POST-MARKETING SURVEILLANCE GUIDE

FOR
SMALL ISLAND DEVELOPING STATES

Medicines Quality Control and Surveillance

Department
The Caribbean Public Health Agency is the Caribbean region’s collective response to strengthening
health systems and addressing public health challenges which threaten development.

To obtain additional information, please contact:

Caribbean Public Health Agency (CARPHA)
Medicines Quality Control and Surveillance Department (MQCSD)
Hope Gardens
Jamaica
Tel: 876-977-3540; 876-702-4235
Email: [email protected]
Website: http://carpha.org/

Citation.
Caribbean Public Health Agency. Post-Marketing Surveillance Guide for Small Island Developing
States. Port of Spain, Trinidad, and Tobago: CARPHA; 2019

ISBN 978-976-8114-47-1

A publication of the Caribbean Public Health Agency (CARPHA)

16-18 Jamaica Boulevard Federation Park
Port of Spain,
Trinidad and Tobago
Tel: 868-299-0895 Fax: 868-622-2792
Email: [email protected]
Website: http://carpha.org/

© Caribbean Public Health Agency 2019

Contents
Acknowledgements .............................................................................................................................................. 3
Abbreviations ......................................................................................................................................................... 4
Glossary .................................................................................................................................................................... 5
Lists of Figures and Tables ................................................................................................................................ 9
INTRODUCTION.................................................................................................................................................. 10
Background..................................................................................................................................................... 10
Purpose of the Guide ................................................................................................................................... 12
Intended Users .............................................................................................................................................. 12
Additional Context ....................................................................................................................................... 13
SECTION I: GUIDANCE FOR NATIONAL POST-MARKET SURVEILLANCE SYSTEMS ........ 14
1.0 National Post-Market Surveillance Systems ............................................................................. 15
1.1 Role of NMRAs and Stakeholders ................................................................................................... 15
1.2 System Objectives and Operational Elements ........................................................................... 15
1.2.1 Prevention ........................................................................................................................................ 16
1.2.2 Vigilance and Detection ............................................................................................................... 16
1.2.3 Operational Elements .................................................................................................................. 17
1.2.4 Voluntary Reporting system ..................................................................................................... 17
1.2.5 Database Management ................................................................................................................ 19
1.3 Setting Priorities for Risk-Based Post-Market Surveillance................................................. 19
1.3.1 Determining Priority Medicines for Testing ....................................................................... 19
1.3.2 Collection sites and sampling methods ................................................................................. 21
2.0 Incident Management, Risk Assessment and Decision-Making ...................................... 23
2.1 Handling Reports .................................................................................................................................. 23
2.2 Risk Assessment and Prioritization ............................................................................................... 24
2.2.1 Risk assessment categories ....................................................................................................... 24
2.2.2 Risk classification and prioritization matrix ....................................................................... 25
2.3 Regulatory Decision-Making and Action...................................................................................... 29
2.3.1 Review of Incidents for Regulatory Actions ........................................................................ 29
2.3.2 Taking Regulatory Action ........................................................................................................... 30
2.4 Strengthening Regional Decision-making and Global Surveillance .................................. 32
2.4.1 Leveraging Key Regional and International Regulatory Programmes ..................... 32
2.4.2 Improving Local, Regional and International Post-Market Surveillance ................. 33
2.5 Case Study ................................................................................................................................................ 34
1.3.3 USP’s Risk-Based PMS Tool ....................................................................................................... 36
SECTION II: GUIDANCE FOR QUALITY TESTING OF MEDICINES ............................................. 37
3.0 Guiding Principles for Risk-Based Testing ................................................................................ 38
3.1 Applying a Risk-Based Approach to Testing .............................................................................. 38
3.1.1 Guidance for Visual and Field-based Screening (Levels 1 and 2) ............................... 41

