator is defined as a measur-
large medicines preparation department in a hospital phar- ing point that gives a good indication about the func-
macy, frequencies may be set at: tioning of a process. Examples of performance
Once a year: indicators are:
• Aseptic handling and preparation • The time that a complaint is open
• Processes with doubtful track records (non-conformities • The time that is taken up by adjusting the process
in internal audits or related to inspections) • Number of recall procedures.
Every 2 years: And specifically for preparation in pharmacies:
• Quality Control • The number of preparations produced without an
• Production of parenterals approved preparation protocol
• Quality Management • The number of stock preparation without a product
• Other production processes file
Every 3 years: • The ratio between non-standardised and standard
• Other departments, entities and processes preparations
Plans for internal audits are revised regularly, for instance Performance indicators can help management or exter-
biannually. Quality management reviews will include moni- nal auditors to roughly get an insight into the function-
toring of audit outcomes and may consider whether audit ing of the quality system.
frequencies are appropriate. Phased monitoring is inspection focussed on
Some additional suggestions for the performance of the locations with the highest risks for irresponsible care.
internal audit are: The latter methodology consists of three phases:
• The audit is preferably performed by persons not directly • Gathering quality data, analysis, and reporting from
involved in the subject. all institutions
• Results of the self-inspection must be justified through a • Further investigation at specific institutions, assess-
protocol and reported to the senior management or the ment, and decision on measures
head of Quality Management. • Administrative sanctions, tracing, and prosecution
• If corrections of the subject of the audit prove to be Within the context of phased monitoring, the
necessary, the corrective action must be documented inspectors request annual information on the quality
along with a deadline and the name of the department or of care from healthcare providers. For application of
person who is responsible for corrective or preventive phased monitoring it is important that the
action. professionals have knowledge of the extent in which
• The self-inspection is completed only after the auditor they adhere to regulatory and professional standards.
has reviewed and approved the corrective or preventive
action.
For the preparation of licensed medicines and preparations
for clinical trials, an inspection is always performed because
35.6.12.2 Inspection the provision of a manufacturing license requires it.
Any institution or company that is preparing medicines will
be inspected by the relevant regulatory Competent
When after one or more audits the inspected
Authority.
organisation does not comply with the standards and
shows insufficient improvement, the Inspection Team
In the Netherlands, for instance, the Healthcare may advice to put the organisation under “increased
Inspectorate monitors the organisation and the quality monitoring”. This is a severe type of monitoring that
and safety of all provided care. It uses general moni- often precedes enforcement measures such as
toring, but apart from that, phased monitoring imposing an administrative fine, requesting the Minis-
becomes more prominent. ter for an instruction, or imposing a sanction. In the
Netherlands the Inspectorate publishes cases of professional pharmaceutical body or a certification

increased monitoring on its website, including the organisation.
inspection reports.
The frequency and scope of audits of production sites by

the Inspectorate may be determined by taking into account, 35.6.13 Non-conformities (Deviations
according to one of the illustrations at ICH Q9 [25]: and Complaints)
• Existing legal requirements
• Overall compliance status and history of the company Non-conformity means that a requirement is not fulfilled.
• Robustness of a company’s quality risk management Non-conformities can occur related to any of the quality
activities characteristics and its related quality objectives.
• Complexity of the site, manufacturing process, product Non-conformities may refer to defects, mistakes and errors
and its therapeutic significance in processes, violations and deviations of regulations or
• Compliance status and history procedures, problems with equipment, customer complaints,
• Results of previous audits/inspections etcetera. Near misses, incidents and adverse events in clini-
• Number and significance of quality defects (e.g. recall) cal or occupational health context can be treated as
• Major changes of building, equipment, processes, key non-conformities concerning patient or employee safety.
personnel In a pharmaceutical production environment non-
• Experience with manufacturing of a product (e.g. fre- conformities are usually called ‘deviations’. In production
quency, volume, number of batches) of pharmaceutical preparations planned deviations are com-
• Test results of official control laboratories monly distinguished from unplanned deviations.
Planned deviations are a foreseen result of a planned and
documented temporarily event such as using the appropriate
35.6.12.3 External Audits and Certification
type of filter while the batch preparation instruction
In some countries community and hospital pharmacies may
mentions an alternative one. An unplanned deviation, such
opt for external audits by independent quality institutions
as a content of 115 %, is unexpected and requires investiga-
which may lead to certification. Such an external audit may
tion of the root cause, next to an assessment of the quality
be required by stakeholders, such as their patients or health
consequences.
insurance companies, or in some situations pharmacies to
PRODUCTION
Complaints are non-conformities as well. Complaints
which their pharmacy preparations are supplied.
may originate from patients but may also be brought by
Certification is about confirmation of certain
one department to another. The pharmacy or company will
characteristics of the organisation to a standard. When exter-
also bring complaints to suppliers or starting materials, for
nal auditing institutions audit a pharmacy as an organisation,
instance.
they usually audit according to ISO 9001 or ISO 9001/EN
Deviations may be noticed within the organisation with-
15224 (see Sect. 35.7.2).
out leading to a defective product or service. In a less strictly
Manufacturers are, in addition to the Inspection’s audits,
organised situation such as a pharmacy, deviations may be
legally subjected to (external) audits from companies that
expected to be less noticed. In contrast patient’s complaints
have outsourced their activities to them. Auditing of
will, in pharmacies, come through quite quickly. Patients are
suppliers of starting materials by companies, pharmacies or
the end users and in fact ‘test’ each element of the batch, but
associations of pharmacists is also possible.
a patient complaint about a slightly deviating content is quite
unlikely.
In the Swiss ‘quality reference system’ RQS [8] (see Deviations and complaints can be classified into minor,
also Sect. 35.7.6) audits are performed by a certifica- major and critical. An example of a minor deviation in
tion expert together with a professional expert: a hos- preparation is a raw material for which one test for identity
pital pharmacist who has received extra audits fails, while another test undoubtedly determines the identity
training. The certification amounts to RQS as well of the active substance. A major deviation may be that the
as ISO. amount of active substance exceeds internal limits, is Out of
In Germany, as in several other European countries, Specification (OOS), for instance outside 95–105 %, while
all pharmacies must or are supposed to have a PQS. not exceeding the legal limits of 90–110 %. Moreover sta-
Certification is optional and can be performed by a bility testing of this medicine has demonstrated that within
the shelf life the content remains constant. A critical
(continued)
deviation means that the patient may be immediately at risk preventative actions (CAPAs) should be identified and taken in
for example due to the presence of unexpected degradation response to investigations. The effectiveness of such actions
should be monitored and assessed, in line with Quality Risk
products. Management principles.
The handling of non-conformities and the actual content
are to be included in product quality reviews and manage- Root-cause analysis (RCA) is meant to identify the root-
ment reviews. cause of an important incident, in order to be able to take
measures to prevent recurrence of the incident.
A standard method and a standard form is used to deter-
35.6.14 Recalls mine which incidents are severe enough to analyse. Three
questions are to be put:
When a pharmacy is faced with a recall it is usually related • What happened? (reconstruction)
to a defective licensed medicine. According to ISO 9001, a • How did this happen? (evaluation)
recall is considered to be a complaint and should be dealt • What measures can be taken to prevent recurrence?
with according the general complaint procedure. This also (prevention)
applies to complaints due to medicines prepared in the RCA has proven most effective when used for severe
pharmacy. incidents that occur relatively often of which the cause is
GMP Chap. 8 Complaints and Product Recall refers, for rather obvious.
licensed medicines, to legislation as the principle of a proce- For the structured over-all analysis of deviations the
dure to be followed in case of a potential defective product: Corrective And Preventive Action system (CAPA system)
“All complaints and other information concerning poten- can be used. This system means to document, analyse, solve,
tially defective products must be reviewed carefully and if possible prevent all problems and deviations. It uses
according to written procedures. In order to provide for all data from other quality assurance systems, such as:
contingencies, and in accordance with Article 117 of Direc- complaints, deviations, recalls, out of trend (OOT) and out
tive 2001/83/EC and Article 84 of Directive 2001/82/EC, a of specifications (OOS) data, notices from internal and exter-
system should be designed to recall, if necessary, promptly nal audits. By combining all these data in one system, a
and effectively products known or suspected to be defective better overview of confounding factors is obtained, which
from the market.” GMP is listing in Chap. 8 all actions that enables an organisation to address problems structurally and
have to be part of a recall procedure. prevent recurrence.
If a decision is made to recall, this must be executed after Either corrective actions can be taken: actions that restore
discussion with other staff, quality control laboratory, an actually occurred deviation, or preventive actions: actions
experts, board of directors and competent authority (this that prevent a potential deviation.
must be laid down in the complaints procedure), regarding A CAPA system does not only lead to quality improve-
the impact of the decision. ment, but also to fewer (product) errors and thus to cost
reduction. For the implementation of a CAPA system,
forms, a (excel) database, or even especially developed
software systems can be used.
35.6.15 Root Cause Analysis and Corrective
An appointed person controls the CAPA system and takes
and Preventive Action System
care of timely determination and execution of actions, and
thereby closing of pending problems. System actions that
The way in which Root Cause Analysis (RCA) and a Cor-
lead to structural changes should be evaluated following the
rective and preventive action system (CAPA) can be used to
change procedure, to establish the effects of the modification
improve quality is given by the statement from GMP Chap. 1
on other parts of the quality management system.
Pharmaceutical quality system:
A CAPA system only works properly when the system is
An appropriate level of root cause analysis should be applied carefully drafted. It should be clear what information should
during the investigation of deviations, suspected product defects
and should not be put into the system, to prevent soiling it
and other problems. This can be determined using Quality Risk
Management principles. In cases where the true root cause(s) of with irrelevant problems. Furthermore, it should be known
the issue cannot be determined, consideration should be given to who enters the data into the system, who is responsible for
identifying the most likely root cause(s) and to addressing those. solving pending deviations, and who checks the efficacy of
Where human error is suspected or identified as the cause, this
the system: if problems are solved within a predetermined
should be justified having taken care to ensure that process,
procedural or system based errors or problems have not been period of time, if recurrence of incidents is really
overlooked, if present. Appropriate corrective actions and/or prevented etc.
35.7 Structuring a PQS continual improvement, factual approach to decision

making, mutually beneficial supplier relationships.
35.7.1 Desire for Structuring The current ISO 9001 standard applies to quality
management systems for products and services, all
As said, in many pharmacies and even industries a pharma- kinds and in a universal sense; ISO 9001 is considered
ceutical quality system may have started with a list of tech- useful for services in health care as well.
nical SOPs. As a next step GMP (or PIC/S GPP) may have Specifying ISO 9001 for healthcare into ISO 9001/
been used to group SOPs in chapters and to add SOPs for EN 15224 has adjusted and specified the requirements
general quality activities. With a PQS developing, the num- for healthcare as well as the product concept and
ber of PQS elements can become considerable and the over- customer perspectives. Products in health care are
view may get lost. Clustering of the elements in sections and always trying to value the interactions between
a visual structure (diagram) may help. Using a diagram may patients (‘customers’), health care personnel,
stimulate the perception of quality management as a process, suppliers, insurers, industry and governmental bodies.
such as reflected by the Deming circle (Fig. 35.1) in its ISO 9001 states that a quality policy for products
simplest way. and services in general:
This section discusses four possible structures for PQSs: • Is appropriate to the purpose of the organisation
ISO 9001/EN 15224, GMP Chap. 1, ICH Q10 and 7 Pillars; • Includes a commitment to comply with
the latter two using diagrams. Which structure is considered requirements and continually improve the effec-
useful depends on the extent of the processes or organisation tiveness of the quality management system
that has to be covered. Should the PQS indeed cover the • Provides a framework for establishing and
complete product life cycle of a medicine or just the prepa- reviewing quality objectives
ration/manufacturing process. Is the PQS meant for the • Is communicated and understood within the
production department of a pharmaceutical manufacturer organisation
or of a hospital pharmacy or for the complete clinical • Is reviewed for continuing suitability
services of a community pharmacy. EN 15224 adds that a quality policy of health care
The experiences about failures of PQSs in practice organisations:
stimulated the development of the 7 Pillars visualisation • Is based on ethical values and the specific quality
[26]: requirements and characteristics
• Key processes (such as validation, pharmacovigilance, • Includes a commitment to clinical process manage-
PRODUCTION
purchasing) were not included in the PQS. ment including clinical risk management
• Silo management: separate systems had evolved within
different departments or functions, which leads to lack of
communication and harmonisation. Table 35.3 gives the chapter titles of ISO 9001 with some
• Gaps between the GxPs, especially performing clinical subchapters that may be relevant for preparation of
trials within a proper PQS. medicines as well as those health care elements added
• Design faults within individual elements of a QMS, such from EN 15224. The last column tries to connect the ISO
as an extremely complex documentation system. structure to quality system elements common to pharmaceu-
ISO 9001/EN15224 and 7 Pillars, although very different, tical quality systems, including specific items for
offer a structure that can be used for a PQS that covers the pharmacies.
clinical aspects of preparation in pharmacies as well. Would pharmaceutical preparations be within the focus
of EN 15224 or not? To put it differently: are pharmaceu-
tical preparations to be considered products or clinical
services?
35.7.2 ISO 9001/EN 15224
EN 15224 states that ‘material products such as (. . .. . ...)
pharmaceuticals (. . ...) and medical devices have not been
ISO 9001 is the global standard for quality management
focused in the scope as they are regulated elsewhere’. Exten-
systems. It has been specified for healthcare by EN
sive regulations exist for licensed medicines indeed (see
15224 [27].
Sect. 35.5.2). These regulations allow pharmacists to prepare
medicines for individual patients on the base of their needs.
ISO 9001 is based on eight management principles: The assessment of the patient’s need for a pharmacy prepa-
customer focus, leadership, involvement of personnel, ration is definitely a clinical process. Quality characteristics
process approach, system approach to management, used in such an assessment (see Sect. 2.2) are included in
the EN15224, for instance availability, continuity of care,
(continued)
Table 35.3 Connections between ISO 9001, EN 15224 and elements common to Pharmaceutical Quality Systems
Elements common to
ISO 9001 Additional elements for health pharmaceutical quality
Chapter titles Some ISO subchapters care systems (ISO 9001/EN15224) systems
General quality Quality in healthcare Patient focus, clinical need,
principles/process Clinical risk benefit/risk ratio
approach
Quality management Quality manual
systems Documentation
Knowledge management
Management Management commitment Patient focus Management responsibility
responsibility Quality policy Quality objectives such as Management review
Customer focus availability, continuity of care, Quality policy, plans, objectives
Planning effectiveness, efficiency, Management of outsourced activities
timeliness etcetera and purchased materials
Quality objectives
Responsibility, authority and Quality risk management
communication
Resource Provision of resources Personnel
management Human resources Organisational chart
Infrastructure Training
Product Customer-related processes Clinical risk assessment Prescription assessment
realisation Design and development Product design
Purchasing Quality characteristics, quality requirements
Production and service provision Change management, change control,
quality control
Control of monitoring and Product quality review
measuring equipment Outsourcing
Procurement
Supplier management
Measurement, Monitoring and measurement Clinical process management Audits, inspection, certification/accreditation,
analysis Analysis of data management review
and improvement Improvement (CAPA) Non-conformities (deviations, complaints)
Recalls
Pharmacovigilance
Analysis of deviations (RCA, CAPA)
Quality risk management
effectiveness, efficiency, timeliness. These may help to

frame decisions into the PQS of the organisation about The quality policy could define the position of phar-
situations such as: macy preparation in relation to licensed medicines in
• A recall of an industrially produced medicine leads to line with EN 15224 as follows:
unavailability of an essential medicine and pharmacy Unavailability of licensed medicines:
preparation could provide a solution, but with limitations Unavailability of licensed medicines is the situation in
as to quality control. which a medicinal product is not available as a
• To improve patient’s adherence to his medication, a licensed preparation, or temporarily not available, or
pharmacy preparation that combines licensed medicines if no licensed medicine suits the patient well enough to
or adapt them, would really make a difference. comply with his therapy, or if a pharmacy preparation
• A pharmacy prepared medicine would improve the safety will improve the safety of the healthcare process or
of the health care process on wards or at home care. diminish the health risk of healthcare providers.
• A medicine is available when imported from another In such situations the attending pharmacist
country, but will not be reimbursed in that situation. A examines, in consultation with the prescriber and
pharmacy preparation may (temporarily) solve the patient or health care providers, the possibilities for
problem.
(continued)
35.7.3 Pharmaceutical Quality System of GMP

import or a pharmacy preparation. The decision Chapter 1
whether or not to choose a pharmacy preparation is
based on a risk assessment that is documented. Chapter 1 of EU GMP gives guidance for a Pharmaceutical
The clinical benefits and risks are weighed against Quality System. It starts with a Principle emphasising the
the risks of design failure and of preparation failure responsibility of senior management, participation and com-
and take feasibility into account. The documented mitment of all staff and suppliers, full documentation, suffi-
considerations are the transparent testimony of the cient resources, and the relationship between quality
pharmacist about his legal responsibility for the prep- management, GMP and QRM.
aration including the pharmacotherapy. It consists of guidelines on five issues:
• Pharmaceutical Quality System
• GMP for medicinal products (including a reference to
The only accessible PQS for pharmacies that has been
Good Distribution Practice)
published to our knowledge, the Swiss PQS for hospital
• Quality Control
pharmacies, is based on the ISO 9001 methodology as well
• Product Quality Review
as on the EFQM quality model [28].
• Quality Risk Management
The guidelines on the Pharmaceutical Quality System
The Swiss PQS was developed before the EN 15224 was may be used as a structure for a PQS, however GMP
created. It applies to the hospital pharmacy as a whole. Chap. 1 already points at ICH Q10 as being more suit-
This PQS contains elements for pharmacy able for that purpose. ICH Q10 provides structure for
preparation: the design processes and for skills such as knowledge
• For legislation for extemporaneous or small-scale and quality risk management, review of trends and
preparation reference is made to the Swiss Pharma- patient satisfaction. These skills ‘enable’ effective quality
copoeia (which is for that part almost identical to management.
PIC/S GPP, see Sect. 35.5.5) and for stock
preparations to EU-GMP (this Swiss PQS was
developed before the Ph. Eur. monograph Pharma- 35.7.4 ICH Q10 as a Structure
ceutical Preparations, see Sect. 35.5.3 and the
Council of Europe Resolution, see Sect. 35.5.). As said (Sect. 35.5.9) the ICH Q10 guideline [24] is devel-
• For the hygiene concept and quality control refer- oped as a PQS model for the whole life cycle of a licensed
PRODUCTION
ence is made to those standards as well. medicine. It starts with the design phase of the product and
• For specific preparation activities reference is made ends with product discontinuation. ICH Q10 is included in
to national guidelines. part III of current GMP (see Sect. 35.5.7).
• A yearly list of stock preparations including the ICH Q10 clusters PQS elements in four subsystems:
amount produced should be available. 1. Process performance and product quality monitoring
• Every preparation is evaluated at least every 2 years system
as to efficacy and efficiency. 2. Corrective action and preventive action (CAPA)
• Prescriptions for extemporaneous preparations are system
assessed for formulation, dose, clinical and eco- 3. Change management system
nomic benefit. 4. Management review of process performance and product
• Attention is paid to the relation between stress and quality
quality of aseptic handling. These subsystems can be applied to each of the stages of
• Maintenance of equipment for preparation and the product lifecycle (see Sect. 35.3). Many parts of ICH
quality control. Q10 are relatively easy connectable with ISO 9001. How-
• Outsourced preparation activities. ever some are not, such as Enablers, Management responsi-
• Licences for handling narcotics, for pharmacy bilities etcetera. The relationship between all parts of ICH
preparation as such. Q10 is visualised in the diagram of Q10 Annex 2, see
Fig. 35.2.
Fig. 35.2 Diagram of the Q10

PQS model (Copyright # 2014
ICH (ich.org))
The relationship between the parts of the diagram is pharmaceutical use across the whole product life cycle is
explained as follows: explained and illustrated.
This diagram illustrates the major features of the ICH Q10
Pharmaceutical Quality System (PQS) model. The PQS covers
the entire life cycle of a product including pharmaceutical
35.7.5.1 Description of the Model1
development, technology transfer, commercial manufacturing, Principles
and product discontinuation as illustrated by the upper portion of The 7-Pillars model is a ‘patient benefit model’ and applies
the diagram. The PQS augments regional GMPs as illustrated in only to the pharmaceutical environment. It was not intended
the diagram. The diagram also illustrates that regional GMPs
to have the general applicability of the ISO standards. Indeed
apply to the manufacture of investigational products.
The next horizontal bar illustrates the importance of man- it was developed in the 1990s because the ISO standards
agement responsibilities (. . ..) to all stages of the product life were not then considered as appropriate for the production of
cycle. The following horizontal bar lists the PQS elements medicinal products. The model was aimed originally at the
which serve as the major pillars under the PQS model. These
industrial and hospital preparation of medicines only and the
elements should be applied appropriately and proportionally to
each life cycle stage recognising opportunities to identify areas GMP environment. It has since been extended to cover the
for continual improvement. whole product lifecycle, all the GXPs and all functions
The bottom set of horizontal bars illustrates the enablers: involved in the preparation and production of pharmaceuti-
knowledge management and quality risk management, which
cal products, including QC, Regulatory Affairs, Develop-
are applicable throughout the life cycle stages. These enablers
support the PQS goals of achieving product realisation, ment etcetera. This has been done by developing the concept
establishing and maintaining a state of control, and facilitating of ‘the product’: thus, for example, test results might be
continual improvement. considered to be the product of a QC department; a registra-
tion dossier could be the product of a Regulatory Affairs
department. Once the concept of product is accepted, the
35.7.5 Seven Pillars Model
Quality Attributes necessary for patient benefit can then be
defined and the 7-Pillars Model adapted and applied.
Another visualisation of a PQS (described in the model as a
The primary principle for the 7-Pillars Model is that
Quality Management System QMS) is the 7 Pillars model
patient wellbeing is secured by supplying a medicine (‘prod-
[26], see Fig. 35.3, developed by Dr. Tom Duffy of Lowden
uct’) with the correct Quality Attributes and by compliance
International to help getting involved in quality management
with regulatory requirements. Regulatory requirements do
in a proper and understandable way, using the pharmaceuti-
cal vocabulary.
The model is first described when applied to the prepara-
1
tion of a medicinal product. Subsequently its wider As described by Dr. Tom Duffy.
Quality Management System

The “7 pillars” Model
Release
Batch Specific
Production
Systems Testing Deviation
Sampling Review
Management
Batch Independent Environmental Materials Components

Management Control Control
Systems
Documentation Management
Change Management
Supplier Management
Self-Inspection
Maintenance
Validation
Training
General Quality
Systems
The ‘7 Pillars’
Product Quality
Surveillance Stability Complaints
Systems
Senior Management Quality Quality Risk Process Qualified

Recall Review Improvement Management Optimisat Personnel Person
Systems ion Development
Quality Policies
©Lowden International
Fig. 35.3 7 Pillars model (Copyright # Lowden International, with permission)
not just mean regulations in the sense of legal requirements; Specific because they are operated during the preparation of
they include codes of practice, ethics and professional every batch or lot and generate data specific to that lot. These
PRODUCTION
standards. They have also existed ever since the practice of are Sampling, Testing, Review of Production Documents
Pharmacy began and the apothecary of old had to have a and Deviation Management.
‘Release System’ which was in effect a primitive Quality Batch Independent Systems. Monitoring what happens
Management System. Hence the Release System sits on the during an individual batch is not enough since other factors
top of the model (which is an ancient temple) and all the can affect product quality and hence must also be managed
other 24 elements in the model (the pillars and building by QMS elements. These are the systems for controlling and
blocks in the temple) exist to support the Release System, monitoring Environment, Materials and Components which
thereby safeguarding patient benefit by assuring appropriate have major impact on quality but are not associated with any
quality and regulatory compliance. one specific lot. These are represented as the second level of
The second principle for the model is that no QMS can be systems supporting Release.
effective unless it is supported by the senior management of General Quality Systems. There are seven of these and
the organisation. Management support must be exercised they give the QMS model its name since they are represented
through a system of senior management processes and as seven supporting Pillars which are the third level of
policies. These therefore sit at the base of the model forming systems supporting the Release process. They are the
the foundations of the temple. systems used to manage Training, Documentation Control,
The third principle is that all of the 25 elements in the Validation (including Qualification), Change Control, Main-
QMS are defined as processes which are documented in 25 tenance (including Cleaning), Supplier Control and Self-
formal procedures. A Quality manual contains 25 separate inspection.
policy statements formally endorsed by senior management. Product Surveillance Systems. The presence of these
acknowledges that the QMS must still operate after Release.
Explanation of the Model Thus Complaints must be investigated and there must be
Batch Specific Systems. The first level of system elements on-going assessment of the ‘product’ to assure that it
which support the Release process are referred to as Batch continues to meet its Quality Attributes throughout its life
(Stability). These represent the fourth level systems 35.7.6 Suitability of Structures for PQS
supporting Release. in Pharmacies
Senior Management Systems. The fifth level supporting
the Release process are the foundation stones, the senior The preceding Sects. (35.3, 35.4 and 35.5) have shown that a
management systems (see the third principle above). These PQS for pharmacy preparation may need at least the same
are the systems for managing Recalls, Quality Performance elements (including the design phase) as the industrial
Review, Quality Improvement (including CAPA), Risk, Pro- manufacturing, but will differ in several ways:
cess Optimisation, Personnel and QP Development (or QP 1. A PQS for pharmacy preparation moreover needs the
equivalent in non-production functions). Quality Policies are element of controlling and documenting the therapeutic
the final base layer (a concrete raft) and are also part of the aspects, as well as the prescription assessment in case of
Senior Management Systems. In this QMS they are extemporaneous preparation; for licensed medicines this
statements of what is done for each of the 25 elements. part is separately regulated in the registration process.
The process based procedures for each of the individual 2. It should contain a system (and procedure) on how to
elements define how the element operates. handle medical-ethical issues for instance in cases of
A major advantage of the 7-Pillars QMS Model is that, non-availability or non-compliance to quality standards.
owing to its pictorial nature, it enables personnel at all levels 3. It preferably has to be integrated with the PQS of the
in the organisation to accurately explain their QMS and how pharmacy or even of the hospital, so with their clinical
it works. Indeed a picture of the model can be inserted into and logistic activities, as well as with human resourcing
the Quality Manual and used to give an overview to and accounting.
inspectors. 4. It has to implement different legislation.
5. The smaller the scale, the easier it will be to have all
elements connected and in concise overview, especially
35.7.5.2 Wider Pharmaceutical Use
when many elements will be executed by the same
of the Model person.
The model seems to be focused on the release of medicinal
The first three conclusions require an extension of the PQSs
products. However it is also applicable to the ‘release’ or
described until now. The fourth will have some influence on
quality management of other pharmaceutical ‘products’,
the level of detail. The fifth conclusion suggests that for
such as a product dossier, a patient dispensing operation or
pharmacies the PQS will be much easier to be surveyed
a laboratory analysis. Many efforts to control the quality are
than for industries.
similar and the model can be used for the integration of the
With a PQS modelled according to ISO 9001/EN 15224
quality management of all ‘products’.
the clinical phase can be included. This may also be possible
For the wider use, at first the product has to be defined
with the 7 Pillars model but not with GMP Chap. 1 or Q10.
with its quality attributes. Subsequently each element of the
As to standards, a distinction can be made as well, being
7 Pillars model is worked through and checked whether each
relevant because a PQS structure may be directed to them.
element applies to the product in view. Two elements may
Table 35.4 shows the coverage of the pharmacy prepara-
be merged into one or renamed in order to best suit the
tion life cycle by the different models and standards. The life
organisation.
cycle phase Distribution is included for completeness. The
standard GDP is discussed in Chap. 36.
A validation report or the therapeutic assessment of a The general model for a Quality Management System for
pharmacy stock preparation exists and needs to be healthcare establishments: ISO 9001/EN 15224 is applicable
accessed and up to date as soon as related activities to the pharmacy as a whole, including pharmacy preparation.
are performed. Providing availability and readability All pharmaceutical specificities have to be created, for
has to be an element of the quality system. It would which the Swiss system [8] may be useful if updated to EN
mean for instance that a file system has to be devel- 15224. The 7 Pillars model is applicable to the whole phar-
oped whether physically or digitally. In case of digital macy as well. If used to preparation terminology, this system
storage care has to be taken that the documents remain offers the advantage of using familiar terminology.
accessible when programs are updated. Table 35.4 shows which standards (discussed in Sect.
Keeping procedures up to date is notoriously diffi- 35.5) may be useful for details of the several phases of the
cult organising. If up to date procedures are seen as a life cycle.
product, it may be well organised in the quality If a complete PQS for the whole pharmacy is not aimed
system. at, Q10 can be used as a model or a model based on a
relevant Standard.
Table 35.4 Suitability of models and standards upon which a quality systems for pharmacy preparation may be based
Life cycle phases to be Easy connection with the Coverage of pharmacy preparation life cycle
covered by the PQS other pharmacy processes? Pharmacotherapy Product design Production process Distribution
Models
ISO 9001/EN 15224 + a
7 Pillars +
Q10 –
and Standards
Pharmaceutical +
preparations Ph. Eur.
PIC/S GPP –
USP Compounding –
standards
CoE resolution on pharm –
preparation
GMP chap. 1 –
GMP other chapters –
Q8
GDP –
a
ISO however does not address the position and responsibilities of a QP
11. NVZA. Richtlijn GMP-Z. http://www.kennisplein-nvza.nl/thema_

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pharmacies for the special needs of patients. (Adopted by the 18. Code of Federal Regulations Title 21, Part 211 Current good
Committee of Ministers on 19 January 2011at the 1103rd meeting manufacturing practice for finished pharmaceuticals. http://www.
of the Ministers’ Deputies https://wcd.coe.int/ViewDoc.jsp? accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
id ¼ 1734101&Site ¼ CM. Accessed 13 Sept 2012 CFRPart¼211. Accessed 30 Oct 2014
6. PIC/S guide to good practices for the preparation of medicinal 19. WHO Expert Committee on specifications for pharmaceutical
products in healthcare establishments PE 010–3. 2008. www. preparations. WHO good manufacturing practices for pharmaceuti-
picscheme.org cal products: main principles. WHO technical report series,
7. Scheepers HPA, Busch G, Hofbauer E et al (2010) Abridged survey no. 961, 2011. Annex 3. Download from http://apps.who.int/
report on quality and safety assurance standards for the preparation medicinedocs/documents/s18652en/s18652en.pdf
of medicinal products in pharmacies. PharmEuropa 22:405–13 20. Pharmaceutical Inspection Convention and Pharmaceutical Inspec-
8. GSASA/APEQ. Modell Referenzsystem Qualität für tion Co-operation Scheme. http://www.picscheme.org
Spitalapotheken. Version 1.2. 10/2009. Available for members at 21. Explanatory notes for industry on the preparation of a site master
www.gsasa.ch file (PE008-3). IIC/S inspection guide. http://www.picscheme.org
9. ADKA. Leitlinie für die Herstellung und Prüfung in der 22. ICH. Pharmaceutical development Q8(R2) (2009) Downloadable
Krankenhausapotheke. http://www.krankenhauspharmazie.de/ from http://www.ich.org/products/guidelines/quality/article/qual
fileadmin/kph/leitlinien/2005_9_347-362-Herstellung.pdf ity-guidelines.html
10. ADKA (2012) Aseptische Herstellung und Prüfung applikations- 23. The rules governing medicinal products in the European Union. EU
fertiger Parenteralia. http://www.krankenhauspharmazie.de/ Legislation – EudraLex – Volume 10 Clinical trials guidelines. http://
fileadmin/kph/leitlinien/Leitlinie_Parenteraliaherstellung.pdf ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm
24. ICH. Pharmaceutical Quality System Q10 (2008) Downloadable 26. The perfect pharmaceutical quality management system – does it
from http://www.ich.org/products/guidelines/quality/article/qual exist? Interview with Dr. Tom Duffy, Lowden International, www.
ity-guidelines.html lowdeninternational.com. Pharmafile 11/2011
25. QRM as Part of integrated Quality Management. Auditing/ 27. CEN. European Standard EN 15224:2012. Health care services –
Inspection. ICH Q9 Briefing Pack. Application. Integrated Quality management systems – Requirements based on EN ISO
Quality Management. http://www.ich.org/products/guidelines/ 9001:2008
quality/q9-briefing-pack.html July 2006: slide 26. Accessed 28. European Foundation for Quality Management. The EFQM Model.
4 Nov 2014 http://www.efqm.org
Logistics
36
V’Iain Fenton-May and Hana Šnajdrová
Contents 36.11 Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805

36.11.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
36.1 Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798 36.11.2 Recall (as a Manufacturer/Preparer) . . . . . . . . . . . . . . . . . . . . 805
36.2 Quality Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798 36.11.3 Recall (as a Receiver) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
36.2.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798 36.12 Education, Experience, Training . . . . . . . . . . . . . . . . . . . . . 806
36.2.2 Competent Authority and Inspectorate . . . . . . . . . . . . . . . . . 798
36.2.3 Traceability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798 36.13 Falsified Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
36.2.4 Good Distribution Practice (GDP) . . . . . . . . . . . . . . . . . . . . . . 798
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
36.3 Stock Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
36.3.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
36.3.2 Shortages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
36.3.3 Stock Turn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
36.4 Procurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
36.4.1 Procurement Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
36.4.2 Tendering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
36.4.3 Types of Contracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
36.4.4 Suppliers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800 Abstract
36.5 Medical Gasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802 Medicines are not normal commodities of commerce, due
to their special nature and the need to protect the health
36.6 Goods Receipt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
and safety of the public. Legislation has made the phar-
36.7 Returned Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802 macist the custodian of the Nations medicines. The phar-
36.8 Controlled Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802 macist has the duty to ensure the availability of the
36.9 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803 appropriate medicine at the time of need. This objective
36.9.1 Pharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803 is achieved by an expert knowledge of medicines backed
36.9.2 Wards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803 by a robust system of procurement logistics. The outline
36.9.3 Other Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804 of which is described in this chapter where logistics is
36.9.4 Temperature and Humidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
36.9.5 Waste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804 about procurement, distribution and storage. Storage and
distribution is controlled through Good Distribution
36.10 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
Practices (GDP). The range of products handled by hos-
36.10.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
36.10.2 For Goods Received into the Pharmacy . . . . . . . . . . . . . . . . 804 pital pharmacies across Europe varies but medicines are
36.10.3 For the Delivery to the Patient’s Home of Fridge usually the prime focus for the hospital pharmacist and
and Freezer Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805 the preparing pharmacist in particular. Where other
commodities are included such as medical devices, nutri-
tion supplements etc. other legislation may apply. How-
ever when the pharmacy has the responsibility the
V. Fenton-May (*) controls outlined in this chapter will apply to all the
Former Quality Control Pharmacist to the Welsh Hospitals, Cardiff,
commodities handled.
United Kingdom
Keywords
H. Šnajdrová
Thomayer Hospital Pharmacy, Prague, Czech Republic Stock control Procurement Suppliers Goods receipt
e-mail: [email protected] Storage Distribution Recalls GDP

798 V. Fenton-May and H. Šnajdrová
quality and efficacy of the medicine will be compromised

36.1 Scope by poor storage and distribution.
Where items or products are referred to in this chapter the

terms will mean all the products for which pharmacy is
responsible. Depending on the local policies these may 36.2.4 Good Distribution Practice (GDP)
include healthcare services, other healthcare products such
as dressings and other medical and surgical products. The Pharmacies are exempt from the legislation covering GDP
chapter covers all aspects of procurement in a pharmacy but for medicines, unless they are wholesaling or importing/
is focused on the needs of the preparing department which exporting medicines, however the principals outlined in the
may have its own independent procurement section or may legislation should be considered when drawing up the Qual-
be part of the main (hospital) pharmacy procurement func- ity System of the pharmacy.
tion. Whatever is the arrangement the preparing section must Distribution of medicines by licensed Wholesalers is
take responsibility for the products that it uses and makes. controlled by the European Commission Guidelines of 5th
November 2013 on Good Distribution Practice of medicinal
products for human use (2013/C 343/01).
Under these Guidelines The Distributor is required to
36.2 Quality Requirements
have in place a suitable
1. Quality System (see Chap. 35), which includes:
36.2.1 General
• Documentation system which has the prime objective
of preventing errors arising from spoken communica-
As with all functions in the pharmacy the logistics function
tion and to permit the tracking of relevant operations
will be controlled by a Quality System. This is described in
during the distribution of medicinal products.
Chap. 35.
• Management of outsourced activities such that the
General guidelines that will be applied are known as:
principal is that there should be a written contract
Good Procurement practice [1–3]
between the Contract giver and the Contract acceptor
Good Distribution practice (GDP) [4] (See Sect. 36.2.4)
such that there will be no confusion over the duties of
either party
• Management review and monitoring
36.2.2 Competent Authority and Inspectorate • Quality risk management
• Qualification of Suppliers
The setting of the standards for the conditions under which • Qualification of customers
stock is stored and distributed from manufacturers and • Receipt of medicinal products
wholesalers is the responsibility of the Competent Authority • Storage
and is enforced by it’s Inspectorate. The controls placed on • Handling of Complaints
hospital pharmacy and community pharmacy is Country • Product recalls
dependent. There will be a system of accreditation but 2. Sufficient competent personnel with an understanding of
again, with whom, and the extent to which this is applied, their role and suitably trained in GDP. The guideline also
will be different in each Country. introduces the role of the ‘Responsible person’ (RP). This
person should meet the qualifications and conditions
provided for by the legislation of the Member State.
36.2.3 Traceability The Guidelines state that a degree in Pharmacy is desir-
able and that the person should have appropriate compe-
The prime purposes of medicines legislation is to ensure tence as well as knowledge of and training in GDP.
the quality, efficacy and traceability of products throughout The role of the RP is analogous to that of the QP in
the supply chain. The manufacturer, wholesaler and manufacturing (see Sect. 25.3.4).
pharmacies are pivotal in ensuring those objectives remain 3. Suitable premises and equipment. The premises should be
with the product when received by the patient. Falsified so designed to allow for separate storage and monitoring
medicines (see Sect. 36.13) enter the supply chain when of the different categories of stock e.g. stock for distribu-
parts of this chain do not adhere to the agreed rules. The tion, cold storage, returns etc. The equipment should suit
36 Logistics 799
its intended purpose and be qualified, validated and the pharmacist should endeavour to rotate some of the stock
maintained appropriately (see Sects. 28.2 and 34.15). through the normal hospital stock e.g. antibiotics. The fol-
lowing is a description of some of those categories.
36.3 Stock Control 36.3.3.1 Emergency Medicines

The public health role of pharmacists becomes specialised in
36.3.1 Overview situations of pandemics and emergencies where ‘Emergency
Medicines’ will be required. The list of such medicines is
Stock Control is about the ability to have medicines for Country specific and are to cover such situations as
patients when needed, i.e. to avoid out of stock situations pandemics, air disasters, explosions involving large sections
and not to have wastage through out of date stock, usually of the public etc. Pharmacists must have a knowledge of
caused by over stocking. Stock Control is also about the best national legal and organisational requirements and of the
use of resources in terms of costs of storage and staff time. national organisation who will be active in those situations.
Stock movements are used to predict future requirements. The national government generally takes the lead in
Good stock control relies on the principal of first to distribution.
expire, first out which means that, with manual storage of
articles, the one with the shortest expiry date have to be 36.3.3.2 Essential Medicines
placed so that they will be picked first. Robotic systems “Essential medicines are those that satisfy the priority health
rely on the computer program to select the product with care needs of the population. They are selected with due
the shortest expiry date. regard to public health relevance, evidence on efficacy and
The stock of pharmaceutical products must be regularly safety, and comparative cost-effectiveness.
checked for products nearing their expiry date, accounting Essential medicines are intended to be available within
for a reasonable usage period for the user e.g. patient, stock the context of a functioning health systems at all times in
hold on wards etc. Expired products must be removed from adequate amounts, in the appropriate dosage forms, with
the shelves immediately (see also GDP [4] Sect. 5.5). assured quality and adequate information, and at a price
the individual and the community can afford” [5].
The term is more relevant to Countries who have diffi-
36.3.2 Shortages culty in obtaining any medicines and for such areas the list
will usually be defined by the World Health Organisation
Shortages of Medicines is a growing concern throughout (WHO). However in times of National disaster individual
Europe and elsewhere in the World. How such shortages Countries may specify their own list. This is a separate list to
should be handled is dealt with in Sect. 3.2.2. the Emergency Medicines described above which are to
cover single, specified incidents.
36.3.3 Stock Turn 36.3.3.3 Seasonal Medicines

Some medicines may be considered seasonal and require
Procurement of items must be at the most appropriate level special attention with regards to stock control at different
in order to obtain the best value for money while ensuring times of the year for example, flu vaccinations. The concept
the quality of the product and the supply chain. This level of a ‘stock turn’ for these materials has to relate to the period
will vary according to local/national policies. It will include in which they will be required and not to the usual yearly
consideration of the most appropriate Stock Turn for the considerations.
individual items. A Stock Turn is the rate at which a
DISPENSING
company’s goods are sold and replaced. With main line 36.3.3.4 Raw Materials for Preparations
stock there should be a turnover of around five or six times Many raw materials used in preparations will not be packed
a year. However in pharmacies there are a number of in containers suitable to comply with a normal Stock Turn
medicines which require different considerations when and therefore should be considered to be outside such rules.
applying stock control principals. The medicines in these For example they may only be available in 500 g when the
categories may never be used but it is essential to have them needs of the preparation unit is for 10 g per year. Neverthe-
available if needed. Therefore, for these medicines the con- less care should be taken to minimise stock loss through out
cept of a ‘Stock Turn’ will not apply. However, if possible, of date materials on the shelves.
Orders will be placed in accordance with the required