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 3.1.2 Prioritizing for Compendial Testing (Level 3) ................................................................... 45
4.0 Medicines Quality Testing at The MQCSD ................................................................................... 47
4.1 Services at the Medicines Quality Control and Surveillance Department (MQCSD)... 47
4.1.1 Testing Services and Accreditation ........................................................................................ 48
4.1.2 Medicines Tested by the MQCSD ............................................................................................. 49
4.2 The MQCSD Post-Market Surveillance Programme................................................................. 49
4.2.1 Risk-based Criteria used in Selection of Medicines .......................................................... 51
5.0 SAMPLING PLANS AND PROCEDURES ........................................................................................... 52
5.1 Developing Sampling Plans ............................................................................................................... 52
5.2 Sampling Preparation.......................................................................................................................... 52
5.2.1 Training of Sample Collectors ................................................................................................... 52
5.2.2 Preparing for Sample Collection .............................................................................................. 53
5.2.3 Sampling Facilities ........................................................................................................................ 53
5.2.4 Health and Safety ........................................................................................................................... 54
5.2.5 Minimum Number of Sample Units ........................................................................................ 54
5.3 Sample Collection Procedures ......................................................................................................... 55
5.3.1 Target Medicines............................................................................................................................ 56
5.3.2 Drawing Samples ........................................................................................................................... 56
5.3.3 Packaging Materials (primary and secondary) .................................................................. 57
5.3.4 Labelling ............................................................................................................................................ 57
5.3.5 Handling ............................................................................................................................................ 58
5.3.6 Visual and Physical Inspection ................................................................................................. 58
5.3.7 Site Storage Conditions ............................................................................................................... 59
5.3.8 Storage Containers and Transportation of Samples ........................................................ 59
6.0 SUBMITTING PRODUCTS FOR TESTING TO THE MQCSD .................................................... 61
6.1 The Medicines Quality Testing Process at the MQCSD ........................................................... 61
6.1.1 Process for MQCSD’s Post-Market Surveillance Programme ....................................... 61
6.1.2 Process for Requests for Standard Product Testing ........................................................ 62
6.2 Submitting a Request for Testing of Samples ............................................................................ 64
6.3 Submitting Samples for Testing ...................................................................................................... 65
6.3.1 Sending Samples by Courier ...................................................................................................... 65
6.4 Communication with the MQCSD.................................................................................................... 66
6.4.1 Estimated response times for requests for analysis ........................................................ 66
6.4.2 Communication of Results ......................................................................................................... 67
APPENDIX I: WHO Suspected SF Products Incident Management – Aide Memoire...... 69
APPENDIX II: Tool for Visual Inspection of Medicines ................................................................ 71
APPENDIX III: WHO Tool - Identifying Substandard and Falsified Medical Products. 74
APPENDIX IV: MQCSD List of Pharmaceutical Products with Accredited Tests ............. 76
APPENDIX V: Sample Collection Form .................................................................................................. 79
REFERENCES....................................................................................................................................................... 80

2
Acknowledgements

This document was developed through collaborative efforts of:

 Mrs. Sonia Thomas-Gordon, Acting Head, CARPHA Medicines Quality Control and
Surveillance Department and staff of the MQCSD
 Dr. Virginia Asin-Oostburg, Director - Surveillance, Disease Prevention and Control,
Caribbean Public Health Agency (CARPHA)
 Dr. Charles Preston, Regional Advisor, Pan American Health Organization/World
Health Organization, and
 Dr. Rian Marie Extavour, Consultant.

Special thanks to Dr. Princess Osbourne and members of the CARICOM Expanded Technical
Advisory Committee on Pharmaceutical Policy (TECHPHARM).

3
Abbreviations

API Active pharmaceutical ingredient

BP British Pharmacopoeia
CARICOM Caribbean Community and Common Market
CARPHA Caribbean Public Health Agency
CRS Caribbean Regulatory System
COA Certificate of Analysis
GMP Good Manufacturing Practice
GSMS Global Surveillance and Monitoring System
HPLC High-Performance Liquid Chromatography
INN International Non-proprietary Name
IR Infrared
JANAAC Jamaica National Agency for Accreditation
MQCSD Medicines Quality Control and Surveillance Department
NMRA National medicines regulatory authority
PAHO Pan American Health Organization
PMS Post-market surveillance
PQM Promoting the Quality of Medicines
SIDS Small Island Developing States
SF Substandard and/or Falsified
SMS Short-messaging service
TBD To be determined
TECHPHARM CARICOM Expanded Technical Advisory Committee on
Pharmaceutical Policy
TLC Thin-layer chromatography
USP United States Pharmacopeia
UV-VIS Ultraviolet-Visible
VIGICARIB Caribbean Network for Pharmacovigilance and Post-market
Surveillance
WHO World Health Organization
WHPA World Health Professions Alliance

4
Glossary

Accredited laboratory A laboratory that has received formal recognition that it meets
or exceeds a list of standards, including the ISO/IEC 17025, and
is competent to perform specific tests, or calibrations.