36.4 Procurement stock turnover of the specific item required.
36.4.1 Procurement Process

36.4.2 Tendering
The section or person in pharmacy responsible for procure-
ment shall evaluate and select suppliers based on their ability Technically all purchasing, whether it be for one item or
to supply product in accordance with the pharmacy’s thousands, will be by contract. This involves defining the
specified requirements. Information on the quality attributes product required, the quantity, the quality, delivery times
of each item or service will be maintained by the pharmacy and the price and agreeing these with the supplier. In order to
procurement system and this information will be used in the reach this contract a tendering process is required. This may
procurement function be a simple process such as agreeing to purchase off a price
Those requirements should include: list for a small number of items purchased locally to a
• The required legal status of the supplier of the product, complex tendering process, for example e-procurement [6]
i.e. is the supplier appropriately licensed to supply the controlled by the EU legislation [7] on tendering for supplies
goods required to a public body.
• Quality criteria both of the product (e.g. if purchasing an
eye drop is an integral dropper required or a separate
The Basic Principals of the EU Legislation are:
dropper) and the required method of delivery (e.g. is
1. Contracting authorities shall treat economic
there a need for validated cold chain etc.)
operators equally and non-discriminatorily and
• Criteria for specified timeliness of delivery
shall act in a transparent way.
• Criteria defining the acceptable shelf life remaining on a
2. Contracts whose value exceeds the specified
delivered product
amount (excluding VAT) over the period of the
• Availability of technical support and product information
proposed contract (EUR 134,000 in 2013
(e.g. if the product is a device, can the Company give
(EU 1336/2013) which is updated every two
technical assistance in setting it up or, especially for
years) must be advertised in a standard format in
medicines, has the supplier an acceptable Medicines
the Official Journal of the European Union (OJEU).
Information Department)
3. Specifications which are non discriminatory and
The procurement process may also be applied when using
which refer to EU or other recognised standards
internal or external services, for example in-house support
must be used where ever possible.
services, services provided by one department to another,
4. Objective criteria must be used when selecting
clinical laboratory and imaging services. Where services are
suppliers and awarding contracts.
being procured a service level agreements (SLA, see Sect.
33.9.1) will be required
The criteria for selection, evaluation and re-evaluation
shall be established, see also Sect. 21.5.1. Records of the
results of evaluations and any necessary actions arising from 36.4.3 Types of Contracts
the evaluation shall be maintained.
The purchasing information shall describe the • rolling contracts which does not have a specific end date
requirements for the approval for each product to be pur- but does have an agreed review date, usually one year,
chased, including, where appropriate: and an agreed cancellation period
• Full description of the product with the procedures to be • fixed term contracts, which last for a fixed length of time
followed to assess compliance which will include the which is set in advance or can end when a specific task has
necessary equipment and processes needed been completed or when a specific event has taken place
• Requirements for risk assessment • one off contracts as the title infers this type of contract is
• Requirements for compatibility with existing procedures, for a single purchase with no on going agreement.
equipment, devices, infrastructure and software
• Quality management system requirements
• Purchase history 36.4.4 Suppliers
The pharmacy shall ensure the adequacy of specified pur-
chase requirements prior to placing the order with the Products can be sourced from a variety of different suppliers.
supplier. The main ones are discussed below.
36 Logistics 801
36.4.4.1 Manufacturers
Companies licensed by the Competent Authority to manu- Specialised pharmacies pack medicines for each dose
facture are also licensed to supply those items for which they (semi-automated medicine distribution system). Nor-
have been granted a Marketing Authorisation. They can sell mally they unpack medicines from their original pack-
directly to pharmacies and elsewhere in the medicines sup- age, store the unpacked medicines and repack them for
ply chain e.g. to licensed wholesalers and registered a specific patient. This activity has been designed to
pharmacies. A number of bulk items such as intravenous increase medication compliance and to support
fluids are often supplied directly to pharmacies. patients, on difficult dose regimes, to stay at home.
These pharmacies will be responsible for:
• Assessing the suitability of medicines for
36.4.4.2 Wholesalers repackaging in distribution packages
Wholesale distribution covers all activities consisting of • Implementing suitable controls over
procuring, holding, supplying, exporting or importing – The process of unpacking from the original
medicinal products, it does not include supplying medicinal package the process of repacking in the chosen
products to the public [8]. There are special categories of the distribution package (including apparatus and
Wholesaler Dealers licence for some of these activities software) and all relevant validation (see also
e.g. importing. Sect. 22.6.2)
A wholesale distributor has to hold a wholesale distribu- – And the possibility of mix-up and cross
tion authorisation and must comply with Good distribution contamination
Practice (GDP). The Company has to maintain the quality • Converting shelf lives from original package to the
and integrity of the delivered product, to keep it in the legal shelf life in containers for storage and then to the
supply chain during storage and transportation. shelf life in the distribution package
A wholesaler has to qualify his customers and monitor his • Light protection where relevant
transactions. The Company delivers either to persons with • Ensuring that sufficient occupational health and
wholesale distribution authorisation or someone authorised safety precautions have been taken (see also
or entitled to store and supply medicinal products to the Sect. 26.7.3)
public, usually pharmacists, medical practitioners, dentists,
or veterinarians.
Wholesale dealers must have a GDP Responsible Person
(RP) nominated on their license and it is this contact that the 36.4.4.4 Homecare
pharmacist should use if they have any queries as to the There is now a growing market, in the UK for example, for
legitimacy of any product supplied though a Wholesale supplies to be made directly to patients at home from private
Dealer. companies in order to continue their medication after leaving
Most pharmacies have contracts with a number of hospital. These are known as ‘HomeCare’ companies. This
Wholesalers and the choice will depend on the normal pro- can also involve nurses to administer cytotoxic products, TPN
curement criteria; speed of delivery, availability etc. Deliv- and some psychiatric medicines. The purpose is to remove
ery times can vary from a couple of hours to 24 h depending patients from hospitals to save money, and make them more
whether the pharmacy is in a city or a town and whether the comfortable, but the hidden costs maybe huge and therefore
item is a stock item. needs careful assessment. The quality and responsibilities of
the various professionals involved in the process also needs
defining and monitoring. Whoever is responsible for approv-
36.4.4.3 Central Stores (Centralised Pharmacies) ing the contract with such Companies they must specify, in
Some Countries will have centralised pharmacies which are writing, where the relevant professional responsibilities lie.
DISPENSING
specialised pharmacies that pick, package and label medicines For example what doctor is responsible for managing the
to be dispensed by the pharmacy. This category would also patient, what pharmacist is responsible for the final dispensing
include those preparative units which will prepare specialised of the product and who is to approve the costs.
medicines according to a supplied prescription. These
centralised facilities may be part of the pharmacy or they
may be a different legal entity (see Homecare, Sect. 36.4.4.4). 36.4.4.5 Importation
Whatever the commercial status of the facilities, it is the Some products are not available within the Country but are
purchasing pharmacist who is responsible for ensuring that available elsewhere in the World. In that case the pharmacist
the appropriate quality systems are in place including regis- has to apply to a specialised wholesaler or manufacturer for
tration with the appropriate licensing authority, in the facil- importation. Hospital pharmacies can also hold Wholesale
ity from which the purchase is made. (Import) licenses.
Import is relatively easy between countries within the The verification shall be in proportion to the risks involved in
EEA (see Sect. 3.7), because quality requirements and the use of product or delivery of a service.
GMP [9] are the same. However when importing from Where the pharmacy or its customer intends to perform
outside the EEA different quality requirements may apply. the verification at the supplier’s premises, the pharmacy
A full risk assessment is required before considering shall state the intended verification arrangements and
importing the medicine. Some medicines may have previ- method of product release in the purchasing information.
ously been licensed in Europe but then withdrawn due to Verification may vary from simple checks on expiration
health concerns, however they may remain licensed in other dates of pharmaceutical products, visual inspection of items,
parts of the World. In such cases a full risk assessment would e.g. surgical instruments, to acceptance testing of equip-
be required before contemplating importation. ment, e.g. an infusion pump, a linear accelerator or software
The attending pharmacist has to deliver the patient infor- (see also Sect. 34.15).
mation in a language and style that a patient will understand. The pharmacy must have written procedures for receiv-
ing, handling and dealing with any returns of supplied
36.4.4.6 Suppliers for Products Other Than medicinal products. Those procedures must include:
Medicinal Products • Check if the received goods match the ordered ones.
Raw materials and packaging will usually be purchased from • Putting aside any which were not ordered.
wholesalers. Wholesalers for raw materials and packaging • Note and complain about items not received.
do not usually need a wholesalers licence. However some • Check if the beyond use date allows a reasonable usage
countries have specific regulations requiring such whole- period for the patient.
saler to hold a license. • Register if necessary medicines into a beyond-use
Clinical trial materials [8] (see also Sect. 35.5.10) are system/database.
usually supplied directly by the initiating Company. In those • Check on the legal status of the medicine and record as
cases where the clinical trial is a non commercial, internal necessary any controlled medicines.
trial, then the hospital pharmacist will have to obtain supplied • Check for damage and contamination. If necessary
from any of the above mentioned sources. The comparator cleaning of the outer package.
product usually has a Marketing Authorisation and is there- • Ensure that non-accepted medicines cannot be used or
fore obtained from either a Manufacturer or a Wholesaler. It dispensed.
should be checked to see if the Trial requires a single batch of • Identify those pharmaceutical products that require
comparator and if so a special purchase of sufficient product special storage conditions.
of the same batch number to cover the trial is often required. • Check for certificates of conformance where required
such as for Raw Materials.
36.5 Medical Gasses 36.7 Returned Medicines

These are usually medicines with a Marketing Authorisation The pharmacist must provide a safe storage for pharma-
and are usually obtained from the specialist gas manufac- ceuticals marked for return to a supplier, prior to return or
turer due to their bulk and handling hazards. Some of the destruction. There must be procedures in place which will
liquid gasses (see also Sect. 23.13) may be on an automatic prevent the use of such medicines. See also Sect. 38.5.2 for
top up agreement. The responsibility for the ordering receipt, handling medicines brought back by the patient.
storage and distribution of medical gasses can become
confused between pharmacy and other departments
e.g. engineering. Written protocols should exist specifying 36.8 Controlled Substances
those responsibilities with due reference to the Licensed
nature of the gas. In some Countries e.g. the UK and The Medicines legislation of the European Union has the objec-
Netherlands, the pharmacist is responsible for the quality of tive of “preventing and combating crime, organised or oth-
the gasses in the pipelines in the hospital. erwise, in particular terrorism, trafficking in persons and
offences against children, illicit drug trafficking and illicit
arms trafficking, corruption and fraud” [10].
36.6 Goods Receipt The EU legislation, which follows on from the 1961 and
1971 UN Conventions, treats an international control system
The pharmacy shall establish and implement an inspection to monitor the production of narcotic drugs and psychotropic
procedure or other activities necessary for ensuring that a substances by prohibiting any use of substances not previ-
purchased product meets the specified purchase requirements. ously permitted by the national authorities. Under these
36 Logistics 803
Conventions, any use, possession, production and so on of The layout should support the prevention of abuse and
scheduled substances is forbidden, except when exclusively theft. The pharmacist must always be aware that medicinal
intended for ‘medical and scientific purposes’. products in the pharmacy provide a risk of abuse. This is
The preamble to the 1961 Single Convention recognises: not only with regard to the criminal aspect of theft, but also
That the medical use of narcotic drugs continues to be to the risk to public health from improper use. The criminal
indispensable for the relief of pain and suffering and that risk is greatest for narcotics. But also certain chemicals that
adequate provision must be made to ensure the availability are innocent in itself can be as precursors for synthesis of
of narcotic drugs for such purposes. drugs of abuse. The pharmacist shall take measures to
Narcotic and psychotropic substances (see also Sect. prevent abuse as much as possible. Access to the stored
2.3.5) are listed in the four Schedules to the 1961 Conven- medicines by anyone other than the employees of the
tion and the four Schedules to the 1971 Convention pharmacy is limited and must be organised physically or
according to their therapeutic value, risk of abuse and health electronically.
dangers. In all Countries the ordering, recording of receipts In some Countries, e.g. the UK, Controlled substances are
and issues and the storage of items listed in the schedules are required to be stored in a secure room or vault, protected by
subjected to strict rules. alarms that can be monitored 24 h a day. However in some
Patients may be in possession of these items provided that Countries the pharmacist is responsible for deciding on the
there is a legitimate prescription in existence. This also most appropriate storage conditions to ensure that controlled
relates to patients crossing borders while in possession of substances are stored in such a way that the risk of abuse is
such items. Some Countries may require the authenticity of low
the prescription to be verified by some government agency The Pharmacy must have procedures for the entrance of
in the issuing Country. third parties to the pharmacy.
Other substances (see also Sect. 2.4.7) will be identified Premises and cupboards must be maintained, clean and
by individual Countries as requiring controls on their pur- germ free.
chasing, record keeping and storage and use e.g. diazepam, The pharmacy personnel must know how to operate when
codeine ergotamine and ephedrine. There are also an emergency occurs and how to handle it, and know where
substances which may be hazardous in another way i.e. the to find the relevant materials and safety equipment such as
explosive nature of potassium permanganate. Pharmacies gloves face masks, buckets and mops etc. (see Sect. 26.9).
must be aware of these requirements and comply with all Emergencies cover a wide range of accidents that disrupt the
local legislation. normal pharmacy process. This is about relatively limited
Many controlled substances are used in preparation areas accidents, such as the breakage of packaging liberating the
and it is the responsibility of the preparing pharmacist to content to disasters like fire, flood and pandemic. A pan-
comply with the relevant record keeping and storage demic could cause the illness of nearly all the pharmacy
requirements. Particular attention should be paid to the rec- staff, thereby rendering the reliable dispensing of medicines
onciliation of the powders in this category. from the pharmacy almost impossible.
36.9.1.1 Spilled Substances

Hazardous substance may be spilled at preparation, but also
36.9 Storage
during transport, unpacking of incoming goods, delivery and
dispensing. All employees of the pharmacy, and if applica-
36.9.1 Pharmacy
ble, the employees of the institution where the pharmacy
belongs, therefore should be aware how they should act.,
The layout in pharmacies should provide easy cleaning,
thus they should be trained. This applies also to logisticians,
sufficient lighting, separated product flows and dedicated
delivery personnel and nurses (see also Sect. 26.9).
DISPENSING
areas (products to be dispensed, products to be delivered,
products to be returned, products suspected of falsification
and damaged products). Also dedicated areas for hazardous
products such as medicinal gases, combustibles, flammable 36.9.2 Wards
liquids and solids. The storage of hazardous products above
a certain limit have specific requirements for the premises Storage requirements and responsibility for stock on the
e.g. Facilities with ‘blow off’ roofs. wards may differ between countries. In general the pharma-
Items should be stored as to prevent spillage, breakage, cist, if not directly responsible, is responsible for the training
contamination and mix-ups. They should not be stored of ward staff on how to store and handle pharmacy supplied
directly on the floor except for single gas cylinders. stock.
36.9.3 Other Areas 36.9.5 Waste
Medicines, including specially prepared medicines, will Pharmaceutical waste must be separated from other waste,
often be stored under conditions which are not controllable properly and safely packed and appropriately labelled for
with respect to the temperature e.g. Doctors emergency removal to destruction. For the removal the pharmacy will
bags, cardiac arrest boxes in wards, ambulances etc. In need to have a contract with a specialised company. For
such cases the pharmacist should advise on the adjustment industrial waste, other rules apply. See also Sect. 38.4.6.
of expiry dates (see Sect. 22.6.1)
36.10 Distribution
36.9.4 Temperature and Humidity
36.10.1 Overview
The temperature of the storage room for medicines should
not exceed 25 C. This requirement may bring about the The principals of GDP ensures that the right product reaches
need of climate control, for example air conditioning. There the intended destination under appropriate conditions in a
must be provisions for refrigerated and deep-freeze storage, timely manner. In order to achieve this strict attention must
both at 2–8 C and at up to 18 C (see also Sect. 28.9). be paid to:
Now there is a growing requirement for storage at 40 C, • Temperature sensitive products: cold chain (but also pre-
for some clinical trial materials. vention from freezing e.g. of vaccines)
The temporary storage space for overnight delivery must • Hazardous products and radioactive materials
provide a means for storage at 2–8 C. Frozen products are • Medicines with a potential for abuse
typically delivered in a special packaging making a short • Other specific requirements of individual medicines
storage period outside the freezer possible. e.g. those containing proteins that must not be shaken
The temperature of these storage areas must be monitored GDP not only applies to goods supplied to pharmacies but
and are equipped with an alarm if the temperature exceeds to the distribution of goods from pharmacies to areas such
specified limits. If the storage temperature, is exceeded for as: Wards, Clinics, Theatres, and Off site purchasers
instance because of a power failure, the pharmacist shall The pharmacist should use a validated cold chain distrib-
assess the measures to be taken. The capacity of the cold utor for pharmaceutical products that require fridge or
storage to withstand power outs should be known freezer conditions. This also applies to the overnight deliv-
i.e. measure the rate at which the storage warms when ery and for the delivery to the patient’s home (see also
power is switched off. Some fridge products can stand tem- Sect. 36.10.3). Any delivery exceeding the recommended
porary storage at higher temperatures for short periods. The temperature, for example as a result of a power failure, has
product information from the manufacturer (SPC and Scien- to be investigated.
tific Discussion in the European Public Assessment Reports
[11]) may contain such data.
The ICH stability testing guideline defines mean kinetic 36.10.2 For Goods Received into the Pharmacy
temperature (MKT) as ‘a single derived temperature which,
if maintained over a defined period, would afford the same The pharmacist should understand the method by which the
thermal challenge to a drug substance or drug product as supplier maintains the cold chain for example in the case of
would have been experienced over a range of both higher delivery to the pharmacy the refrigerator or cool box with ice
and lower temperatures for an equivalent defined period’ packs, in the transporter must have been validated
This Mean Average Temperature calculation has been • If medicines are to be kept in the freezer then they must
used, for short excursions from the required storage temper- be transported in coolers with freezer cooling elements.
ature, to calculate the likelihood of damage to stored • The temperature must be monitored during transport. If
products [12]. the medicines have to be kept frozen it must be offered
If medicines are kept in their original packaging it should personally and unpacked by the pharmacy staff for imme-
be sufficient if the humidity at storage does not exceed diate, appropriate storage. Such items cannot be delivered
approximately 60 % RH. Medicines with a desiccating car- out of hours. Items requiring refrigeration only may be
tridge in their packaging must not be repackaged, unless it is delivered out of hours provided a fridge is available for
known by how much the shelf life will be decreased. temporary storage.
36 Logistics 805
36.10.3 For the Delivery to the Patient’s Home A person should be designated as responsible for execu-
of Fridge and Freezer Products tion and co-ordination of recalls and should be supported by
sufficient staff to handle all the aspects of the recalls with the
The following should be part of the protocol for delivering to appropriate degree of urgency. This responsible person
a patient’s home: should normally be independent of the sales and marketing
• The person delivering the medicines must be trained in the organisation. If this person is not the Qualified Person
important aspects of transporting and handling medicines. (QP) or equivalent in hospital, the QP or equivalent should
• The products must be stored in the freezer or refrigerator be made aware of any recall operation.
until the delivery occurs. • There should be established written procedures, regularly
• The delivery person should be informed of freezer and checked and updated when necessary, in order to organise
fridge products so that priority is given to the delivery of any recall activity.
those items. • Recall operations should be capable of being initiated
• Provide a cool box, a cooler bag, a refrigerator or airco promptly and at any time.
(in the delivery car) during transport of: • All Competent Authorities of all countries to which
– Vulnerable fridge medicinal products. products may have been distributed should be informed
– For frozen products. promptly if products are intended to be recalled because
– On days when the average (outside) temperature is they are, or are suspected of being defective.
above 25–30 C. • The distribution records should be readily available to the
– If delivery takes more than 2 h. person(s) responsible for recalls, and should contain suf-
– Ice packs should be used where necessary must not be ficient information on wholesalers and directly supplied
allowed to come into contact with the medicinal prod- customers (with addresses, phone and/or fax numbers
uct due to the danger of freezing. Bubble wrap may be inside and outside working hours, batches and amounts
used as insulation. delivered), including those for exported products and
– If the delivery is to institutions such as nursing homes medical samples.
then arrangements should be made such that the • Recalled products should be identified and stored sepa-
articles are placed in a refrigerator immediately after rately in a secure area while awaiting a decision on
arrival. their fate.
For the instruction for the patient who is taking his • The progress of the recall process should be recorded and
medicines home see Sect. 35.7. a final report issued, including a reconciliation between
the prepared, delivered and recovered quantities of the
products.
36.11 Recalls • The effectiveness of the arrangements for recalls should
be evaluated regularly.
36.11.1 Overview
The preparing pharmacist must have procedures in place to 36.11.3 Recall (as a Receiver)
handle drug recalls from two different perspectives. Firstly
as a ‘manufacturer’ the preparing pharmacist may have to In the case of a recall arising from a defect in a product
initiate a recall on a product that has been prepared in the manufactured or prepared outside the pharmacy, in some
pharmacy. Secondly there must be a procedure to handle Countries, a Direct Healthcare Professional Communication
recalls initiated from outside the pharmacy. This latter pro- (DHPC) will be received. In most cases it is the EMA
cedure is usually the responsibility of the main pharmacy. or the national Competent Authority who initiate a DHPC
However the preparing pharmacist must be part of the team but it is sent under the responsibility of the manufacturer
DISPENSING
which acts on recalls if the recalled product is associated itself.
with a prepared medicine because of the legal responsi- The responsibility of the pharmacy is to verify that inter-
bilities held by the individuals in the preparing section. nal action is needed. If so,
This may initiate a recall as a ‘manufacturer’ • Remove packs of the appropriate batch(s) from the stock,
mark them as blocked and place them in quarantine.
• Check to see if external action is needed (i.e. recall from
36.11.2 Recall (as a Manufacturer/Preparer) patients). Replace the recalled batch(s) by unaffected
batches.
For Recall as a part of the Pharmaceutical Quality System, • If supplying an unaffected batches is not possible, con-
see also Sect. 35.6.14. sider therapeutic substitution. The recall letter may
suggest a therapeutic alternative, but this should always EU legislation tries to decrease this phenomenon by the
with the prescriber’s approval. Directive 2011/62/EU of the European Parliament and of
• Prioritise patients who are already using the product. the Council of 8 June 2011 amending Directive 2001/83/EC
• Inform the users about the backgrounds and risks. on the Community code relating to medicinal products for
• Maintain a recall balance and use it to support the risk human use, as regards the prevention of the entry into the
assessment for the patients of the pharmacy. legal supply chain of falsified medicinal products [15].
• Send the affected batches back to the supplier according The pharmacist must be alert to the occurrence of falsified
to the instructions in the recall letter. medicinal products (counterfeit) and is aware of his role in
• Make a risk assessment and decide if a pharmacy prepa- preventing falsified medicines reaching the patient. Patients
ration must be destroyed or recalled (see Sect. 36.11.2). should be informed of the dangers of ordering medicinal
• Adjust the stock in the pharmacy. products through internet sites which have not been
• Evaluate causes and take corrective measures if neces- validated.
sary. Record all actions, even if there were no packs of the Safety features, initiated by the Pharmaceutical Industry,
recalled batch in the pharmacy. should assist in the verification of the authenticity and iden-
tification of individual packs, and provide evidence of
tampering.
36.12 Education, Experience, Training The pharmacist can contribute to a safe supply chain as to
falsified medicines by:
All staff involved in procurement require the appropriate • Validating their supply chain and being aware that
initial training and to participate in continuous professional falsified medicines can also enter the legal supply chain
development. • Being alert about those medicines that are susceptible to
The categories of staff usually involved in these falsification
procedures are: • Have a decision tree for action when suspicion are raised
• Pharmacists regarding a product
• Technicians • Taking seriously complaints by the patient about
• Store Keepers medicines that look unfamiliar or have a different or no
• Secretarial and administrative Staff effect
They should receive training on the requirements of GDP • If in doubt contact the Competent Authority and the
relevant to their role. The training should be based on written Supplier immediately
procedures and in accordance with written training A suspicious product may be compared with the original.
programme. They should receive specific training in identi- Pay attention to the following aspects:
fication and avoidance of medicines entering the supply • The packaging and sealing system. Tablets that normally
chain. are blistered, may be in a different packaging. The colour
Those personnel dealing with specialised products which of a pack might be pale, seals may be missing and any
require more stringent handling should receive specific train- holograms may be more vague than on the original.
ing. The senior pharmacists should also receive specialist • The labelling. Text and prints may contain spelling errors
training in, for example, Contract Law, negotiating with or batch numbers may be constructed differently. Also
suppliers, and obtaining best value for money through the name of a medicine may be spelled different: Vi@gra
good procurement. Some Countries have specific degree or V!agra).
courses in the subject [13]. • The product information. This may contain spelling
A record of all training should be part of the documenta- mistakes. Different fonts may be used or different kind
tion system in the pharmacy and the effectiveness of the of paper may be used.
training should be regularly tested. • Regarding the external features of the product. Compare
if possible with an original product that has been obtained
through a reliable supplier. Tablets should look uniform,
36.13 Falsified Medicines break lines, inscriptions or coatings may be missing.
Any product suspected of being a falsified medicine
Falsified medicines (the term ‘falsified’ is used to distinguish should be immediately segregated and stored in a dedicated
the issue from patent violations, so-called ‘counterfeits’) are area and the Competent Authority should be informed
a major threat to public health and safety [14]. at once.
36 Logistics 807
See also Toolkit by World Health Professions Alliance 8. Regulation (EU) No 536/2014 of the European Parliament and of
(WHPA) [16]. the Council of 16 April 2014 on clinical trials on medicinal
products for human use, and repealing Directive 2001/20/EC Text
with EEA relevance. http://eur-lex.europa.eu/legal-content/EN/
TXT/?uri¼uriserv:OJ.L_.2014.158.01.0001.01.ENG
References 9. Eudralex. Volume 4. Guide to good manufacturing practices for
medicinal products. http://ec.europa.eu/health/documents/
1. European Commission. Golden book of e-procurement good practice, eudralex/vol-4/index_en.htm
catalogue. http://ec.europa.eu/internal_market/publicprocurement/ 10. European Monitoring Centre for Drugs and Drug Addiction. Inter-
e-procurement/golden-book/catalogue_en.htm national conventions. http://www.emcdda.europa.eu/html.cfm/
2. CIPS/NIGP. Partnership for procurement. Principles and practices index5772EN.html
of public procurement. http://www.globalpublicprocurement.org/ 11. SPC and Scientific Discussion in the European Public Assessment
Resources/Procurement-practices/ Reports http://www.ema.europa.eu/ema/index.jsp?
3. European Commission. Public procurement. http://ec.europa.eu/ 12. European Compliance Academy. GMP News 07/05/2014. http://
internal_market/publicprocurement/index_en.htm www.gmp-compliance.org/enews_04209_GDP-Question-When-
4. Guidelines of 7 March 2013 on good distribution practice of medic- to-use-Mean-Kinetic-Temperature-Calculation--MKT-.html
inal products for human use (2013/C 68/01). http://eur-lex.europa. 13. Chartered Institute of Procurement and Supply. https://www.cips.
eu/LexUriServ/LexUriServ.do?uri¼OJ:C:2013:068:0001:0014: org/Qualifications/
EN:PDF 14. European Commission. Falsified medicines. http://ec.europa.eu/
5. World Health Organisation. Essential medicines. http://www.who. health/human-use/falsified_medicines/index_en.htm
int/topics/essential_medicines/en/ 15. European Parliament and the Council of the European Union.
6. European Commission. e-procurement. http://ec.europa.eu/inter Directive 2011/62/EU of the European Parliament and of the Coun-
nal_market/publicprocurement/e-procurement/index_en.htm cil of 8 June 2011 amending Directive 2001/83/EC on the Commu-
7. European Parliament and the Council of the European Union. nity code relating to medicinal products for human use, as regards
Directive 2004/18/EC of the European Parliament and of the Coun- the prevention of the entry into the legal supply chain of falsified
cil of 31 March 2004 on the coordination of procedures for the medicinal products. http://ec.europa.eu/health/files/eudralex/vol-1/
award of public works contracts, public supply contracts and public dir_2011_62/dir_2011_62_en.pdf
service contracts (Public Contracts Directive 2004/18/EC). http:// 16. World Health Professions Alliance (WHPA). Counterfeit cam-
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri¼OJ: paign. Campaign materials. http://www.whpa.org/counterfeit_cam
L:2004:134:0114:0240:en:PDF paign_materials.htm
DISPENSING
Instructions for the Use of Medicines
37
Suzy Dreijer - van der Glas and Anthony Sinclair
Contents 37.9.2 Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825