Batch A quantity of medicine produced during a given cycle of

manufacture.

Certificate of Analysis A document issued upon approval of test results listing the test
procedures applied to a sample, results obtained, the
specification applied and compliance.

Compendial Related to a compendium that serves as a standard, such as the

British Pharmacopoeia, or the US Pharmacopeia.

Consignment The quantity of bulk starting material, or of a pharmaceutical

product, made by one manufacturer or supplied by an agent,
and supplied at one time in response to a particular request or
order. A consignment may comprise one or more lot-identified
packages or containers and may include material belonging to
more than one lot-identified batch.

Convenience sample A study sample made up of participants or units who meet the
entry criteria and are easily accessible to the investigator.

Cluster sample A random sample of natural groupings (clusters) of individuals

or units of the population.

Falsified Medical products that deliberately/fraudulently misrepresent

their identity, composition, or source.

Medical product Products used in the care of patients to diagnose, prevent or

treat medical or surgical conditions.

Original sample Sample collected directly from the material.

Packaging material Any material including printed material employed in the

packaging of a pharmaceutical, but excluding any outer
packaging used for transportation or shipment. Packaging
materials are referred to as primary or secondary according to
whether or not they are intended to be in direct contact with
the product.

5
Pharmaceutical product Any material or product intended for human or veterinary use
presented in its finished dosage form or as a starting material
for use in such a dosage form that is subject to control by
pharmaceutical legislation in the exporting state and/or the
importing state.

Pharmacovigilance The science and activities relating to the detection, assessment,

understanding and prevention of adverse effects or any other
medicine-related problem.

Post-market Surveillance activities that occur following market approval of

surveillance, or a medicine, including maintenance of product authorization
Post-marketing and/or registration of variations or renewals; regular
surveillance inspections of manufacturers, wholesalers, distributors, and
retailers; quality control testing; pharmacovigilance;
promotion control; public reporting of poor-quality products;
handling of market complaints; and removal and disposal of
non-compliant products.

Note: For the purpose of this document, the term post-

market(ing) surveillance will be used to refer to the aspects of
surveillance that pertain to monitoring the quality of
pharmaceutical products, and not to pharmacovigilance.

Production All operations involved in the preparation of a pharmaceutical

product, from receipt of materials, through processing,
packaging and repackaging, labelling and relabelling, to
completion of the finished product.

Reference material Material sufficiently homogeneous and stable with reference to

specified properties, which has been established to be fit for its
intended use in measurement or in examination of nominal
properties.

Sample A portion of a material collected according to a defined

sampling procedure. The size of any sample should be sufficient
to allow all anticipated test procedures to be carried out,
including all repetitions and retention samples.

Sample collection form A form used to record of the details of the sample collected and
observations made during sampling. A copy may be included in
the sampling record.

Sample Collector Person responsible for performing the sampling operation.

Also, called Sampler.

6
Sampling method The part of the sampling procedure dealing with the method
prescribed for withdrawing samples.

Sampling plan Description of the location, number of units and/or quantity of

material that should be collected, and associated acceptance
criteria.

The complete sampling operations carried out on a particular

Sampling procedure material for a defined purpose. A detailed written description
of the sampling procedure is provided in the sampling protocol.

Sampling record A written record of the sampling operations carried out on a

particular material or product for a defined purpose. The
sampling record should contain the batch number, date and
place of sampling, reference to the sampling protocol used, a
description of the containers and of the materials sampled,
notes on possible abnormalities, together with any other
relevant observations, and the name and signature of the
inspector.

Sampling unit Discrete part of a consignment such as an individual package,

drum or container.

Screening Technologies The qualitative and/or quantitative technologies that could

rapidly acquire preliminary analytical information or data on
the quality of medical products in the field.

Selected sample Sample obtained according to a sampling procedure designed

to select a fraction of the material that is likely to have special
properties. A selected sample that is likely to contain
deteriorated, contaminated, adulterated or otherwise
unacceptable material is known as an extreme sample.

Simple random sample A sample drawn from the population where each member of the
population or unit has an equal chance of being selected.