37.9.3 Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
37.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
37.2 Knowledge and Skills . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
37.3 Label and Patient Information Leaflet . . . . . . . . . . . . . . . . 810
37.3.1 Legal Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
37.3.2 Labelling and Package Leaflet in More Detail . . . . . . . . . . 812
37.4 Instructions on Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
37.4.1 Oral and Written Instructions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
37.4.2 Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
37.4.3 Way of Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816 Abstract
One of the aims of pharmacy practice is to help patients to
37.5 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 818
make the best use of their medicines. This means that
37.6 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819 patients should not only get therapeutic information by
37.6.1 Disabilities or Ergonomic Problems . . . . . . . . . . . . . . . . . . . . . 819
counselling but also the practical instructions and advice
37.6.2 Swallowing Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
37.6.3 Feeding Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821 that they need in the actual use of their medicines.
37.6.4 Compliance Aids and Individualised Dispensing . . . . . . . 821 Generally this is covered by the product information
37.7 Special Types of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822 related to a particular medicine. Directions for use, stor-
37.7.1 Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822 age and expiration date are part of the label and the
37.7.2 Antineoplastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822 package leaflet, owing to legal requirements. For some
37.7.3 Protein Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823 patients or their caregivers however, the instructions on
37.7.4 Sterile Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
the label or in the package insert are not enough to enable
37.8 Instructions for Professional Caregivers . . . . . . . . . . . . . . 824 them to handle a medicine correctly. This may be due to
37.8.1 Reconstitution and Manipulation Outside the Pharmacy 824
the type of medicine, or the needs of a particular patient.
37.8.2 Parenteral Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
37.8.3 Oral Solids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825 Some medicines need reconstitution before they can be
37.8.4 Occupational Health and Safety . . . . . . . . . . . . . . . . . . . . . . . . . 825 used (e.g. antibiotics in oral liquids, injections). Patients
37.9 Special Categories of (Medicinal) Products . . . . . . . . . . . 825 with swallowing problems for instance may need
37.9.1 Veterinary Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825 manipulations with tablets or capsules before they can
take them.
This chapter deals not only with the legal requirements
on labelling and patient information leaflet, but also with
reconstitution and other manipulation needed prior to use
Based upon the chapter Gebruiksadviezen by Suzy Dreijer and Yuen or administration as well as instructing the patient about
Yee Li in the 2009 edition of Recepteerkunde. it, with the focus on the needs of the patient.
S.M. Dreijer - van der Glas
Royal Dutch Pharmacists’ Association KNMP, The Hague, Keywords
The Netherlands
Patient instructions Use of medicines Caregiver
A.G. Sinclair (*) Labelling Storage Feeding tube
Birmingham Children’s Hospital NHS Foundation Trust and Aston
University, Birmingham, UK

810 S.M. Dreijer - van der Glas and A.G. Sinclair
Examples of manipulation include not only the reconsti-

37.1 Introduction tution of powders for suspension by adding water, but also
measuring the right amount of liquid using a syringe, either
The FIP/WHO Guidelines on Good Pharmacy Practice for oral use or injection. Whether the patient or caregiver
defines the aim of pharmacy practice as “contribute to health actually needs help in manipulation or just instruction
improvement and to help patients with health problems to depends on their skills and the type of manipulations. The
make the best use of their medicines”. The idea that patient pharmacist has to take care that it is done properly, whether
counselling mainly deals with pharmacotherapeutic issues is this is done in the pharmacy or at home by patient or
not true. It cannot be taken for granted that patients will use caregiver. This demands not only knowledge of the product,
all the dosage forms defined in the chapters of this book in but also empathy with the patient or caregiver. Special
the correct manner. Thus when dispensing medicines, attention is needed for the instructions of hospital personnel
patients should not only receive information but also on the reconstitution and admixing of parenterals and manip-
instructions and counselling that they need to make the ulation of solid dosage forms.
best use of their medicines.
First of all this means product information related to a
particular medicine. Directions for use, storage and expira- 37.3 Label and Patient Information Leaflet
tion date are normally part of the label and the package
leaflet, as a legal requirement. This chapter describes how 37.3.1 Legal Requirements
to deal with these requirements.
Helping the patient goes further than the legally required In the Product-information templates of the European
instructions. It is focused on the needs of a particular patient Medicines Agency (EMA) the requirements for the labelling
in the use of the medicine. Some medicines for instance need and package leaflet for licensed medicines are published [1].
reconstitution before they can be used (antibiotics in oral Particulars to appear on the outer package and the imme-
liquids, injections). For some patients or their caregivers, diate package:
instructions on use are not enough to enable them to handle a • Name and strength of the medicinal product *
medicine correctly. They may need help in manipulations • Statement of active substance(s), qualitatively* and
required to use the product. To what extent the pharmacist quantitatively, per dosage unit or for a given volume or
should help will depend on the type of medicine and the type weight
of patient. Instructing the caregivers may sometimes be the • Excipients known to have a recognised action or effect
best option. Therefore this chapter not only deals with dis- (in some dosage forms all excipients)
pensing, but also with reconstitution and other manipulation • Pharmaceutical form and content of the package*
needed prior to use or administration. • Method and route(s) of administration*
• Instructions on use
• Special warning: “Keep out of the sight and reach of
37.2 Knowledge and Skills children”
• Expiry date, stating month and year*
In order to be able to give appropriate advice on the use of a • Storage conditions
medicine a pharmacist will need to draw on their underlying • Instructions on use
knowledge in three broad areas: • Special warnings e.g. for disposal, if appropriate
1. Knowledge of the product characteristics • Name and address of the marketing authorisation holder
2. Information and directions for use and administration, for • Marketing authorisation number
patient and caregiver • Batch number*
3. Reconstitution and other manipulation to be carried out • Information in braille (if possible)
on the product The items marked * are the minimum to appear on small
Product knowledge implies an understanding of how the primary packages.
product is produced and the consequences for use and stor- In licensed medicines this information can be printed on
age. In other words the physico-chemical properties such as the outer package when there is not enough space on the
storage temperature and compatibility with bulk parenterals actual label on the primary container. In many countries it is
and infusion tubing. It may also mean awareness of possibly permitted to include part of the information in a patient
unwanted excipients, e.g. ethanol. Product knowledge and information leaflet, as it will often not fit within the label.
instructions for the patient are always needed, reconstitution A reference to such a leaflet should be made in that case.
and manipulation prior to use or administration only for Since 2013 the European Pharmacopoeia (Ph. Eur.) mono-
particular (groups of) patients or particular medicines. graph on Pharmaceutical Preparations have made most of
37 Instructions for the Use of Medicines 811
these regulations apply to the labelling of unlicensed phar- [4] or just for an active substance. Much of this type of
maceutical preparations with the exception of the data on information can also be found on websites published by
market authorisation [2]. Relevant requirements given in the pharmacy organisations, or by (groups of) pharmacies or
general dosage forms monographs are also required in unli- hospitals.
censed products. In addition, “relevant EU or other applica-
ble regulations apply”.
The medicines for children organisation in the UK
The Ph. Eur. monograph Pharmaceutical Preparations
has a set of information leaflets [5] that parents can
does not clearly mention a package leaflet, although it says
download free of charge for individual medicines.
under the heading Labelling that “relevant European Union
These leaflets are designed for paediatric use advice
or other applicable regulations apply”. Most national
and don’t have warnings for example that would worry
regulations do not require a package leaflet either. A short
a parent giving a medicine to a child, off-label.
overview of the requirements of the EMA for package
leaflets is shown below.
Items to appear in the package leaflet of licensed The EMA templates on labelling state: “on the printed outer
medicines: packaging material an empty space should be provided for the
• Name, active substance and therapeutic indications prescribed dose”. When a medicine is dispensed on prescrip-
• Contra-indications, special warnings and precautions tion in a pharmacy, often a (additional) label is attached,
• Interaction with other medicines, food and drink intended for a specific patient. In many countries this is com-
• Possible side effects pulsory, but when no (national) legislation exists, dose and
• Instructions on use frequency are sometimes written on the package. Legislation
• What to do in case an overdose has been taken or a dose may vary between countries, but the label on a (licensed)
was missed medicine that is delivered on a prescription to an ambulant
• Storage patient should contain at least the following information:
• Contents of the pack and other information • Name of the patient
Many of these items are important for the users of • Name (and address) of the pharmacist (or pharmacy)
(unlicensed) pharmaceutical preparations as well. From a • Directions for use (dose and frequency)
strictly legal point of view therapeutic benefits and side • Date of dispensing
effects cannot be claimed, not being agreed by any licensing According to the existing national rules for the labelling of
authority. But in many countries the needs of the patient pharmacy preparations, the labelling often is a combination
will prevail and patient information leaflets for unlicensed of the requirements for a specific patient and the general
pharmaceutical preparations have been developed. These requirements for licensed medicines. A good example is the
may be specific for a preparation included in a formulary, standardised label of the Formulário Galénico Português
e.g. the Formularium der Nederlandse Apothekers (FNA) (FGP) [4] (Fig. 37.1).
[3] see Sect. 39.4.5, the Neues Rezeptur Formularium The legal rules for specific labelling for ambulant patients
(see Sect. 39.4.2)] or the Formulário Galénico Português in most countries do not apply to hospitalised patients. But
Fig. 37.1 Standardised label for

Lugol’s Solution FGP (From Identification of the Pharmacy Identification of the prescribing Doctor
Formulário Galénico Português Identification of the Pharmacy Director Identification of the Patient
with permission) Address and telephone of the Pharmacy
Aqueous Solution of Iodine 0.5%, 1%, 2% OR 5%

(Portuguese Galenic Formulary A.I.9.) DISPENSING
100 g of solution contain 0.5, 1, 2 or 5 g of iodine (Date of preparation)
(Quantity dispensed) (Beyond-use-date)
Contains potassium iodide and purified water Storage at room temperature in a
tight container
Medicine for cutaneous application
External use (Batch number)
Do not swallow Keep away from the reach of
children
many hospital pharmacies will have their own guidelines, country. A blue strip is often used, but a red label is common
normally including the following minimum requirements for in other countries, e.g. Croatia and the Czech Republic. Also
labelling for an individual patient: other colours on the label may be used as a signal for certain
• Name of active substance, form and strength and quantity groups of medicines, e.g. in hospitals.
issued
• Essential warnings i.e. do not crush or chew; shake the 37.3.2.2 Name of the Pharmacist or Pharmacy
bottle Although legislation will vary, name, and address or tele-
• Patient’s name (and sometimes a hospital identification phone number of the dispensing pharmacy should always be
number) clearly indicated. Sometimes the legislation specifies that the
• Date name of the owner or the pharmacist should be on the label,
• Ward that the patient is on or other ways of identification of the pharmacy are used.
In some countries professional standards are in force. The Pharmacy Practice Order (Apothekenbetrieb-
In these countries guidelines for the labelling of sordnung) in Germany demands, besides the name of
medicines in the hospital have been published. the owner, the initials of the person who has dispensed
In other countries working groups of hospital the medicine on the label, or the name of the
pharmacists are preparing such guidelines for special supervising pharmacist [7]. In Croatia and the Czech
groups of medicines, i.e. antineoplastics or paediatric Republic this applies for the label of pharmacy
medicines. preparations. In the UK it is good practice to write
the initials of the pharmacist and those of the dispenser
if they are different, but this is not law.
37.3.2 Labelling and Package Leaflet in More

Detail 37.3.2.3 Date
Usually the date the medicine is dispensed will appear on the
Labelling should fulfil the legal requirements, preferably in a label. It is important to notice that this date may be different
way that helps the patient. In some countries, organisations from the date it is actually delivered to the patient. The date
of, for example, hospital pharmacists may have developed can be used as an instrument for tracing a dispensed medi-
their own guidelines on labelling. This section comments on cine, but in most of the national legislation a batch number is
how to deal with the legal requirements, more or less in the required for pharmacy preparations
order they appear on the label. It is important to note that
legislation at this point varies from one country to another. 37.3.2.4 Name of the Patient
As a consequence this chapter can only give general Just the name is usually not enough to identify a patient.
recommendations. Date of birth, first name(s) and address give additional
information. Hospitals may use a unique identification num-
37.3.2.1 Route of Administration ber. In delivering a medicine to someone else than the
The uppermost zone of the label shows the route of admin- patient in person, the pharmacist assumes responsibility.
istration, if this not the oral one. Officially the Standard When in doubt, inquiries from the patient himself, or a
Terms of the European Directorate for the Quality of proof of identity may be asked.
Medicines and Health Care (EDQM) [6] should be used,
but in some countries all non-oral routes may be indicated 37.3.2.5 Name and Strength of the Medicine
as ‘Not to be taken’. A more specific term such as Eye drops, For the indication of the active substance in the name of
Ear drops or ‘For rectal use’ is to be preferred. Some patients pharmacy preparations the generic or International Non Pro-
may not know the meaning of the term ‘rectal use’. Also the prietary Name (INN) is to be preferred. The purpose of the
words ‘Not to be taken’ sometimes need explanation, for strength in the name is to indicate the quantity of the active
instance in the case of a mouth rinse. substance, which is relevant for the correct use and identifi-
The use of colours, either for the complete label or for a cation of the product, and its distinction from similar
strip at the top to emphasise non-oral use is widespread, and presentations. The strength in the name should, therefore,
in some countries compulsory. The colour may differ per be based on user/prescription criteria rather than analytical
criteria according to the Recommendations on the expres- obtain this type of information. Special editions of a national
sion of strength in the name of centrally licensed human formulary, intended for prescribers, exist in some countries.
medicines from the Quality Review of Documents group If the product is not a standard formula, the names of all
(QRD) [8]. the active ingredients have to appear on the label, and
At the same time it should be clear which form of the preferably of all the excipients as well. At least preservatives
active substance is meant in the indication of the strength. and antioxidants should be mentioned. The EMA requires
This can for instance be the hydrate of a salt, or just the active excipients known to have a recognised action or effect to be
moiety, without the salt or hydrate water (see Sect. 23.1). mentioned [1]. A list of such excipients is available on the
For instance, in morphine preparations normally mor- EMA website [10]. Examples are ethanol and propylene
phine hydrochloride trihydrate or morphine sulphate glycol, and benzyl alcohol, especially in medicines for chil-
pentahydrate will be used as raw material. These salt dren. See also Sect. 5.4.5.
hydrates are included in the Ph.Eur. and BP (British Phar- In naming pharmacy preparations with more than one
macopoeia) respectively [9]. Then if the name would say just active substance, it will in practice not always be possible
morphine, the strength should refer to the morphine base to follow the rules about the name and the strength. If for
moiety. But as usual doses refer to the salts, the salts should instance 0.1 % triamcinolone acetonide is added to ketoco-
be indicated in the name. Examples are: nazole cream, the name on the label for the patient would
• Morphine sulphate injection 10 mg/ml BP probably be: 0.1 % triamcinolone in ketoconazole cream,
• Morfinehydrochloridedrank (Morphine Hydrochloride simply because the full name would not fit.
Oral Solution) 20 mg/mL FNA Therefore it is important to list the full formula on a
The same applies to many generic medicines, e.g. Metformin separate label.
hydrochloride 1000 mg tablets. These could also be called: Names of substances should be written in full, including
Metformin 780 mg tablets (as hydrochloride), but this would water of hydration, if appropriate. For substances of phar-
be very confusing, as dosing regimens always use the macopoeia quality the name as mentioned in the Ph. Eur.
hydrochloride. may be used, followed by the initials, Ph. Eur. In this
For inorganic compounds both cation and anion are notation it is usually not necessary to state the amount of
always mentioned. Abbreviations for the elements are water of hydration, as this will be defined in the Ph. Eur.
allowed. The EMA now recommends that name and strength monograph. Using the Latin name of the Ph. Eur. for the
of licensed medicines should refer to the active substance or substance may be an alternative way to indicate their quality.
moiety [1]. Therefore in preparations that were licensed by
EMA recently, the name and dosing schemes usually refer to
37.3.2.7 Content of Active Substance
the active substance only, even if it is present in a salt form.
in Pharmaceutical Preparations
For instance Pradaxa® 75 mg capsules contain dabigatran
The amount of active substance should be declared as ‘pure
etexilate mesilate, equivalent to 75 mg dabigatran etexilate.
substance’. This means the content that would be determined
Sometimes the strength is indicated in two ways. For
in a chemical assay. For example, in the preparation a
instance in Sifrol® 0.7 mg each tablet contains 1.0 mg
calculated excess of active substance is processed, because
pramipexole dihydrochloride monohydrate equivalent to
the material may contain water of hydration. This excess
0.7 mg pramipexole. Because doses, as published in the
should not appear on the label (i.e. the label claim), as the
literature, refer to the salt form, the name on the package is
assay refers to the active substance without water.
Sifrol® 1 mg (0.7 mg base).
However, when the quantity of active substance refers to
a hydrate, this should appear on the label. The content of the
37.3.2.6 Ingredients of the Medicine hydrate should then be determined.
In some countries it is permitted to use, for preparations For preparations presented in single-dose-units it is
included in a national formulary, the product name men- important to indicate the composition per dosage unit, as
DISPENSING
tioned in that formulary, provided the formulation well as the number of units supplied. As a consequence it
corresponds exactly with the one in the formulary will sometimes be necessary to calculate the quantity of
(e.g. Hydrocortisonacetaatcrème FNA in the Netherlands). excipients per unit from the amount used for the whole
Adding the name of the formulary is necessary in that case to batch (i.e. fillers in capsules). When only the quantities of
identify the formulation. Additional information about the ingredients for the whole batch are indicated in the label,
ingredients should be in the package leaflet. For cutaneous there is the risk that other caregivers will interpret the com-
preparations in particular it is important that prescribers can position falsely. For the same reason, according to the EMA
the concentration of oral liquids and other multidose forms Theophylline 200 mg ¼ 1 ml
should be indicated per millilitre or per dose, so not as a Heparin 5,000 IU ¼ 1 ml
percentage [8]. For semisolid preparations like creams and The EMA has developed recommendations for the
ointments, the concentration or strength should be indicated expression of the strength of liquids [8], including parenteral
as amount per unit weight (e.g. mg/g). medicines, where the way of expression also depends on the
way of use, see Table 37.1.
This means that for injections usually both the total
37.3.2.8 Units
amount of active substance and the concentration should
For the indication of strength or amounts of active
be indicated, whereas for infusions the concentration and
substances and excipients the following physical parameters
the total volume would be enough.
are used: volume, mass and or quantity, with units according
Note that in these recommendations only milligram is
to the international system (SI). The following units and
used, not mole. In practice for electrolytes the amount in
derived units are used:
moles is usually given as well. Doctors prescribe dosages of
• Volume: litre (l), millilitre (ml); however according to the
electrolytes based on blood concentrations that are given in
Ph. Eur. the litre is written with a capital L: litre (L) and
mmoles.
millilitre (mL); mass: kilogram (kg), gram (g), milligram
(mg) and microgram (microgram rather than μ, μg and
mcg) 37.3.2.9 Dose
• Quantity: gram molecule (mol), milligram molecule Dose and frequency are indicated, if necessary at what times
(mmol), microgram molecule (micromol, rather than of the day. In case of variable doses (‘on demand’) the
μmol or mcmol) maximum use per 24 h and sometimes a maximum per
Despite of the fact that μg is the SI unit, the use of this week should be stated. Additional instructions may be
abbreviation should be discouraged. Some fatal errors have needed, i.e. ‘Shake well before use’, or ‘Take with meals’,
occurred in the past, as a result of false readings of drug depending on the type of medicine. Of particular importance
doses in the microgram range. Although modern printers are warnings for staining or bleaching of clothes, or ‘highly
reduce the risk of reading errors, they may never be flammable’. Lack of information of this kind may result in
completely excluded. There is also the risk of false interpre- damage to the user or his property.
tation of this kind of symbols, when changing from one data In some countries, e.g. Switzerland, a warning that the
carrier to another. preparation contains ethanol is compulsory for oral mixtures
Dimensionless notations like percentages are only used in with >0.7 %.
preparations for external application, and, by exception, in According to the European Regulation on Classification,
traditional combinations (normal saline 0.9 %, dextrose Labelling and Packaging of Substances and Mixtures (CLP
5 %). If possible, a percentage should be indicated as m/m, Regulation) [13] (see Sect. 26.6.3) hazard symbols are not
m/v or v/v. According to the EMA the use of percentages compulsory in the labelling of medicines; for patients safety
should be discouraged, and the indication in mg per unit however, symbols referring to the risk of flammability and
weight or per unit volume is to be preferred [8]. explosion are needed. For flammable substances the need
For substances that are standardised biologically, depends mainly on their flashpoint.
biological units are allowed. According to the international As already mentioned, it is not always possible to fit all
system (SI) only the International Unit may be abbreviated the information within the label. Examples are a dosage
(IU). All other units should be written in full. In the UK the schedule for different times of the day, or a reduction
National Patient Safety Agency has recommended that even scheme for corticosteroid treatment. In these situations addi-
IU is not used but should be written out in full [11]. This was tional oral and sometimes written explanation will be
due to a number of deaths that have occurred owing to errors needed.
with abbreviations of (international) units. Also in other
countries errors in dosing were discovered, due to lack of Table 37.1 Recommendations for the expression of the strength of
clarity in the necessary calculations from mg to USP liquids [8]
units [12]. Preferred strength
When labelling infusions or injections concentrations can Parenteral preparation in name Format
be indicated in different ways, as in the following examples: Single dose (in case of total use Total amount in z mg ¼ z mL
of ampoule) container (1 mg/mL)
Potassium chloride 10 mmol ¼ 10 ml (1 mmol/mL) or Single dose (in case of partial Amount per unit X mg/mL
Potassium chloride 10 mmol in 10 ml (1 mmol/mL) or use) volume (z mg ¼ y mL)
Potassium chloride 745 mg ¼ 10 ml (74.5 mg/mL) or Multidose Amount per unit X mg/mL
Potassium chloride, K 1 mmol/mL, Cl 1 mmol/mL volume
In treatments that should have a limited duration for

In the UK patients on steroid treatment receive a pharmacotherapeutic reasons, the duration should be stated
Steroid Treatment Card [14] so that they carry a warn- with the dosing scheme. Examples are strong topical
ing against suddenly stopping therapy (and other infor- steroids, or nose drops with decongestants.
mation) in addition to the dosage schedule.
37.3.2.11 Storage
Storage instructions that are important for the usage period
Dose administration aids, also called compliance aids,
should be on the label (e.g. Keep refrigerated, or Store at
may help the patient to keep the overview. These weekly
room temperature). Sometimes only the pharmacy stock
pill boxes are reusable boxes that allow medicines to be
needs to be kept in the refrigerator, while this is not neces-
housed in grid like compartments, in preparation for sequen-
sary for the short period the patient uses the medicine.
tial dosing according to a prescribed regime. Most boxes
Examples are Acetic acid Ear drops and Atimos® or
cater for up to 4 doses per day for 7 days. See also
Foradil® aerosol. Both ear drops and preparations for inha-
Sect. 37.7.4
lation should be at least at room temperature when used,
because low temperatures can be unpleasant for the patient.
37.3.2.10 Expiry Date and Beyond-Use Date
Expiry date and storage instructions are legally required on 37.3.2.12 Where to Attach the Patient Label
the label of all medicines. After the expiry date the manu- In pharmacy preparations usually the primary container is
facturer cannot guarantee the quality and safety of the prod- labelled. The label on tubes should be near the cap, in order
uct, no matter whether the package has been opened or not. to keep it visible as long as possible during use of the
For most patients however it is more important to know the product. A transparent film can be stuck on top of/over the
expiration period after opening. This is the usage period, or label to protect it from the ointment in the tube. Cartridges
period until the beyond-use date. Therefore the beyond-use that are filled for use in insulin pumps should not be labelled,
date should be on the patient label, rather than the expiry as a label may interfere with the fitting of the cartridge into
date. In some countries pharmacists are required to affix the pump. In such cases the label should be placed on the
beyond-use dates, supposing that the package will be opened secondary packaging instead. Very small containers, such as
shortly after dispensing. In licensed medicines, a beyond-use eye ointment tubes or ampoules, can be labelled with a flag
date is legally required only for special categories, such as label with the minimal information that is required legally on
parenteral medicines, ear drops and eye preparations. the patient label. The remaining information should then
For pharmacy preparations, usage periods per dosage appear on the label of a secondary package, or in a patient
form are given in Table 22.7. These general suggestions information leaflet (see Sect. 37.3.1).
are mostly based on microbiological factors, and sometimes For licensed medicines the patient label is often attached
on physical properties. Often they may also be used for to the secondary packaging. This has the disadvantage that
licensed medicines. See Sect. 22.7. for details. the label with the dosing information becomes lost if the
The general advice for the maximum usage period only patient discards the secondary package. But many primary
apply when there are no limits due to (chemical) instability packages, such as blisters or small vials, are unsuitable for
of the active substance. For nationally standardised labelling or it may simply not be allowed to open the pack-
formulations, both shelf life and usage period usually have age before dispensing. In such cases patient labels can only
been determined. Examples are formulations in the German be attached to the secondary package; preferably a label on
NRF (see Sect. 39.4.2), the Portuguese Galenic Formulary each single container of medicine when more than one is
(PGF) [4] and the Dutch FNA [3], see Sect. 39.4.5. delivered.
The expiry date of pharmacy preparations depends on the
date of preparation, the conditions under which the prepara-
DISPENSING
tion is made, the type of container and the storage 37.4 Instructions on Use
conditions. It should always be part of the label of stock
preparations. In practice, it will not always be necessary for 37.4.1 Oral and Written Instructions
the patient to know this expiry date, as long as the beyond-
use date lies before the expiry date, and the container is When dispensing medicines, oral instructions on use should
opened shortly after dispensing. Most important for the be given in the pharmacy together with additional written
patient is that the label is clear and unambiguous on the information as appropriate. The way patients (or caregivers)
maximum period of storage. receive instructions is one of the factors determining the
quality of their manipulations with the medicine. Also it is

important to try to understand a patient’s capabilities, lan-
guage skills and situation. Research has shown that
demonstrating, followed by copying by the patient, and
additional written instructions all lead to better results, com-
pared to just oral instructions [15]. This study focused on
measuring liquid medicines with a measuring device, but the
same applies to eye drops or inhalers.
Many countries have websites where patients can find
instructions, or let them reproduce the instructions. Drug
manufacturers give information on their websites and
instruction videos for specific medicines. This product infor-
mation is often not appropriate for drugs used in off-label
Fig. 37.2 A tablet in bits and pieces (Photo Marcel Terlouw, Argos.
situations, so in those cases the pharmacist’s advice is even Source: Recepteerkunde 2009, #KNMP)
more important. Information for specific patient groups can
often be found on websites specialising in their disease
(e.g. cancer or diabetes patients). But not all people have
access to internet to access that information.
37.4.2 Packaging
Opening a package in the right way may require explanation

(e.g. eye drop bottles, suppository strips, orally disintegrating
tablets). Sometimes a user may prefer a specific container, for
instance a jar instead of a tube for ointments.
37.4.3 Way of Use

Fig. 37.3 Tablet splitters (Photo Luuk Dreijer. Source: Recepteerkunde
2009, #KNMP)
37.4.3.1 Tablet Types
Solid oral dosage forms need explanation on the type. An information for details of the formula. Enteric coatings, for
effervescent tablet has to be dissolved before use, but small instance, have characteristic components, see also Sect. 4.10.
dispersible tablets could also be swallowed as a whole, with When tablets may be subdivided and they have a break-
a glass of water. Taking the medicine with water is allowed, mark, the halves have to comply with the requirements on
but not necessary in orally disintegrating tablets, which are the uniformity of mass of the Ph. Eur. under Subdivision of
designed to disintegrate on the tongue. Enteric coated tablets tablets [2]. Up till now these requirements only apply for
and dosage forms with controlled release usually must be scored tablets where subdivision is necessary to meet all the
swallowed whole. In Sects. 4.9 and 4.10 an overview is doses that are mentioned in the product information, not for
given of tablet types. break-marks intended to ease swallowing. There are also
requirements proposed on the loss of mass by subdivision
37.4.3.2 Dividing Tablets and the ease of breaking. In a Dutch study on a representa-
Dividing or breaking tablets is another point of interest, and tive selection of tablets with a market authorisation only
not only when it is mentioned in the prescription, or as a 24 % complied with the requirements on the uniformity of
means of obtaining the prescribed dose. In many cases mass of the halves, and 34 % with the proposed standards on
patients divide tablets on their own initiative, to ease ease of subdivision [19]. These results were comparable to
swallowing or because they want to take a lower dose [16, those of other studies on patient experiences with the perfor-
17]. Such actions are not always successful (Fig. 37.2). mance of score lines [16, 17]. A so called tablet splitter can
The package leaflet does not always indicate whether a be useful (Fig. 37.3), although it does not always give better
tablet may be divided, and the presence of a score line does results than a kitchen knife or breaking by hand.
not guarantee that splitting is possible or even allowed That tablets break into unequal halves may not be clini-
[18]. When in doubt, the pharmacist can refer to the product cally relevant, but patients tend to think it is important.
Therefore it would be better if the requirements on unifor-

mity of mass of the Ph. Eur. would apply to all tablets with a do this with a syringe. This percentage rose to nearly
break-mark, whether this is needed for authorised doses 100 % when the participants were given instruction
or not. and a demonstration with the syringe [20]. In 2005
In the meantime the pharmacist can try to reassure EMA has published a guideline on the suitability of the
patients on this point, by using pharmacological knowledge. graduation on measuring devices. Points of attention
are the possibility to measure the minimal and the
maximum dose, the dosing steps in relation to the
37.4.3.3 Measuring Liquids
advised dose, and the readability of the graduation
In pharmacy preparations packaging and measuring devices
[21]. In general it is recommended that a measuring
are part of the design of a product. In other words, attention
cup or syringe should be filled to at least 40 % to
should be paid to the feasibility of measuring the expected
obtain dosing with adequate accuracy (see Sect.
quantities with the supplied device from the container chosen.
29.1.7). For very small volumes this will not always
For licensed medicines however, it is not uncommon that
be possible.
the dosing device in the package is unsuitable to measure the
prescribed quantity to particular patients. In that case the
pharmacist should supply a better measuring device. In
young children administration of liquids with an oral syringe
37.4.3.4 Homogenising
is often easier than with a measuring spoon. Cleaning
When the label of a medicine bears the warning ‘Shake well
instructions for oral syringes and pipettes are important
before use’, some explanation to the patient may be needed
when oily liquids are dispensed. A problem can be that the
to avoid mistakes. For nose sprays, which are suspensions
markings of the oral syringe may begin to wear off with
for instance, the patient should first shake well and then start
normal use in a very short time. To measure the right dose of
pumping, to prevent clogging of the tube.
liquids for use in nebulisers, sometimes sterile syringes and
However suspensions of insulin or other proteins should
needles are needed Fig. 37.4.
not be shaken, but gently rolled to homogeneity. So this kind
of preparations should definitely not be labelled with: ‘Shake
The devices supplied and the way the manipula- well before use’ but ‘Roll gently until well mixed’ instead
tions are carried out can greatly influence the dosing (See also this chapter Sect. 37.7.3).
accuracy.
In a study from the USA, 14 % of the participants
could measure 5 ml of an oral liquid within an accept- 37.4.3.5 Special Devices
able range with a measuring cup, whereas 67 % could Preparations for inhalation are supplied with special devices,
see Sect. 6.5. Inhaling the proper way is essential in order to
(continued)
Fig. 37.4 Measuring spoons,

cups and syringes (Photo Luuk
Dreijer. Source: Recepteerkunde
2009, #KNMP)
DISPENSING
get a sufficient amount of the medicine on the right place,

i.e. the lungs. Young children and many elderly people have • Suppositories may melt with heat. But perhaps they
to use a spacer to be able to inhale the right way. Spacers do not have to be stored in the refrigerator. Look at
exist in different models, depending on the manufacturer of the storage instructions.
the medicine. Often a spacer can only be used with the • Liquids such as oral mixtures or ampoules with
products of the supplier. In these situations counselling starts injection fluids should not be refrigerated as a rule,
with the choice of the right devices, in accordance with the because the cold may affect them in an unwanted
medicine and the age of the patient. After that, (repeated) manner. For instance, crystals may appear in a mix-
instruction will be needed, and control of the patients way of ture. Look at the storage instructions.
inhaling. Section 24.4.19 deals with dosage delivery devices • Eye drops, ear drops and enema’s should maybe not
in general. In the chapters on dosage forms, information on in the refrigerator. Look at the storage instruction.
special devices is included. If these preparations are stored in the fridge, it is a
good idea to warm them in your hands for about
5 min before use. Otherwise they will be very
unpleasant to use.
37.5 Storage
• Always, but especially for medicines in the refrig-
erator, remember: keep medicines away from chil-
An example of storage instructions for the patient is “Store
dren. Put the medicines in a box that cannot easily
below 25 C”. “Keep refrigerated” means: store between
be opened.
2 C and 8 C. The instruction “Keep cool” means between
8 C and 15 C. This advice is often difficult, as not many Carrying your medicines home:
households will have that possibility. Some explanation It can be hot when you are on your way home,
may be needed in the instruction “Keep refrigerated, do coming from the pharmacy.
not freeze”. Depending on the season and the climate, the • Take care that your medicines are in the warmth for
patient has to be warned to put the medicine in the refrig- a period as short as possible. So, if you need to do
erator as soon as possible, to avoid either warming or more shopping, visit the pharmacy at the end and go
freezing. home straight from there. For some medicines a
The following is an example of a patient information cool box may be useful.
leaflet about storage of medicines. • Do not leave medicines in a hot car.
• When you are carrying your medicines going on
Keeping Medicines holiday: do not store your medicines on your body
Store medicines in such a way that they do not deterio- (in your trousers for instance). Keep them in a bag.
rate. For most medicines this is quite simple. When in • Ask your pharmacist if you expect problems in
doubt, check with your pharmacist. For certain categories keeping your medicines refrigerated when
of medicines your pharmacist will give special advice. travelling or on holiday.
Cupboard:
A good place to store most medicines is a dry Typical patient questions on this subject have to do with
cupboard, where the temperature will not exceed storage during holidays and temporary storage at temperatures
25 C. Even during periods of extreme warm weather higher than they should be. Information on this subject is not
your medicine is safe there. Such a cupboard is accept- always clear from the information leaflet, but often medicine
able if the label does not mention any special storage manufacturers will have additional data on request. A large
instruction. The bathroom is not a good place to store amount of such data has recently been compiled [22]. That
medicines: it is too damp there. booklet covers storage of a broad range of medical products.
Refrigerator: Especially the sections on insulins, vaccines and medical
• Do you have to store medicines in the fridge when it devices give much information.
is hot? Not necessarily. Look at the storage instruc- For the application of the theoretical background of sta-
tion on the label or the package leaflet. Ask your bility at different temperatures in daily practice see Sect.
pharmacist when in doubt. 22.6. More detailed information about storage and transport
in general can be found in Sects. 36.9 and 36.10.
(continued)
alteration of the dosage form should be done in cooperation

37.6 Special Patient Groups with the physician.
The need for (extra) help and counselling by the pharmacy

37.6.2.1 Easing Swallowing
depends not only on the type of medicine, but also on the
The taking of medicines which need to be swallowed is not
cultural, educational, linguistic and medical condition(s) of
easy for every patient. Severe swallowing problems are
the patient.
called dysphagia and require treatment. But every patient
can benefit of knowing how to swallow most easily. When
taking medicines, people often automatically tilt their head
37.6.1 Disabilities or Ergonomic Problems back but this interferes with the swallowing action. If tilting
the head slightly forward while swallowing, the throat adopts
For patients with rheumatism several assistive devices exist, the natural curve and widens. As a result, the oral solid
such as easy to open tablet containers and devices for open- medicine slips easily inside and does not stick in the throat.
ing blister packaged medication [23]. Tablet splitters have A sip of water before and after swallowing also helps the
already been mentioned (Sect. 37.4.3). A variety of assistive medicine to go down.
devices are available for the administration of eye drops. See As an alternative dosage form to ease swallowing, not
Sect. 24.4.19.8. only are oral liquids an option but also chewable tablets,
According to the EMA templates the name of a licensed granules, disintegrating tablets. oromucosal or orodisper-
medicine should be on the package in Braille, for blind or sible tablets.
short-sighted patients. If this is not possible, the manufac- Being unable to swallow tablets and capsules is not
turer has to provide justification for such exclusion and the uncommon and occurs in any age group, most common
relevant national authorities must agree with it [1]. The however in young children and the elderly.
Braille is only readable if the label of the pharmacy is not Children under 2 years cannot swallow oral solids. Only
put on top of it. Patients with impaired hearing may have from the age of 7–8 the swallowing of tablets generally gives
problems in hearing the ‘click’ of an insulin pen or an auto- no problems [24, 25] although a throat infection may bring
inhaler. the problems back again.
When the patient is not able to carry out the In the elderly, a stroke, neurological problems such as
manipulations that are needed, the pharmacy can offer to Alzheimer’s disease or Parkinson’s disease may give rise to
help. Examples of this are: dysphagia as well as specific medication.
• Opening a package or a seal Some people may have an aversion to swallowing
• Supplying ready to use mixtures for nebulisers, provided medicines because they imagine the medicine getting stuck
of course that the mixture has sufficient stability; see in the throat or they fear retching. Patients who have had a
Sect. 6.6.5 feeding tube may also experience swallowing difficulties.
• Breaking tablets (in amounts for a limited period, as the Pharmacists may advice patients to consult a speech or
package and therefore the storage conditions are swallowing therapist for the assessment and eventual treat-
changed) ment of dysphagia. In severe cases of dysphagia, the patient
may need a feeding tube to bypass the part of the swallowing
mechanism that is not working normally.
37.6.2 Swallowing Problems
A patient, who got crushed medicines because of
Swallowing problems often make patients ask for a liquid swallowing difficulties, was referred to a speech ther-
dosage form of (licensed) medicines that are on the market apist at the request of a new nursing home doctor. The
only as a tablet or capsule. Or worse, they may crush tablets speech therapist investigated the patient’s swallowing
DISPENSING
that are to be taken as a whole. The careful choice of active and noticed that the swallowing function was all right
substance and dosage form is an important step in pharma- but that the patient was afraid of tablets getting stuck
ceutical care for this kind of patients. Instruction about in the throat. The fear was overcome by exercises and
easier swallowing may be worthwhile. But even then the medicines did not needed to be crushed anymore.
some adaptation of the medicine may be necessary. Any
37.6.2.2 Suspension from Tablets is not that

Simple
The preparation of a suspension by crushing a number of
tablets will lead to a mixture of uncertain quality. Therefore
this is not the method of choice to change a solid oral dosage
form into a liquid one that can be used for some period. Badly
formulated suspensions create too great a risk for a patient to
be acceptable. The suspended part consists of the excipients
and possibly (part of) the active substance. The various
components that are needed to make a tablet may affect the
physical stability of the formulation, once in solution. The
physical form of the active substance is not always clear and
cannot be found out by visual control. The quality of such a
suspension depends on the suspension base, the tablet formula
and the way of preparation. To know the stability and storage
period of a suspension, physico-chemical data are needed. For
many suspensions made by crushing tablets data of this kind
may have been published, but often only the chemical stabil-
ity of the active substance was investigated. Although this is
useful information, it does not say much about the physical
stability of the suspension. Besides, the physical stability of
the suspension may be different when tablets of a different
brand are used as raw material. See also Sect. 5.5.1.
It is the physical stability that determines the dosing
accuracy of a suspension. To assure the quality of the final
product, it is best to process just one dosage unit shortly
before administration.
Fig. 37.5 PillDrink device for crushing tablets in case of

37.6.2.3 Methods of Processing Tablets swallowing problems (Photo Inresa, France, with permission)
for Ingestion
Two ways exist of processing a tablet to obtain a dosage
form suitable for patients with swallowing difficulties: For reasons of unintended exposure to medicines the
crushing the tablet first, or letting it disintegrate in water syringe method is preferred, especially when it is not the
by shaking in a capped syringe. In most cases lukewarm patient who carries out the preparation. The disadvantage of
water (35 C) will do for processing a tablet in a syringe. For shaking in a syringe is that it can be time-consuming. When
some dosage forms (coated tablets, soft capsules) it may be a number of tablets have to be processed, time is often
necessary to use warm water (60–70 C). But crushing important. For all of these methods it is best to process one
tablets, followed by mixing with food, is normal practice. solid dosage unit at the time.
Crushing in a mortar causes more loss of material than Only regular (coated) tablets should be crushed to powder.
shaking in a syringe. There are however automated tablet Enteric coated tablets and tablets with controlled release will
crushers on the market that minimise the loss of material. lose their pharmaceutical properties when they are crushed.
Cleaning of this type of apparatus is important, because of The active substance will be released on the wrong site, or all
the risk of cross contamination when different tablets are at once, leading to an unacceptable overdose [27].
crushed one after another. When crushing and mixing with food care must be taken
due to physico-chemical or pharmacokinetic interactions
A so-called crushing syringe is another possibility for with food. Because dairy products show many interactions,
crushing tablets. It includes a barrel and a plunger with a product such as apple sauce is generally preferred (see
abraded surfaces on each. The plunger is meant to Sect. 16.1.6)
work as a pestle and after crushing liquid can be
sucked up in the syringe. A variation of this method 37.6.2.4 Capsules
is obtained with the PillDrink [26], see Fig. 37.5. Most licensed hard capsules can be opened. After opening
the capsule, powder content can be handled in the same
(continued)
manner as crushed tablets. Granules often may be mixed differ from injection syringes in such a way that needles
with food, provided they are not crushed. The pharmacy cannot be attached.
can prepare capsules, if a dose is needed that does not Especially on a hospital ward it may be quite normal for
correspond with one tablet or half a tablet, and no liquid injection solutions to be held as stock. This brings the risk
form is available. The methods of processing a tablet are not that a request for the nurse to administer is misinterpreted,
suitable when only part of the dose is needed. Lactose is and the injection solution is administered parenterally in
preferred as filler for capsules, because it is soluble in water error. For that reason the oral use of injection solutions in
and artificial feeding. hospital wards is in general not recommended, although in
paediatrics it is often unavoidable.
37.6.3 Feeding Tubes 37.6.3.3 Solid Oral Dosage Forms