Small Island Developing A distinct group of developing countries facing specific social,
States (SIDS) economic and environmental vulnerabilities.
SIDS are a recognized group of 58 low-lying island nations
across 3 geographical divisions – Caribbean, Pacific, and
Atlantic, Indian Ocean, Mediterranean, and South China Sea
(WHO/CCU/17.08)

Substandard Also called “out of specification”, these are authorized medical

products that fail to meet either their quality standards or
specifications, or both.

7
 Uniformity A starting material may be considered uniform when samples
drawn from different layers do not show significant differences
in the quality control tests which would result in non-
conformity with specifications.

Unregistered Medical products that deliberately and/or fraudulently

misrepresent their identity, composition or source.

Verification The process by which a pharmacopoeial method or validated

analytical procedure is demonstrated to be suitable for the
analysis to be performed.
Source: Definitions have been adapted from References1-4.

8
Lists of Figures and Tables

Figures
Figure 1: Steps for Planning Risk-based Surveillance of Medicine Quality 20

Figure 2: Overview of Stages of Incident Management by NMRAs 27

Figure 3: Flowchart for Visual and Physical Screening (Level 1) 39

Figure 4: Guidance for Field-based Screening (Level 2) 41

Figure 5: Recommended Prioritization for Compendial Testing (Level 3) 43

Figure 6: MQCSD Post-Market Surveillance Programme Sequence 47

Tables
Table 1: Categorization of Risks of Falsified, Unregistered and Substandard 22
Medical Products

Table 2: Three-Level Approach to Medicines Quality Control 37

9
INTRODUCTION
Background
Access to medicines and other medical products of good quality is essential to successful
treatment and management of diseases and disability. Quality assurance in pharmaceutical
supply systems aims to help ensure that each medicine that reaches patients is safe, effective
and of appropriate quality. The national medicines regulatory authority (NMRA) is primarily
responsible for implementing quality assurance measures prior to market authorization and
while medicines are on the market, to ensure their quality and safety.5
The Pan American Health Organization/World Health Organization (PAHO/WHO), with
endorsement by the Pan American Network of Drug Regulatory Harmonization (PANDRH)
recommends that NMRAs of small island developing states with limited resources, like the
Caribbean, perform the following essential functions:6
• Product registration, or marketing authorization: to review and evaluate products for
legal sale in the market based on safety, quality, and efficacy
• Licensing of establishments: to license warehouses and distributors on the bases of
compliance with good practices, such as good distribution practices
• Market surveillance and control: to conduct import and export control, and monitor
medical products in the market, including substandard and falsified medicines
• Vigilance: to carry out the collection and evaluation of information related to safety
of medicines and adverse events, and to make regulatory decisions from the
information obtained
• Regulatory inspections: to perform inspection activities of establishments in order to
verify compliance with regulations and standards.

Therefore, NMRAs, which are primarily based within Ministries of Health in the Caribbean,
are responsible for monitoring the quality of pharmaceutical products while on the market.
This role is an essential component of market surveillance and control and vigilance, also
known as “post-market surveillance”. The WHO Global Benchmarking Tool (GBT) for
evaluation of national regulatory system of medical products provides various indicators
that may be used by NMRAs to identify areas for system strengthening, including indicators
for medicines registration and market authorization, market surveillance and control,
vigilance, and laboratory testing.7
As in other small island developing states (SIDS) around the world,4 several Caribbean
countries lack the capacity to undertake all aspects of post-market surveillance, including a
lack of trained personnel, testing laboratories and information technology for regulatory
activities. The Caribbean Community (CARICOM), the Caribbean Public Health Agency
(CARPHA), and other stakeholders including PAHO/WHO are implementing strategies to
strengthen regulatory systems and post-market surveillance capacity in the small states of
CARICOM. This is in accordance with regional mandates such as the PAHO Directing Council’s
resolution CD50.R98 and World Health Assembly resolution 67.20.9 With endorsement by

10
CARICOM’s Technical Advisory Committee on Pharmaceutical Policy and the Council of
Human and Social Development, and consistent with the Caribbean Pharmaceutical Policy
adopted in 2011,10 a regional regulatory mechanism called the Caribbean Regulatory System
(CRS) has been launched. This system is managed by CARPHA in close technical cooperation
with PAHO/WHO.
CARPHA Medicines Quality Control and Surveillance Department, in collaboration with its
partners and stakeholders, has expanded its medicines quality testing and developed a post-
market surveillance programme to address medicines quality issues in the region. This
technical support, along with shared guidance, training and information exchange, will
support medicines regulatory systems of CARPHA Member States.11

11
Purpose of the Guide
This guide provides information to CARPHA Member States on the conduct of post-market
surveillance and the procedures for medicines quality testing at the Medicines Quality
Control and Surveillance Department (MQCSD). The aims of the guide are:

i. To assist national medicines regulatory authorities of CARPHA Member States and

associates in the design and conduct of programs for national post-market
surveillance of medicines and
ii. To describe the procedures for sample collection, and the submission of samples of
medicines for compendial testing to the MQCSD.

Section I of the guide will assist administrators of NMRAs with limited regulatory capacity
by serving as a resource for policy development and planning of operations. It describes a
risk-based approach to post-market surveillance in limited resource settings like the small
states of CARICOM. This includes the systems required for post-market surveillance, such as
a voluntary reporting system, quality testing equipment or facilities, data management,
incident management protocols, policies for regulatory action, communication, financing,
and human resources. Essentially, this guide will provide key insights into how to establish
systems that can collect and analyse patient adverse events, and respond to substandard,
falsified, and unregistered medicines.

Section II will provide guidance to supervisors and sample collectors on the procedures
involved in the sample collection, and submission of samples of medicines for compendial
testing at the CARPHA MQCSD.

Intended Users
The guide is written for:

• Administrators and staff of national regulatory agencies for medicines involved in

planning and supervision of quality surveys
• Regional focal points for pharmacovigilance and post-market surveillance
responsible for assisting with policy development and implementation
• Quality officers or officers of regional health authorities involved in monitoring the
quality of medical products, planning and implementation of quality surveys
• Health professionals and technical personnel who work in or with agencies
responsible for medicines distribution and/or the monitoring the quality of
medicines in Caribbean markets with responsibility for monitoring the quality of
medicines

12
 • Supervisors of regulatory units responsible for implementation of medicines quality
surveys
• Sample collectors (Section II).
Other stakeholders, such as regional focal points for pharmacovigilance and post-market
surveillance, quality administrators or officers within NMRAs and educators may use this
document as a reference to develop policies, procedures and training material.

Additional Context

Post-market surveillance of the quality of medicines is a dynamic but essential function of

national medicines regulatory authorities. Although post-market surveillance generally
extends to all medical products (e.g. medicines, vaccines, in vitro diagnostics), the focus of
the guide will be the surveillance of medicines or finished pharmaceutical products. This
guide serves as one of many tools that may be used by NMRAs, as it may be supplemented
by training workshops, and updated as new approaches are developed to improve
pharmaceutical systems and to meet the evolving needs of the Caribbean people.

Note: This document is written to provide guidance and should be used in the context of the
national or regional reality. It is not meant to subvert the established policies and procedures
of national regulatory authorities.

13
SECTION I: GUIDANCE FOR NATIONAL POST-
MARKET SURVEILLANCE SYSTEMS

14
1.0 National Post-Market Surveillance Systems

1.1 Role of NMRAs and Stakeholders

Post-market surveillance (PMS) of medicines is essential to ensure that the products used to
treat conditions remain of sound quality while on the market. Several activities may
encompass safety assessments and quality monitoring, including clinical trials in
populations that were omitted during pre-marketing trials and periodic national surveys of
the quality of medicines. National PMS for quality assurance of medicines used by
populations should include the development of passive surveillance (spontaneous reports
by users), which would provide information to guide the development of risk minimization
activities.5,7 It may also include risk-based approaches to conducting quality surveys of
products in the field.12

In addition to monitoring the quality of medicines on the market, national medicines

regulatory authorities are also responsible for taking reasonable and appropriate regulatory
actions to prevent and minimize harm arising from the use of unregistered products,
substandard medical products and falsified medical products. This responsibility is also
shared among various stakeholders including licensed distributors, manufacturers, and
retailers (e.g. pharmacists, shopkeepers), who may be inspected to ensure good distribution
and storage practices. The NMRA may strengthen its PMS activities through strategic
collaborations with other agencies, such as the Customs divisions of National Security
agencies to identify and prevent the entry and distribution of substandard, falsified or
unregistered medical products.