The methods that were mentioned under the heading
Some patients with a feeding tube are still able to swallow. ‘swallowing problems’ can also be used when making
In those cases they can take their medicines orally, along the medicines ready for gastro-enteral administration. The
feeding tube. For enterally tube-fed patients not able to particles that are obtained after crushing or disintegrating
swallow alternative routes of administration may be a possi- must be small enough, so that they will not block the feeding
bility. If no other routes are available, medicines will have to tube. After crushing the powder is brought into a cup with
be administered through the enteral feeding tube, although the aid of water, and sucked up with a syringe. Crushing
this has limitations (see also Sect. 5.4.3). Apart from tablets followed by moving the powder will lead to loss of
interactions of medicines with enteral feeding, there may material, thus to lower dosing. This can be avoided by
be the risk of blockage of the tube, or interactions between rinsing with water and taking care that nothing is left. This
medicine and tube material Solvents other than water in applies especially to medicines with a small therapeutic
particular are at risk of interactions. The emulsifier acetem, window, such as acenocoumarol [28].
for instance, cannot be used in PVC tubes. PVC contains Using extra water for rinsing may be a problem in
plasticisers that can migrate to the acetem. When crushed patients with fluid restriction. Letting the tablet disintegrate
solid dosage forms are given, too coarse particles may block directly in the syringe reduces loss of material without using
the tube. Especially the narrow tubes for children are prone extra water, but the disintegration time may be a practical
to this kind of problems. hindrance.
For gastro-enteral administration the following dosage
forms are possible, each with their own points of attention
in the manipulations before passing down the tube: 37.6.4 Compliance Aids and Individualised
• Liquid oral medicines Dispensing
• Injections
• Solid oral dosage forms (after processing) Many types of compliance aids exist, all with the aim that
patients take their medicine at the correct time and do not
omit them. There are several systems of individualised dis-
37.6.3.1 Liquid Oral Medicines pensing of medication by a pharmacy besides the boxes for
Liquid licensed medicines or standard pharmacy arranging weekly medicines that can be filled by the patient
formulations should be diluted when they are too viscous. himself. This means that the medication is packed in an
organised way, according to a time schedule, for a specific
37.6.3.2 Injections patient. These systems are mainly used in nursing homes and
The gastro-enteral administration of an injection is a possi- residential homes, but also for individual ambulant patients
bility; provided the active substance will tolerate the acid they are becoming more popular in many countries. Particu-
DISPENSING
environment of the stomach, and the pH of the solution is not larly elderly patients taking many different medicines and
too high to be tolerated. Especially in young children atten- psychiatric patients may benefit of this service. Patients
tion should be paid to unwanted excipients, e.g. ethanol or receive their medication every week (or every 2 weeks) in
benzyl alcohol. Good instructions and clear labelling will a week tray (so called blister pack) or in small bags, one for
help in preventing administration errors by the patient or each day and each time of the day.
caregiver. The solution for injection can, for instance, be Besides advantages these systems may have drawbacks:
transferred to a bottle in the pharmacy and provided with an opening of the package can be a problem for the patient and
oral syringe before dispensing. For Percutaneous Endo- the manufacturer’s package leaflet is lacking. The labelling
scopic Gastrostomic (PEG) ports special adaptors for oral needs extra care, and should preferably enable identification
syringes exist. Oral syringes and syringes for feeding tubes of each tablet in the package. It is perhaps even more
important that the pharmacy should provide the right infor- 37.7.2 Antineoplastics
mation to the patient or caregiver. In nursing homes or
hospital wards the distribution or administration of medica- Dispensing most antineoplastics or other medicines with
tion often has to be ticked off on a list that is produced by the carcinogenic substances, requires specific warning and
pharmacy. Especially for patients with swallowing information and possibly supply of the materials needed
problems, it is of great help to the caregivers to give infor- for safe handling (e.g. needle containers, gloves or dispos-
mation on this list what manipulations are allowed for the able mats). The effects of these medicines on other people
solid dosage forms. than the patient who has to use them can be seriously
Repacking solid dosage forms for individualised dispens- harmful. The patient and his or her caregiver(s) have to
ing results in changed storage conditions. This implies that handle preparations with carcinogenic substances in such a
the date of expiry on the label of the original package is not way that the risk of exposure to caregivers and house mates
valid anymore. This has to be kept in mind in those situations is minimal (see also Sect. 26.5.4). Patient information on
when the patient needs medication for a period longer than handling this type of medicine at home should contain at
1 or 2 weeks, i.e. for a holiday. least the following topics:
• Storage
• Instructions on use for that particular dosage form
37.7 Special Types of Medicine • What to do if medicine is spilt
• Disposal of waste and excretion products
37.7.1 Suspensions Store antineoplastics in a separate box when they have to be
kept refrigerated, to avoid contact with food. Tablets should
The chemical stability of some active substances, typically not be broken and capsules not opened. Reconstitution of
antibiotics, makes it impossible to bring them on the market powders for suspension should be done only if suitable
in a liquid dosage form. In these cases the licensed medicine precautions have been taken to protect the persons who
is a powder for suspension that has to be mixed with water carry out this kind of preparations.
before use. In some countries this mixing is done in the The use of disposable, absorbant mats are recommended
pharmacy, shortly before dispensing, as patients usually do in handling liquid preparations, to absorb any spilt material.
not have a graduated cylinder to measure the prescribed Patients should wash their hands after use to prevent con-
amount of water. Sometimes the manufacturer has put a tamination of the eyes or other objects. For caregivers wear-
grade mark on the bottle, but this does not guarantee that ing disposable gloves is recommended. The more so in the
the patient can produce an adequate suspension. The powder administration of cutaneous medicines like coal tar
contains viscosity enhancers that may produce insoluble preparations. After unprotected exposure during clinical
lumps with water. Shaking the bottle first, to loosen the coal tar treatment a small rise of the amount of PAH’s
powder, is an important step. The second problem can be (Polycyclic Aromatic Hydrocarbons) in the urine was
that surface active substances in the powder will cause foam, found in 70 % of the nursing personnel [29].
which makes it difficult to see if the grade mark has been If this type of medicine gets accidentally on the skin, it
reached already. Section 5.4.6 gives detailed information on must be washed off immediately. Spilt antineoplastics must
the formulation and preparation of oral suspensions. be absorbed in disposable material before any further
Suspending a powder for injection in a solvent before use cleaning. The disposable material, waste material of wound
is another common procedure. In these dosage forms homo- care and empty packages should be disposed of in a double
geneity is important in order to get the complete dose out of waste bag that can be closed securely. Needles and syringes
the vial. Too coarse particles or too high a viscosity may can be put in a needle container. Because the medicine and
cause problems by blocking the needle. its degradation products will also get into urine and faeces,
Oral suspensions should best be prepared in the pharmacy special precautions are required in going to the toilet and in
just before dispensing, but in situations where this is not the handling of bedpans or urinals. This means that the toilet
possible, e.g. on holidays, it will have to be done by the should only be used in sitting position (for gentlemen also),
patient. In such cases the pharmacy could supply a bottle and flushed twice with the lid closed. Aprons and gloves are
with a grade mark, to measure the right amount of water. needed in the handling of bedpans and urinals.
Some suspensions have such a limited stability, that they From a medication safety point of view, the exact number
have to be prepared just before use. An example is an enema of tablets for one course of treatment should be dispensed to
with budesonide, where the active substance is incorporated the patient, not less and not more. In practice, this may be a
in a dispersible tablet, that has to be added to a solution for risk for pharmacy personnel, especially in the dispensing of
rectal suspension. Here again, correct instruction of the user non-blistered tablets. If for this reason a larger number of
or caregiver is important. tablets have to be delivered, it is important to inform the
patient, for instance on intermittent use and the return of infusion). The manipulations may be done in a (hospital)
leftovers to the pharmacy. From case reports is known that pharmacy in a Laminar Airflow (LAF) cabinet (cross or
even the combination of oral and written information is no down flow) or isolator, or by nurses on the ward, or by the
guarantee that the patient will understand how the medica- patient at home. If aseptic handling is carried out under quite
tion should be used, in particular for complicated dosing different conditions, it may lead to a difference in the risk of
schemes [30]. A safer way would perhaps be to call the contamination of the sterile product. Or the other way round:
patient by telephone at the end of the foreseen course of the risk of contamination of the product defines the
treatment, to make sure that the information was understood conditions for reconstitution of parenterals (aseptic
properly. handling). See Sect. 31.3.1 for more information. The degree
of product protection and the complexity of the handling are
the two factors that determine whether the preparation may
37.7.3 Protein Medicines take place some time prior to the administration. The greater
the complexity of the handling, the more often the prepara-
Many new active substances are proteins or peptides, which tion will be done in the (hospital) pharmacy, rather than on
can only be administered parenterally. Proteins and peptides the ward or at home. It is only in a purpose-built aseptic unit,
are often unstable, and therefore need extra care in recon- in or outside the (hospital) pharmacy, that aseptic handling
stitution, storage and transport. Most protein medicines can be carried out with the degree of product protection
have to be kept refrigerated (2–8 C). Storage at too high needed (see Sect. 37.8.2). Chapter 31 deals with the details
temperatures will soon cause loss in biological activity. of aseptic handling and processing.
Temperatures below zero give even more risk of breaking
up the protein structure. See also Sects. 22.2.5 and 18.4.1. 37.7.4.1 Simple Reconstitution (Often by
Any form of shear stress applied to proteins will have an the Patient)
adverse influence on their stability. Peristaltic pumps are In order to make reconstitution of sterile products simpler
best avoided, and solutions should not be shaken, as shaking for the patient, new types of packaging have been developed.
may also cause foaming. The material of primary containers After instructions most patients can manage the more simple
and of devices for reconstitution and administration may types, for example pre-filled syringes and auto-injectors.
affect the activity of the protein. Not only adsorption is This type of packaging is usually intended for once-only
possible, but also interaction with plasticisers or other administration of a fixed amount of liquid. Some pre-filled
components of the packaging material. When proteins syringes however are intended to administer different doses.
come into contact with hydrophobic surfaces, aggregation The patient first has to measure the correct amount. From a
may occur. Protein aggregates are undesirable, not only medication safety point of view this is not the preferred
because of loss of activity. Aggregates are thought to cause method, because it requires special instructions to remove
immunogenicity [31]. part of the content of the syringe in a safe way. Injection
The solubility of (freeze dried) proteins in powder form pens, that contain a cartridge filled with injection solution,
may diminish when moisture is attracted. are intended for multiple use when needed in different doses.
Many proteins are not on the market as a ready-to-use This type of medicine requires to be made ready to adminis-
solution. The licensed product consists of a vial with freeze ter. It may also need to be brought to room temperature and
dried powder, and sometimes an ampoule of the solvent. in addition homogenising, setting the right dose and
This kind of products should be reconstituted just before inserting a new needle. These pens require carefully worded
use. Gently swirling, not shaking, is the way to get such instructions and some skills from the patient. The best
powders into solution. Protein suspensions for example known examples are the insulin pens, which appear in new,
long-acting insulins, should be resuspended by rolling the improved types rather frequently. Besides instructions, sup-
ampoules between palms instead of shaking. plying patients with a container for used needles and syrin-
DISPENSING
ges (so called sharps bin) should be part of the counselling.
Patients should handle this waste in the same manner as
37.7.4 Sterile Products unused medicines, that is as hazardous waste. The options
to dispose of it will vary in different countries, or even per
Sterile medicines, and parenterals in particular, often require area within a country, but a secure package for the needles is
reconstitution (sometimes in excess of the SmPC) to make the first condition. See also Sect. 38.5.2.
them ready to administer. Reconstitution of parenteral
products requires aseptic handling (see Sect. 31.1). This 37.7.4.2 Complex Reconstitution (in the Hospital)
handling can be simple (drawing up of a solution in a syringe For reconstitution in excess of the information in the SPC
for direct injection) or complex (preparation of a cassette (meaning in ways not indicated in the SPC), product knowl-
reservoir with a number of substances for continuous edge is one of the main conditions (see Sect. 22.6). This
means information on reconstitution, possible dilutions,

chemical stability and incompatibilities. Instructions for the In emergency situations drawing up 0.1 mL might
nurses should describe, for each medicine, the reconstitution also be chosen, because diluting first would take too
or preparation process (including diluents and incompat- much time.
ibilities), the route of administration (route, site and rate)
and, if relevant, storage of the ready-to-administer product
and the necessary in-process controls . In the description of
the reconstitution the necessary care should be given to the
accuracy that is required to obtain the correct dose. The 37.8 Instructions for Professional Caregivers
pharmacist though needs background information about the
active substance, such as solubility, pKa and stability in 37.8.1 Reconstitution and Manipulation
relation to pH. This information enables him to answer Outside the Pharmacy
questions, or to write instructions where these are lacking.
Physico-chemical knowledge is the indispensable basis upon In nursing homes, residential homes and hospitals reconsti-
which to predict incompatibilities. tution and other manipulation, and often administration as
On occasion parenteral therapies are given at home well, are tasks carried out by the caregiving personnel. So
instead of in the hospital. Some patients can learn to admin- they are the ones that instructions and coaching should be
focused on. In many cases their level of education will not be
ister the medicine (to) themselves. When this isn’t appropri-
ate, support from home care organisations can be arranged. sufficient for a reliable handling of medicines for their
In these situations community pharmacies can play a role, in patients. From Dutch studies it is known, that personnel in
nursing homes and residential homes do not consider them-
giving advice as well as in the actual reconstitution.
selves sufficiently competent enough to carry out reconstitu-
tion or other manipulation prior to administration in the
Dosing accuracy in parenterals depends on the accu- proper way [34, 35]. This is particularly true for
racy of the syringes used, the dead volume in the manipulating oral solid forms, for patients with swallowing
syringe (see Sect. 29.1.7) and what stays behind in problems or a feeding tube, and for reconstitution of paren-
the needle. This is important in the following teral medicines. In the Dutch Medication Error Report Pro-
manipulations: gram in 2012 5 % of the reports had to do with
• Minimal volume measurable with a given syringe reconstitution. Twenty four percent of the errors were
• Measuring reconstituted solutions ‘wrong dose’ errors, probably as a result of miscalculations
• Diluting solutions by mixing in a (large) syringe [36]. Five years before a study on the mathematical skills of
In a Canadian study on morphine infusions, diluted for nurses in four Dutch hospitals concluded that their level was
syringe pumps, the measured concentration of 65 % of insufficient for the ‘pharmaceutical’ calculations required
the solutions varied >10 % from the ordered concen- [37]. In the meantime various measures have been taken to
tration. The concentration of 6 % of infusions showed improve this situation. However, in a multinational study of
deviations of >20 % [32]. In a second study, a differ- 2009 (27 countries on five continents) on errors in adminis-
ence of >10 % of the intended content was found in tration of parenteral drugs in Intensive Care units, 75 errors
25 % of methotrexate products for intravenous use per 100 patient days were found. Nearly 15 % of them were
[33]. In this study the differences in content turned wrong dose errors, ca. 5 % wrong medicine and ca. 5 %
out not to be clinically relevant, which will often be wrong route [38].
the case. Working routines however should aim for the
reduction of avoidable faults to acceptable values.
What faults are avoidable and what values are accept- 37.8.2 Parenteral Medicines
able will depend on the situation. Generally a differ-
ence of 5–10 % of the intended dose is tolerated, but Whoever will actually carry out the reconstitution and other
there are exceptions. Exceptions may have to do with manipulations to make parenteral medicines ready to admin-
the formulation and availability of licensed products, or ister, instructions will be needed. In many hospitals
with the required speed of working in emergencies. An pharmacists have written a ‘Parenteral guide’ or ‘Parenteral
example is the drawing up of 0.1 mL of a suspension in Manual’ including standard operating procedures to guide
a syringe. It is impossible to measure this amount the personnel and compiled monographs on specific
within the standard limits of accuracy. As diluting products. It has been shown that working according to a
will not be an option for a suspension, there is no protocol can improve the quality of reconstitution and
other choice, other than a less concentrated product. administration of parenteral medicines [39]. Information on
the general procedures can be found in Sect. 31.3.
(continued)
In several countries governmental organisations or exposure to hazardous substances. Normally the manage-
associations of professionals have developed detailed ment of the institution will be responsible for health and
guidelines on this matter [40, 41]. safety at work, but the pharmacist is the person who can give
advice on safe handling of possibly hazardous medicines.
The handling of antineoplastics is dealt with in Sects. 37.7.2
37.8.3 Oral Solids and 26.8. Within health care institutions, transport needs
special attention. Hazardous preparations should be clearly
It is more often than not the case that in nursing homes, the marked so as to make them easy to identify, and transport
percentage of tablets that are crushed before administration personnel should be aware of the risks, and trained to appro-
is often higher than what one would expect as a pharmacist priate action in case of spillage accidents.
[34]. Sometimes enteric coated tablets or slow-release The administration of antineoplastics in hospitals usually
formulations that should be swallowed as a whole are follows special rules. These rules ensure that the risk of
being crushed. National organisations of nurses or exposure to hazardous substances or contaminated material
pharmacists, and also hospitals have published general by hospital personnel is reduced to a minimum.
guidelines on this subject and also an ‘Oral Guide’ or ‘Oral
Manual” with monographs on specific products [35, 42], see
also Sect. 39.2.1. 37.9 Special Categories of (Medicinal)
According to some guidelines, prescribers are to indicate Products
on the prescription if a tablet should be crushed before
administration, preferably after consulting a pharmacist. As 37.9.1 Veterinary Medicines
this does not always happen, it would be more practical if not
only the prescriber but also the pharmacist would know The EMA has published guidelines on the labelling and
when a patient has swallowing problems, or an enteral feed- packaging of veterinary medicines [43]. In addition to
ing tube. In that case, he or she can take into consideration if these guidelines many countries have specific requirements
manipulations with the dosage form are allowed for each for the labelling of veterinary medicines that are available on
new prescription. prescription only. In some countries it is normal practice for
By analogy with monographs on specific products for veterinary medicines to be supplied by pharmacists (see
parenteral use, such data are also wanted and in some Sect. 2.4.4), but often this is done by veterinarians. When
countries already compiled for oral solid medicines. The dispensing veterinary medicines, the pharmacist should be
pharmacist can consult the manufacturer about crushing able to give the correct instructions on use to the owner of
tablets. However, if this information about crushing is not the animal. The administration of liquids, for instance, will
in the SPC, crushing means using the medicine in an unli- be simpler with a syringe than with a spoon. Whether
censed way. Therefore it may be useful to record the crushing of tablets is allowed may be important, although
reasoning of decisions made (for instance by one of the in general it is easier to hide a whole tablet in a piece of meat
forms in Sect. 2.2). than a powder.
When a number of tablets have to be administered, they In short, the same principles apply as in counselling
should preferably be crushed one by one. As this is time- special groups of human patients: focus on the needs of the
consuming, in settings such as nursing or residential homes particular animal species (and its owner) to help them make
different tablets may be crushed together. Usually the risk of the best use of the medicine.
unwanted chemical reactions by this method will be negligi-
ble, so it can be acceptable. But there are exceptions, where
the pharmacist should warn the patient or caregiver to keep 37.9.2 Medical Devices
the tablets separated. Examples are combinations of acid and
DISPENSING
basic substances, i.e. ascorbic acid and sodium hydrogen For the definition and legislation of medical devices see
carbonate. Sect. 2.4.5. Examples range from a simple sticking plaster
to a pacemaker or surgical instruments.
The manufacturer should have drawn up a file with tech-
37.8.4 Occupational Health and Safety nical information on the product, but this is not made public.
Therefore it is often difficult for the pharmacist to get the
When reconstitution and other manipulation to make information needed for instruction and counselling of
medicines ready for administration is carried out in health patients or users. The manufacturer has to provide
care institutions, working conditions have to be considered. instructions on use of his product, but these are not always
Frequent crushing of tablets may cause wrist problems and clear. Besides, specific knowledge may be required to make
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DISPENSING
Impact on Environment
38
Bengt Mattson and Tessa Brandsema
Contents Abstract
It is probably clear to everyone that pharmaceutical
38.1 Environmental Hazards and Risks . . . . . . . . . . . . . . . . . . . . 830
products have increased the quality of life tremendously
38.2 Regulatory Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830 for billions of people around the globe over the years.
38.2.1 Environmental Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
38.2.2 Pharmaceutical Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831 During the last decade it has also become more and more
evident that manufacturing and use of medicinal products
38.3 Manufacturing of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
may impact negatively on the environment.
38.4 Pharmacy Operations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831 The impact on environment may occur throughout the
38.4.1 Preparation of Medicines in Pharmacies . . . . . . . . . . . . . . . . . 831 life cycle, from manufacturing and preparation, through
38.4.2 Preparation from Raw Materials . . . . . . . . . . . . . . . . . . . . . . . . . 832
38.4.3 Generation of Waste Such as Overalls and Gloves . . . . . 832 distribution and dispensing, to patient excretion and final
38.4.4 Packaging Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832 disposal of unused medicines and waste.
38.4.5 Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 The impacts include the potential emissions and
38.4.6 Waste Disposal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
discharges of medicinal substances, so called active
38.4.7 Energy Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
substances, as well as other chemicals and solvents
38.5 The Use of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834 used. Active substances are biologically active, and
38.5.1 Patient Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
38.5.2 Unused Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
hence it is likely that they will potentially affect
38.5.3 Potential Mitigating Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . 836 organisms, e.g. water living organisms, if released into
the environment. Eventually they could also negatively
38.6 Essentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836
affect humans if concentrations in the environment
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836 increase high enough.
This chapter gives a general introduction, with
references to the regulatory framework and briefly
discusses environmental impacts from manufacturing of
medicines, from patient excretion and from unused
medicines. Although releases from manufacturing
operations have received increased interest during previ-
ous years it should be realised that the major cause of the
presence of active substances in the environment is the
excretion of substances by humans and animals that sub-
sequently find their way into surface waters through
Based upon Chapter Milieu by Yvonne Bouwman-Boer en Mirjam Crul municipal waste water treatment systems.
in the 2009 edition of Recepteerkunde. Impacts from pharmacy operations are described and
B. Mattson (*) discussed in more detail and the chapter provides
LIF, The Swedish Research-Based Pharmaceutical Industry, proposals for actions to be taken to minimise the environ-
Box 17608, Stockholm 118 92, Sweden mental burden.
T.E. Brandsema
ZGT Apotheek Almelo, Zilvermeeuw 1, Almelo 7609,
The Netherlands

830 B. Mattson and T.E. Brandsema
Keywords slowly or not at all, it is likely that the concentrations in the

Medicines Environment Pharmacy operations Waste environment increase over time, and hence the environmen-
Packaging materials Energy Excretion Unused tal risk (i.e. PEC/PNEC increases).
medicines Highly lipid-soluble active pharmaceutical substances
may have the ability to bioaccumulate in the fat tissue of
animals. Animals higher in the food chain are most suscep-
tible. They eat animals that in turn have eaten other
38.1 Environmental Hazards and Risks organisms that may have accumulated the substance. A top
predator may hence be exposed to higher concentrations of
The inherent environmental hazard of a pharmaceutical sub- the substance once again the risk has increased. Active
stance is taken to mean it’s toxicity, it’s potential to safely pharmaceutical substances are classified in regard to
degrade and it’s potential for deposition in fat tissue in, for bioaccumulation based on standard laboratory tests.
example, fish. An active substance that is considered highly
potent and toxic for humans and posing occupational
hazards as well to operators and healthcare staff will not
38.2 Regulatory Framework
automatically be the one posing the greatest environmental
risk. For example an antineoplastic, which is very toxic, may
The environmental impact from pharmaceutical
be easy degradable or only given to few patients. In both
manufacturing operations and use of medicinal products is
cases it may result in a negligible environmental risk. Of
regulated on the European level by the environmental legis-
course, it is crucial to use and handle such substances
lation and the pharmaceutical legislation respectively. Gen-
correctly and with the utmost care, but less potent and less
erally: pharmaceutical substances as chemicals are covered
toxic substances used in greater quantities may result in
by legislation on chemicals, unless specific legislation exists
higher environmental risks. Thus it is important to distin-
for medicines, which will prevail over the general legislation
guish between the hazard of an active substance when given
on environmental matters.
to patients, when used by operators and when disposed in the
environment. Subsequently there is a difference between the
environmental hazard and the environmental risk in which
38.2.1 Environmental Legislation
the quantity is taken into account:
Risk ¼ hazard quantity: Environmental regulations that are fully or partly applicable
to pharmaceuticals include, but are not limited to:
To assess whether a pharmaceutical substance poses an
environmental risk or not, first the highest concentration of 38.2.1.1 IED (Industrial Emissions Directive: 2010/
that specific substance has to be discovered which will not 75/EU) [1]
cause negative effects in animals and plants. The tests for Industrial production processes account for a considerable
this level are tests standardised by e.g. the Organisation for share of the overall pollution in Europe: emissions of green-
Economic Co-operation and Development (OECD), Interna- house gases and acidifying substances, waste water
tional Standards Organisation (ISO), Food and Drug Admin- emissions and waste. In order to take further steps to reduce
istration (FDA). Since the classification focuses on possible emissions from such installations, the European Commis-
adverse aquatic environmental effects, the data usually apply sion adopted the Directive on industrial emissions on
to algae, daphnia and fish. From these data the ratio between 21 December 2007. The IED entered into force on 6 January
predicted no-effect concentration (PNEC) and the 2011. The IED is, in essence, about minimizing pollution
anticipated concentration (PEC, predicted environmental from various industrial sources, e.g. manufacturing of
concentration) is calculated: PEC/PNEC gives a number pharmaceuticals, throughout the European Union.
between 0 and infinity, and as long as it is below 1 the risk
is regarded insignificant or low and to be under control. 38.2.1.2 REACH – EC 1907/2006 [2]
There are several ways in which substances naturally REACH is the European Community Regulation on
degrade. Biological degradation takes place in soil or water chemicals and their safe use (see Sect. 26.6.2). It deals
by means of microorganisms. Non-biological degradation is with the Registration, Evaluation, Authorisation and
based on chemical reactions or reactions to UV rays in Restriction of Chemical substances. The law entered into
sunlight. Substances are classified regarding biodegradation force on 1 June 2007. Medicinal Products on the EU market
according to standard laboratory tests. If substances degrade are exempted since they are regulated by the pharmaceutical
38 Impact on Environment 831
legislation (see Sect. 35.5.2). Manufacturing and handling of effects of pharmaceuticals on the environment are studied
active substances as raw materials, as well as Quality Control and adequate precautions taken in case specific risks are
activities are however covered by the REACH legislation. identified. The environmental risk-assessment (ERA) of
medicinal products is to be performed by companies during
38.2.1.3 Packaging and Packaging Waste the development of new medicines. The results are submit-
Directive: 94/62/EC [3] ted to the European Medicines Agency for evaluation in
The directive provides for measures aimed at limiting the conjunction with the scientific data on quality, safety and
production of packaging waste and promoting recycling, efficacy required to support the request for marketing
re-use and other forms of waste recovery. Their final dis- authorisation of medicinal products intended for human or
posal should be considered as a last resort solution. The veterinary use via the centralised procedure.
directive covers all packaging placed on the European mar-
ket and all packaging waste, whether it is used or released at
industrial, commercial, office, shop, service, household or 38.3 Manufacturing of Medicines
any other level, regardless of the material used.
Industrial manufacturing of active substances as well as
38.2.1.4 WFD (Water Framework Directive [4]) medicinal products, like the manufacturing of all other
On 23 October 2000, the Directive 2000/60/EC of the chemicals, is regulated by e.g. the Industrial Emissions
European Parliament and of the Council establishing a Directive as described briefly in Sect. 38.2.1.1. During the
framework for the Community action in the field of water last 5 years, special interest has been given to releases of
policy or, in short, the EU Water Framework Directive active substances from manufacturing facilities. Releases
(or even shorter the WFD) was adopted. There is a list of regarding large quantities of active substances reaching the
so-called priority substances within WFD. For substances on environment have been described e.g. by Joakim Larsson
the list of priority substances an Environmental Quality et al [5] and by US Geological Survey [6]. Releases from
Standard (EQS) have to be developed. The EQS sets the manufacturing facilities could result in environmental
limit on the concentrations allowed in EU water bodies. concentrations at the point of discharge from a factory or a
Three active substances (ethinylestradiol, estradiol, and waste water treatment plant that are larger than the relevant
diclofenac) were included on the so-called Watch List in PNEC and hence will present an environmental risk (see
2013 to be further evaluated for a potential future inclusion Sect. 38.2.2).
on the List of Priority Substances.
38.4 Pharmacy Operations

38.2.2 Pharmaceutical Legislation
38.4.1 Preparation of Medicines in Pharmacies
Pharmaceutical legislation contains requirements on unused
medicines and on an environmental risk assessment of active The International Pharmaceutical Federation (FIP) and
substances: WHO have developed guidelines on good pharmacy prac-
tice. Those guidelines state [7]:
38.2.2.1 Unused Medicines – Good Pharmacy Practice requires that an integral part of
Under Article 127b of EU Directive 2001/83/ (Community the pharmacist’s contribution is the promotion of rational
code relating to medicinal products for human use), as and economical prescribing, as well as dispensing.
amended, all EU Member States “shall ensure that appropri- – The pharmacist needs evidence-based, unbiased, compre-
ate collection systems are in place for medicinal products hensive, objective and current information about thera-
that are unused or have expired”. peutics, medicines and other health care products in use,
DISPENSING
including potential environmental hazard caused by
38.2.2.2 Environmental Risk assessments (ERA), medicines waste disposal.
Directive 2001/83/EC — Community code It is clear from these guidelines that good pharmacy
relating to medicinal products for human practices requires the existence of good environmental
use and Guideline on the ERA procedures. This is well aligned with the requirements in
of medicinal products for human use many regulations, such as the EU directives described
(EMEA/CHMP/SWP/4447/00) in Sect. 38.2 as well as country-specific environmental
Environmental risk-assessment of medicinal products for management acts.
human and veterinary use is the process through which the Based on the Environmental Management Act [8] in the
European Medicines Agency ensures that the potential Netherlands every citizen should take sufficient care of the
environment and everyone who because of his function or

his occupation or trade handles waste has a specific duty to The ‘old’ R(isk)-phrases were legally valid until 2015
care. This may be interpreted such that the pharmacist has [10, 11]:
responsibility for all activities in the pharmacy, whether R 50: Very toxic to living organisms in water
in a community or hospital pharmacy, and hence understand R 51: Toxic to living organisms in water
the possible consequences for the environment from R 52: Harmful to living organisms in water
the operations. Examples of activities that may impact the R 53: Can cause long-term harmful effects in the
environment include, but are not limited to, the storage of aquatic environment
hazardous substances and the collection and transport R 54: Toxic to plants
of surplus medicines and medicinal waste. According to R 55: Toxic to animals
the Environmental Management Act community pharmacies R 56: Toxic to bottom organisms
in the Netherlands don’t need an environmental permit, R 57: Toxic to bees
as would an industrial manufacturer, except when the R 58: Can cause long-term harmful effects to the
pharmacy has a laboratory. Usually the environmental environment
permit of the hospital pharmacy falls within the environ- R 59: Dangerous to the ozone layer
mental permit of the hospital. If the hospital pharmacy is The way the substances are classified and whether
not part of the hospital (a foundation for example), the H(azard)-statements are being assigned, also for
hospital pharmacy has to apply for an environmental permit mixtures, is explained in reference [9]. A hazard in
itself. combination with an exposure to the substance could
generate an environmental risk (risk ¼ hazard
quantity) as discussed in Sect. 38.2.
38.4.2 Preparation from Raw Materials

Starting materials that exceed the expiry date have to be
When medicines are prepared from raw materials, residues disposed of in a safe manner, because they are a potential
will turn up in the cleaning waste. Some guidance about burden to the environment. To minimise the risk for
environmental hazards can be found in the safety informa- materials exceeding expiry date, it is preferable to purchase
tion forms (The Safety Data Sheets, see also Sect. 26.3.4) of smaller packages where relevant.
the different substances. The relevant part of the form is The storage requirements for dangerous substances are
called ecologic information. discussed in Sects. 26.11 and 36.9. These requirements also
aim to protect the environment if a package breaks.
The EU-GHS system which is mandatory for label-

38.4.3 Generation of Waste Such as Overalls
ling since 2010 [9] contains H(azard)-statements
and Gloves
which relate to aquatic environmental dangers:
H400: Very toxic to in water living organisms
When aseptic activities are undertaken as well as the prepa-
H410: Very toxic to in water living organisms, with
ration of medicines with highly toxic substances, commonly
long term effects
a lot of waste, such as overalls, gloves, hairnets, masks and
H411: Toxic to in water living organisms, with long
mats, will be generated. The waste is usually incinerated
term effects
because it may be contaminated with toxic substances.
H412: Harmful to in water living organisms, with long
Safety is of paramount importance and should never be
term effects
compromised. It is not, for example, recommended from a
H413: Can cause long-term harmful effects to in water
health and safety perspective to reuse gloves. It would fur-
living organisms
thermore create a risk of cross-contamination. Sterile clothes
There is also a classification for substances that are
for aseptic work exist in a washable, so reusable, version.
dangerous to the ozone layer:
Washing these clothes could potentially be less harmful to
EUH059: Dangerous to the ozone layer.
the environment than incineration of synthetic overalls.
The EU-GHS uses next to the H-statements, also
P(recautionary) statements. For the environment are
relevant: 38.4.4 Packaging Material
P102: Keep out of reach of children
P273: Prevent from discharging in the environment Pharmaceutical packaging may have an impact on the
environment.
(continued)
Several countries within the EU regard halogenated pack- contact with each other. Also, the laboratory has to collect
aging materials as potentially the most harmful to the envi- separately certain types of solvents such as halogen-rich
ronment. Polyvinylchloride (PVC) is commonly used for ones, since they may be processed separately from
infusion bags and blister packs. Polyvinylidene chloride halogen-free solvents. The company contracted to process
(PVdC) is also used for blister packs. During incineration these solvents, will indicate in its acceptance conditions the
of waste containing PVC, PVdC and other halogenated different categories to be used.
packaging materials dioxins may be generated. Dioxins are
toxic to human health in very low concentrations. Since the
start of the twenty-first century, several attempts have been 38.4.6 Waste Disposal
made to replace PVC in infusion bags and blister packs.
Potential substitutions are polypropylene and other Everyone who is responsible for waste has a duty to ensure
polyolefins or mixtures of polyamides. There are a few that the waste is handled, transported and disposed of in a
examples of PP (polypropylene) blister packs, but they are safe way.
limited due to technical challenges during manufacturing Pharmaceutical waste generally can be divided into three
and to regulatory reasons. When a manufacturer of types of waste [12]:
medicines wants to change the packaging, the manufacturer • Hazardous waste
needs to submit new shelf life studies and an alteration of the • Non-hazardous waste
registration is needed. Therefore, innovations in this field of • Not pharmaceutically active and possessing no hazardous
packaging have been restrained. properties
Aluminium puts a high burden on the environment when The waste from preparation of, for example, antineoplastics
it is first manufactured, due to high-energy usage. Recycled and radiopharmaceuticals is seen as hazardous waste and
aluminium however has a much lower environmental should be collected, disposed of and processed separately.
impact. Aluminium is used in the pharmacy in tubes and in Solid waste from all other preparations (in hospital phar-
blister packs (together with PVC). macies or local pharmacies) is collected as non-hazardous
Medicines dispensing systems (MDS) cause a relatively waste or not pharmaceutically active and possessing no
large amount of packaging waste, because the medicines are hazardous properties.
being repacked. Pharmacies that provide the MDS services Patients who self inject medicines in some countries
change from tablets in blister packs to bulk packs. receive a special container from the pharmacy or the munic-
By choosing the right packaging material, the producer or ipality to collect syringes and needles, because of the risk of
the pharmacy can enhance the possibilities to recycle the contamination and accidents. The full containers should be
material after the patient has used it. Mono material is easier handed in to a pharmacy or a waste management facility
to recycle than mixtures and laminates. Reusing primary (depending on local regulations).
packaging, like blister packs, infusion bags and glass flasks, The community pharmacy has to take back from patients
is not usually recommended because the intensive cleaning medicines that are no longer required, or expired medicines,
process to remove medicine waste before recycling is con- these are the so-called unused medicines (see Sect. 38.4.2).
sidered a larger burden to the environment than incineration. Obviously, the pharmacy has to collect chemical waste
Secondary packaging, like carbon boxes, should however be from its other general functions, e.g. toner cartridges,
collected separately and recycled. separately.
The pharmacy will contract to specialised companies to
process the waste by means of incineration. These
38.4.5 Laboratory companies have to have a permit and the pharmacy has to
ask for confirmation of the permit. The contract with the
Many substances used in pharmaceutical analysis and collector states how the pharmacy has to deliver the waste.
DISPENSING
bio-analysis are potentially harmful to the environment. In addition, the contract states that the company will destroy
When designing analytical methods it is always all the medicine waste. The forms confirming handing over
recommended to use as environmentally sound substances the waste to the contractor should be kept in the pharmacy
as possible. Check the part of the safety data form, called for a certain, country-specific, period.
‘ecologic information’ (see Sect. 38.4.2). At the laboratory,
the waste can be reduced for example by reusing eluents for
chromatographic determinations or by reducing volumes for 38.4.7 Energy Use
preparing stock solutions and control solutions.
A laboratory should not dump toxic substances in the Energy is largely generated in society using fossil fuels.
sewer. The waste has to be collected, and kept separately When fossil fuels are combusted, greenhouse gases are
where relevant because certain substances must not get into emitted which contributes to global warming. Hence,
decreasing energy use in the pharmacy is a good example of

caring responsibly for the environment. The temperature in increase in quantity. Ethinylestradiol, the active sub-
the working areas of the pharmacy probably does not need to stance of the oral contraceptive, wasn’t detected in any
be kept at, for example, 20 C but can more or less follow the of the samples. The concentrations of most medicines
seasons. However for storage areas the temperature has to be are smaller than 50 nanograms/liter and that is by a
kept within limits (see Sect. 36.9.4) When electrical devices factor of 200 till 1000 less than the derived toxicolog-
(for example computers and safety cabinets) are not used, ical limits for drinking-water. However, there are sev-
they should be turned off or put in sleep mode/stand-by. In eral reports from around the globe where surface
certain situations there can be conflicting interests between waters have been reported to contain concentrations
environmental burden and both product quality and safety of medicines in micrograms/liter [17].
for the pharmacist.
The most relevant question is whether the appearance of
As an example: after working hours a parenteral active substances in drinking water is harmful to humans.
product has to be prepared, urgently, in the safety The direct risk for humans seems to be negligible at the
cabinet. If the safety cabinet has been switched off at present time since the concentrations in drinking water are
that moment, it takes approximately 30 minutes extremely low. However, some concerns have been raised as
(depending on which machine and type) before the expressed by Kümmerer and others [18]. Knowledge gaps
preparation can be started. If the preparation was to regard potential effects from constant exposure to very low
be started too soon, the product quality and the protec- concentrations in drinking water over long periods of time.
tion of the preparing pharmacist could not be Furthermore, little is known about the sensitivity of neonates
guaranteed. and of the effect of mixtures of substances. Questions have
also been raised whether the release of antibiotics to the
environment could contribute to antimicrobial resistance
The pharmacist has to formulate procedures so that the
development. The Health Council of the Netherlands has
energy consumption is limited to a minimum without putting
issued a statement on antibiotics in food animal production
product quality and health and safety of the preparing phar-
and resistant bacteria in humans. The statement: “The exten-
macist at risk.
sive use of antibiotics in food animal production, the sector
that produces food of animal origin, plays an important role
in the discussion on resistance development. Since resistant
bacteria can be passed on from animals to humans, the use of
38.5 The Use of Medicines
antibiotics in the treatment of animals contributes to the
problem [19].
38.5.1 Patient Excretion
The risks for any environmental impact from pharmaceu-
tical substances excreted by patients or livestock have been
Medicines used by patients turn up, whether metabolised or
heavily discussed over the recent decade. There are never-
not, in urine, faeces, vomit and sweat and therefore in waste
theless still major knowledge gaps about occurrence in the
water. This is true for humans as well as animals (livestock).
environment and effects from pharmaceutical substances to
The quantity of residues from livestock that turns up in water
e.g. water-living organisms.
is much higher that the medicine waste from hospitals [13].
In order to learn more, and if possibly decrease environ-
mental impacts through adjusted prescription patterns, the
The National Institute for Public Health and Environ- Research-based Pharmaceutical Industry in Sweden (LIF
ment (RIVM) in the Netherlands carries out periodical [20]) has developed an environmental classification scheme
analysis to record the distribution of human and veter- for pharmaceutical substances[21] The model for presenting
inary medicines in drinking water. In 2002 and 2003 environmental data was developed in collaboration with
[14] during measurements, there were remainders of Stockholm County Council, the pharmacy chain Apoteket
four active substances found in drinking water and AB, the Swedish Association of Local Authorities and
drinking water sources. These four medicines were: Regions (SKL), and the Swedish Medical Products Agency
(acetyl)salicylic acid, carbamazepine, clofibric acid, MPA. The goal was to develop a model, which clearly shows
sulfamethoxazol. In follow-up research in 2005 and environmental information, both to interested members of
2006 [15, 16] 22 medicines were found and the the public, to healthcare professionals and pharmacists. The
researchers concluded that this result indicated an environmental information draws on data from the pharma-
ceutical companies, often generated in the preparation phase
(continued)
Table 38.1 Descriptive phrases for environmental risk of substances

Classification phrase PEC/PNEC value Examples of active substance
Use of the substance has been considered to result in insignificant environmental risk Less than 0.1 Omeprazol
Use of the substance has been considered to result in low environmental risk Between 0.1 and 1 Paracetamol
Use of the substance has been considered to result in moderate environmental risk Between 1 and 10 Sertralin
Use of the substance has been considered to result in high environmental risk Higher than 10 Ethinylestradiol
of the environmental risk assessments (see Sect. 38.2.2.2). ensure that appropriate collection systems are in place for
An independent organisation, the Swedish Environmental medicinal products that are unused or have expired”. Mem-
Research Institute, IVL, acts as a reviewer of all data and ber states that have implemented solid systems for the man-
of the assessments and classifications. The environmental agement of unused medicines have to secure that medicines
information and classifications of different substances can be are transported to approved incineration facilities, and
found on the Swedish prescribing guide called Fass [22]. burned under supervision. The gas from incineration is
The relation between the predicted no-effect concentra- cleaned before release. The ash is placed at approved dis-
tion (PNEC) and the anticipated concentration (PEC, posal facilities.
predicted environmental concentration) is described using In order to collect unused medicines from the general
the phrases within the Swedish classification system, see public it is often recommended to return the unused
Table 38.1. medicines to a pharmacy. Pharmacists should establish a
The prescribing guide Fass also provides, in addition to safe procedure for medicines waste disposal at the hospital
information on environmental risk, information on whether a or community pharmacy so that patients and the public are
certain pharmaceutical substance is persistent or biodegrad- encouraged to return their expired and unwanted medicines
able, and whether it can bioaccumulate in aquatic organisms. and medical devices. Alternatively, pharmacists should pro-
The Swedish classification system uses the following vide appropriate information to patients on how to safely
phrases regarding degradability: dispose of expired or unwanted medicines.
• The substance is degraded in the environment The Swedish Medical Products Agency (MPA) have in
• The substance is slowly degraded in the environment their report regarding unused medicines from 2013 [23]
• The substance is potentially persistent estimated the quantity of unused medicines, expressed in
The Swedish classification system uses the following term of money, as 5 % of the total use of prescribed
phrases regarding bioaccumulation: medicines. In order to secure that unused medicines are
• No significant bioaccumulation potential brought back to pharmacies and hence correctly managed
• Potential to bioaccumulate in aquatic organisms from a waste management perspective, the Research-based
Certain pharmaceuticals are exempted from classification as Pharmaceutical Industry in Sweden (LIF) has together with
for various reasons they are considered not to cause any Swedish pharmacies conducted surveys regularly since 2001
environmental effect. This is in line with the EU’s environ- to investigate the level of knowledge in the general public on
mental risk assessment guidelines for medicinal products this issue. The campaigns and the surveys from 2001, 2004,
(see Sect. 38.2.2.2). and 2007 are described in the reference [24] A general
The exemption covers: conclusion from these surveys, and confirmed by the MPA
• Vitamins report, is that roughly 75–80 % of unused medicines among
• Electrolytes the general public are brought back to pharmacies for proper
• Amino acids, peptides, proteins waste management. It is also very obvious that information,
• Carbohydrates e.g. campaigns to patients, are important to secure high
• Lipids compliance to the recommendation of bringing unused
• Vaccines medicines back to the pharmacy. The pharmacists’ role is
DISPENSING
extremely important for success.
38.5.2 Unused Medicines Some patients want to donate unused medicines to

Third World countries. There are even organisations
Unused medicines can pose a health and social risk if they that collect surplus medicines to send. Neither the
come into wrong hands, for example children or addicts; and people, nor the environment of the receiving country
they can pose an environmental risk if they are not disposed wants that. The names and instruction leaflets may
of properly through correct destruction. According to a EU
Directive (see Sect. 38.2.2.1) all EU Member States “shall (continued)
however not be refused for a human medicinal product for

cause confusion, the medicines are also taken when the too high an environmental risk. The need for mitigating
indication isn’t conforming the disorder and unused measures, e.g. restricted use or labelling could however be
medicines stay in the environment. Therefore, the mandated.
WHO has formulated guidelines how medicine
donations can be useful [25]. In these guidelines
there is no place for medicines that have been returned 38.6 Essentials
by patients.
The pharmacist can contribute to a better environment dur-
ing all activities in the pharmacy: during educating patients
about returning unused medicines, during raw material man-
agement, during drafting preparation methods. However,
38.5.3 Potential Mitigating Measures there is still little scientific research conducted into environ-
mental burden by pharmacies. There are legal guidelines for
Any direct danger for humans from environmental exposure processing waste from the pharmacy, but on several other
to medical substances is considered negligible at this environmental topics, there are no concrete rules available
moment, but the concentrations in the environment may which could guide the pharmacist in the daily operations.
rise over time due to the slow degradation of the substances. The environmental burden caused by medicine use is a
It is also important to remember that the knowledge on subject of increasing research. For now, humans seem to run
environmental effects from mixtures of substances is low. no direct risk. Nevertheless, humans may run an indirect risk
Hence protective and mitigating measures could be appro- by harming the environment. In the short term, hope is
priate. The following measures have been proposed [16, 26]: placed upon innovations in the field of waste water treat-
• Propagate restrictive prescribing policy ment, and on the contribution of the patient by returning
• Give education to patients and health care workers about unused medicines to the pharmacy. The development of
the effects of medicines on the environment ‘green medicines’, which do not cause harm to the environ-
• Give information about returning and destroying unused ment, and a responsible use and management of those
medicines medicines (green pharmacy) is the ultimate goal.
• Production of more easily, biologically, degradable
medicines (green pharmacy)
• Extra purification of waste water of health care
institutions
References
• Development of new sanitation systems for drinking
1. The Industrial Emissions Directive (2007) http://ec.europa.eu/envi
water ronment/air/pollutants/stationary/ied/legislation.htm. Accessed
Physicians and patients can contribute by means of reducing 13 Oct 2013
the quantity of unused medicines, and return them to a 2. REACH (2007) http://ec.europa.eu/environment/chemicals/reach/
reach_en.htm. Accessed 13 Oct 2013
pharmacy. The Swedish classification scheme has also
3. Packaging en packaging Waste Directive (1994) http://europa.eu/
been used to bring environmental risk and hazard into the legislation_summaries/environment/waste_management/l21207_
decision of the choice of medicine used [27]. For informa- en.htm. Accessed 13 Oct 2013
tion regarding novel waste water treatment techniques suit- 4. The EU Water Framework Directive (2000) http://ec.europa.eu/
environment/water/water-framework. Accessed 13 Oct 2013
able for removal of pharmaceutical substances, e.g. activated 5. Larsson DGJ, de Pedro C, Paxeus N (2007) Effluent from drug
carbon, ozonation, and ultraviolet radiation, the reader is manufactures contains extremely high levels of pharmaceuticals. J
referred to the references [28–32]. Hazard Mater 148:751–755
An approach that tries to solve the problem more at the 6. The U.S. Geological Survey (2010) http://toxics.usgs.gov/
highlights/PMFs.html. Accessed 20 Apr 2014
source is the so-called green pharmacy. In order to stimulate
7. Joint FIP/WHO guidelines on good pharmacy practice: standards
the development of more easily degradable medicines, both for quality of pharmacy services (2010) http://www.who.int/
for human as well as for veterinary medicines, European medicines/services/expertcommittees/pharmprep/CLEAN-
guidelines are formulated. At the application stage to get a Rev2Final-GPP-StandardsQ-PharmacyServices-QAS10-352_
Sept2010.pdf. Accessed 13 Oct 2013
marketing authorisation the manufacturer has to give infor-
8. Environmental Management Act (Law of June 13th 1979, on the
mation about the effects of the medicine on the environment arrange with regard to some common subjects in the field of
as well as an evaluation of those effects and measurements environmental hygiene). http://www.government.nl/issues/environ
which have to be taken to prevent or reduce these effects ment/roles-and-responsibilities-of-central-government/environmen
tal-management-act. Accessed 13 Oct 2013. Complete text: And:
[33–35]. When veterinary products are concerned,
Wet Milieubeheer. http://wetten.overheid.nl/BWBR0003245/
authorities can even deny the registration if the environmen- Hoofdstuk1/11/Artikel11a/geldigheidsdatum_11-09-2014: article
tal risk is considered too big. Market authorisation can 1.1a and 10.1. Accessed 11 Sept 2014
9. Globally Harmonised System of Classification and Labelling of a4rder%20f%c3%b6r%20att%20minska%20kassation%202012-

Chemicals. http://ec.europa.eu/enterprise/sectors/chemicals/classifi 09-27.pdf
cation/index_en.htm 24. Persson M, Sabelström E, Gunnarsson B (2009) Handling of unused
10. Ministry of Social Affairs and Employment. www.arboportaal.nl/ prescription drugs – knowledge, behaviour and attitude among
stoffencentrum. Accessed 13 Oct 2013 Swedish people. Envrion Int 35(5):771–774. http://www.
11. Ministry of Social Affairs and Employment. http://www. sciencedirect.com/science/article/pii/S016041200800216X
arboportaal.nl/onderwerpen/gevaarlijke-stoffen/veilig-werken/ 25. World Health Organisation. Guidelines for medicine donations.
gevaarsymbolen/ghs.html. Accessed 13 Oct 2013 Revised 2010. Downloaded from http://www.who.int/medicines/
12. Lowe R, Witham K, McIntyre B (2010) Guidelines on the handling publications/med_donationsguide2011/en/index.html
and disposing of hospital pharmacy wastes, NHS Pharmaceutical 26. Kümmerer K (ed) (2008) Pharmaceuticals in the environment. In:
Quality Assurance Committee Source, fate, effects and risks, 3rd edn. Springer, Berlin/Heidelberg.
13. Kümmerer K (ed) (2008) Pharmaceuticals in the environment. In: 411-7. ISDN 978-3-540-74663-8
Source, fate, effects and risks, 3rd edn. Springer, Berlin/Heidelberg. 27. Castensson S, Eriksson V, Lindborg K et al (2009) A method to
16. ISDN 978-3-540-74663-8 include the environmental hazard in drug prescribing. Pharm World
14. Versteegh JFM, van der Aa NGFM, Dijkman E Medicines in Sci 31:24–31
drinking-water and drinking-water sources. RIVM report 28. Ikehata K, Jodeiri Naghashkar N, Gamal El-Din M (2006) Degra-
703719004. http://www.rivm.nl/bibliotheek/rapporten/703719004. dation of aqueous pharmaceuticals by ozonation and advanced
pdf. Accessed 13 Oct 2013 oxidation processes: a review. Ozone-Sci Eng 28:353–414
15. Versteegh JFM, van der Aa NGFM, Dijkman E Medicines in 29. Gebhardt W, Schröder HF (2007) Liquid chromatogra-
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703719016. http://www.rivm.nl/bibliotheek/rapporten/703719016. tion of persistent pharmaceuticals during wastewater treatment
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have to be out of the drinking-water. Pharm Weekbl 142(6):20–21. 30. Snyder SA, Adham S, Redding AM, Cannon FS, DeCarolis J,
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Accessed 13 Oct 2013 carbon in the removal of endocrine disruptors and pharmaceuticals.
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11 ISDN 978-3-540-74663-8 oxidation of the polycyclic musk fragrances with using UV and
18. Kümmerer K (ed) (2008) Pharmaceuticals in the environment. In: UV/H2O2 processes. Arch Environ Prot 34:13–23
Source, fate, effects and risks, 3rd ed. Springer, Berlin/Heidelberg 32. Ikehata K, Gamal El-Din M, Snyder SA (2008) Ozonation and
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20. www.lif.se p 334. ISDN 978-3-540-74663-8
21. Mattson B (2007) A voluntary environmental classification system 34. Regeling Geneesmiddelenwet artikel 3.7 lid d. www.wetten.
for pharmaceutical substances. Drug Inf J 41(2):187–191 overheid.nl
22. www.fass.se 35. EMEA (2006): EU-Guideline on the environmental impact assess-
23. Estberg E, Svensson M Läkemedelsrester i vattendrag. http:// ment of medicinal products for human use. CPMP/SWP/4447/00.
www.lakemedelsverket.se/upload/nyheter/2012/%c3%85tg%c3% Ditto 2007 for veterinary medicines. www.emea.europa.eu
DISPENSING
Information Sources
39
Doerine Postma and Sin Ying Chuah
Contents 39.5 Further Studying . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847

39.5.1 Arbeitsgemeinschaft für Pharmazeutische
39.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839 Verfahrenstechnik: Courses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
39.2 Essential References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840 39.5.2 European Journal of Hospital Pharmacy: Science
39.2.1 Australian Don’t Rush to Crush Handbook . . . . . . . . . . . . 840 and Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
39.2.2 Fiedler Encyclopedia of Excipients . . . . . . . . . . . . . . . . . . . . 840 39.5.3 International Journal of Pharmaceutics . . . . . . . . . . . . . . . . . 848
39.2.3 Handbook of Pharmaceutical Excipients . . . . . . . . . . . . . . . 840 39.5.4 International Journal on Pharmaceutical Compounding 848
39.2.4 Martindale, the Complete Drug Reference . . . . . . . . . . . . . 841 39.5.5 International Pharmaceutical Abstracts . . . . . . . . . . . . . . . . 848
39.2.5 PubMed/MEDLINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841 39.5.6 International Society of Pharmaceutical
39.2.6 Stabilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841 Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
39.5.7 PDA Journal of Pharmaceutical Science
39.3 Textbooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841 and Technology and Technical Reports . . . . . . . . . . . . . . . . 849
39.3.1 Aultons Pharmaceutics: The Design and Manufacture
of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
39.3.2 Martin’s Physical Pharmacy and Pharmaceutical
Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
39.3.3 Pharmatopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Abstract
39.3.4 Rezeptur im Bild . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Amongst the wealth of information sources, specific ones
39.4 Specific References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 may be valuable for pharmacists who are concerned with
39.4.1 British Pharmacopoeia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
39.4.2 Deutscher Arzneimittel-Codex/Neues Rezeptur- product care, preparation, adapting dosage forms and
Formularium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843 reconstitution. This chapter presents an authors’ and
39.4.3 EU Legislation/GMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843 editors’ choice of essential references, textbooks, specific
39.4.4 European Pharmacopoeia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844 references and sources for postgraduate studying. For
39.4.5 Formularium der Nederlandse Apothekers . . . . . . . . . . . . . 844
39.4.6 Handbook of Extemporaneous Preparation . . . . . . . . . . . . 844 each source practical information is given.
39.4.7 Hugo and Russell’s Pharmaceutical Microbiology . . . . 845
39.4.8 Kommentar zum Europäischen Arzneibuch & Keywords
Kommentar zum Deutschen Arzneibuch . . . . . . . . . . . . . . . 845 Sources References Textbook Postgraduate education
39.4.9 Principles and Practice of Phytotherapy . . . . . . . . . . . . . . . . 845
39.4.10 Profiles of Drug Substances, Excipients and Related
Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
39.4.11 Quality Assurance of Aseptic Preparation Services . . . 845
39.4.12 Sampson’s Textbook on Radiopharmacy . . . . . . . . . . . . . . 846 39.1 Introduction
39.4.13 Stabilitätsprüfung in der Pharmazie: Theorie und Praxis 846
39.4.14 Trissel’s Stability of Compounded Formulations . . . . . . 846
39.4.15 United States Pharmacopeia and The National This chapter gives a selection of sources on product care, and
Formulary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846 preparation of medicines. The authors and editors consider
39.4.16 World Health Organization Guidelines . . . . . . . . . . . . . . . . . 847 them valuable and worth to be considered by pharmacists who
are involved in product care, preparation and manufacturing,
adapting dosage forms and reconstitution.
The focus of this chapter is on those sources that are most
useful, apart from Practical Pharmaceutics. Therefore the
D.J. Postma (*) S.Y. Chuah
authors have refrained from mentioning other general
KNMP Royal Dutch Pharmacists Association, Alexanderstraat 11,
2514 JL The Hague, The Netherlands textbooks on ‘practical pharmaceutics’, however valuable
e-mail: [email protected]; [email protected] they may be.

840 D.J. Postma and S.Y. Chuah
Input is given by the members of the Editorial Advisory Published by: The Society of Hospital Pharmacists
Group, the authors of the other chapters and the editors. The of Australia
selection of the sources is based on applicability in practice Editor: Burridge N, Deidun D
and on experience. Publication channel: ring binder
This selection is a suggestion and it is not intended to be Most recent edition: 1st, 2011
complete. There may be more applicable (national) sources Price in 2014: SHPA member: AU$ 110,
that are not listed in this chapter. non-member: AU$ 120
The sources in this chapter are subdivided into the Language: English
themes: essential references, textbooks and specific ISBN: 9780987110336
references. Formularies on pharmacy preparation and qual- More information: www.shpa.org.au/Publications
ity of preparation are also mentioned in this chapter. Fur-
thermore a few sources for further studying are mentioned.
The sources are described in a similar way: a short expla-
nation on the content and information on the publisher, 39.2.2 Fiedler Encyclopedia of Excipients
editor, publication channel, most recent edition, price in
2014 (without VAT), language of the source and ISBN for Fiedler Encyclopedia of Excipients describes the properties
books or ISSN for journals or series of books. of more than 17,000 excipients that are used in pharmaceu-
tical and cosmetic industry. The descriptions contain: chem-
ical name, synonyms, structural formula, pharmacopoeial
references, CAS Registry number (Chemical Abstract Ser-
39.2 Essential References vice), synthesis, properties, use, toxicology, analysis.
Published by: Editio Cantor Verlag
During daily practice, a pharmacist may advise and instruct Editor: Lang S, Reng A, Schmidt PC
patients about handling their medicines. Also a pharmacist Publication channel: book
may have to manage different aspects of pharmacy prepara- Most recent edition: 6th, 2007
tion and the logistics of medicines. Therefore it is useful to Price in 2014: € 385
have some reference works at hand: Language: English
For the therapeutic relevance of a pharmacy preparation: ISBN: 9783804727977
Martindale and Medline/PubMed. More information: http://www.deutscher-apotheker-
For information about adapting oral dosage forms: a verlag.de
handbook like Don’t Rush to Crush.
For more insight on pharmaceutical excipients: the Hand-
book on Pharmaceutical Excipients and Fielders Encyclope- 39.2.3 Handbook of Pharmaceutical Excipients
dia. The Handbook describes the most common excipients in
detail. The Encyclopedia describes almost all excipients, but The Handbook of Pharmaceutical Excipients contains
less in detail than the Handbook. approximately 380 excipient monographs. The data contains
For information on stability of medicines in solution with information on physical properties, safety and potential tox-
emphasis on stability and incompatibility of parenteral icity of the excipients.
medicines: Stabilis gives a practical overview of facts The monographs include pharmacopoeial information,
based on reliable literature. non-proprietary names and synonyms, chemical name,
CAS Registry number, empirical formula, molecular weight,
functional category, applications and incompatibilities,
material description and typical excipient properties, safety,
39.2.1 Australian Don’t Rush to Crush stability, storage and handling precautions.
Handbook Published by: Pharmaceutical Press
Editor: Rowe RC, Sheskey PJ, Cook WG,
This handbook provides Australia-based information for Fenton ME
health professionals on how to administer medicines safely Publication channel: book, online
to people unable to swallow solid oral medicines. Most recent edition: 7th, 2012
It contains over 500 monographs on solid oral medicines, Price in 2014: book: £ 299; online £ 224 (via
which are on the Australian market, listing generic names, MedicinesComplete)
brand names, forms and strengths. Separate Language: English
recommendations for patients with swallowing difficulties ISBN: 9780857110275
and patients with enteral feeding tubes are being given. More information: http://www.pharmpress.com/
39 Information Sources 841
39.2.4 Martindale, the Complete Drug solution, stability in admixtures, factors which affect its
Reference stability, incompatibilities and routes of administration. Rel-
evant references are also mentioned. The stability informa-
Martindale contains approximately 6,000 monographs on tion of parenteral medicines can be useful to determine the
active substances and excipients. It contains information on stability on liquid medicines in general.
uses and administration as well adverse effects, treatment of Stabilis also gives stability information of some other
adverse effects, precautions, interactions, pharmacokinetics. pharmaceutical preparation, such as eye-drops, ointments,
For each substance the following characteristics are given: oral solution. Data about stability of the dilutions and the
synonyms, pharmacopoeial description and solubility if compatibilities are examined by experts, who only include
available, proprietary preparation names. them in Stabilis if the shelf life testing is reliable. Stabilis
Published by: Pharmaceutical Press uses pictograms and the information is translated into
Editor: Sweetman SC 28 languages.
Publication channel: book, online Published by: Infostab
Most recent edition: 38th, 2014 Editors: Vigneron J
Price in 2014: book: £ 459; online: £ 270 (via Publication channel: online
MedicinesComplete); book and Most recent edition: not applicable
online: £ 575 Price in 2014: free
Language: English Language: Arabic, Bulgarian, Chinese,
ISBN: 9780857111395 Croatian, Czech, Danish, Dutch,
More information: http://www.pharmpress.com German, English, Estonian, Finnish,
French, Greek, Hungarian, Italian,
Japanese, Latvian, Lithuanian,
Norwegian, Polish, Portuguese,
39.2.5 PubMed/MEDLINE Rumanian, Russian, Slovenian,
Slovak, Spanish, Swedish, Turkish.
MEDLINE is a bibliographic database of life sciences and More information: http://www.stabilis.org
biomedical information. It contains references to articles
from academic journals covering medicine, nursing, phar-
macy, dentistry, veterinary medicine, health care, biology
39.3 Textbooks
and biochemistry.
PubMed provides free access to MEDLINE. It also
For the design of pharmacy preparations it is necessary to
includes articles from other sources. Pubmed is helpful for
understand the scientific principles. These principles are also
searching additional information on therapeutic relevance of
important for the understanding of the design and production
active substances. It contains abstracts and links to full-text
of licensed medicines and to assess the possibilities of
articles.
adapting these products.
Published by: National Center for Biotechnology
During education Aultons and Martin’s are both valuable.
Information (NCBI)
Martin’s Physical Pharmacy and Pharmaceutical Sciences
Editor: not applicable
focuses on the scientific background whereas the focus of
Publication channel: online
Aultons Pharmaceutics may be more on the design of
Most recent edition: not applicable
medicines.
Price in 2014: free
Pharmatopia and Rezeptur in Bild can

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Yvonne Bouwman-Boer

ISBN 978-3-319-15813-6 ISBN 978-3-319-15814-3 (eBook)

Library of Congress Control Number: 2015933496

Springer Cham Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)

The Hague, The Netherlands Yvonne Bouwman-Boer

18 Physical Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

38 Impact on Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829

AAD Adaptive Aerosol Delivery

MEC Minimal Effective Concentration

QPPV Qualiﬁed Person for PharmacoVigilance

1.1 Structure of the Book

The focus of Practical Pharmaceutics is the medicine as a

Y. Bouwman-Boer et al. (eds.), Practical Pharmaceutics, 1

Fig. 1.1 The structure of the book.1

The authors thank Cathrien Dijken ([email protected]) for the concept.

Starting Material Process Legal status

Fig. 1.2 Terminology of preparation activities

The terminology and deﬁnition of the activities is as 1.3.1 Drug

1.3.3 Hazardous Substance

1.3 Terminology 1.3.4 Terms

standard terms. In other areas terms of the International 1.4.2 Spelling

1.6 Examples, Guidelines, Legislation, 1.7 References

2.1 Pharmacy Preparation: Way Out

Y. Bouwman-Boer et al. (eds.), Practical Pharmaceutics, 7

pharmacovigilance or monitoring systems for pharmacy

Pharmacy Services Pharmacy Services

Pharmacist Name: …………………………………………….….…… Date: ……………………….…. Comments:

Drug Requested: Comments:

Clinical Reason for use: ……………………………………………………………………………….. Section D: Approval

Is an alternative method possible? Yes/No Section E: Preparation

Fig. 2.1 Request form for a non-catalogue extemporaneous product

Assessment of Overall Risk

QC for quality issues

Overall Risk Assessment: HIGH MEDIUM LOW

Fig. 2.2 Extemporaneous product risk assessment matrix

2.2.3.2 German Reason Check 2.2.3.3 Risk-Benefit Form [4]

Is the prescription complete? yes no

Is everything readable? yes no

Are there any perceivable mistakes? yes no

Is the treatment concept obvious? yes no

Is the dosage sensible? yes no

Are the dosage instructions sensible? yes no

3.Qualitative and quantitative composition

Is the concentration of the active substances higher

If so, please specify the source:

Are there any similar standard formulations? yes no

If so, please specify the source:

Are the ingredients compatible? yes no

If no, please specify the incompatibilities:

5. Stability and shelf life

Is there a need for an added buffer? yes no

Is the microbiological stability sufficient for the

Date, Signature Responsible Pharmacist/Delegate

Request for extemporaneous preparation

Availability as authorised medicine Is the design well- Yes / No∗)

Discussion with attending pharmacist: ………

Is the health and safety risk of the pharmacy