1.2 System Objectives and Operational Elements

In order to achieve the mission of sustained national post-market surveillance, NMRAs will
need to establish a system with clearly defined objectives. Broadly, these objectives should
include:

• The facilitation of spontaneous reporting of suspected substandard and falsified

medical products by health professionals, marketing authorization holders and the
public
• Handling of market complaints
• Detection of substandard or falsified medical products
• Removal and disposal of defective and non-compliant products from the market, and

15
 • Implementation of corrective and preventative actions to minimize future non-
compliance.

The World Health Organization’s Member State Mechanism also provides guidance to
NMRAs to develop national plans for preventing, detecting and responding to actions,
activities and behaviours that result in substandard and/or falsified (SF) medical products.13

1.2.1 Prevention

Operational approaches to prevent the distribution and use of substandard, falsified or

unregistered medicines on the market should include:13

(i) The verification of good manufacturing and distribution practices in the supply
chain
(ii) The verification of the medical products distribution chain, by checking the source
and destination or transfer of possession
(iii) The identification of SF products in the chain, through post-market
surveillance, and in coordination with security agencies and market authorization
holders
(iv) The identification and investigation of actions, activities and behaviors that
contribute to SF products on the market
(v) The collection of samples for verification and/or analysis, and
(vi) Recall and/or prohibition of the distribution and use of SF products detected.

1.2.2 Vigilance and Detection

Pharmacovigilance (PV) falls under the broader topic of vigilance and is an important part
of post market surveillance. It is defined as “the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any other
medicine-related problem”. 3 Pharmacovigilance often relates to the intrinsic safety of a
medicine for human use, but it can also relate to the external quality elements that factor
into the product’s manufacture and distribution. For example, substandard and/or falsified
medicines may be part of pharmacovigilance because they may result in adverse events such
as therapeutic failure and/or other adverse effects.
It is not unusual for PMS activities to be included in the operations of a national
pharmacovigilance centre or vice versa, as there are several operational similarities. In
addition, the integration of the two functions under one unit will enable the NMRA to
optimize available resources.

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1.2.3 Operational Elements

For a national post-market surveillance system to undertake the function of monitoring the
quality and safety of medicines in public health, NMRAs may follow WHO’s
recommendations for setting up a pharmacovigilance centre, which includes:3

• A voluntary reporting system including a method of reporting

o E.g. a printable form, or an online form, or telephone service or a short-
messaging service (SMS)
• Information Technology:
o A database for storage, analysis and retrieval of reports
o Subscriptions to electronic databases, newsletters, and/or alert systems of
other NMRAs (e.g. US Food and Drug Administration)
• Human resources: Trained personnel for:
o Follow-up of reports, database searches
o Data handling (entry, analysis)
o Sample collection and
o Use of field screening equipment (detection technologies)
• Policies and procedures for:
o The management of reports
o A risk-based approach to quality testing
o Incident management, including risk assessment
o Risk minimisation activities, including regulatory actions and/or responses
• An advisory committee of experts, with clearly defined terms of reference
• Appropriate legislation and regulations to enable law enforcement and legal action
• Adequate financing to sustain the system and ensure independence, and
• A communication system to engage health professionals and the public.

1.2.4 Voluntary Reporting system

Reporting System:

The post-market surveillance system should facilitate reporting of adverse medicine

reactions, and substandard or falsified or unregistered medical products by health
professionals and patients to the NMRA. To create awareness and to minimize invalid
reports, educational approaches will be needed to teach the public and health professionals
what to report and how to report. In general, when medicines are suspected to cause adverse
reactions, or are suspected of being substandard or falsified, they should be reported.

17
Examples include adverse reactions that occur after taking a medicine such as rash or
difficulty breathing, and product discolouration or malodorous products which may be
substandard or falsified. In addition, substandard or falsified products may present with
labelling or packaging that appear sub-optimal (incorrect colours, distorted text).

The WHO and the World Health Professionals Alliance (WHPA) have developed tools to
approach suspected substandard or falsified products in the field (Appendices II-III).
Government inspectors may also identify unregistered medicines by comparing the products
distributed in local pharmacies or hospital dispensaries to the list of products with market
authorization. Therefore, it is important for countries to make lists of authorized products
available to the public, and to keep the lists current.

Reporting Form:

Each country should develop a reporting form and a database system to receive and manage
reports, where possible.

The reporting form (or alternative medium) should be easily accessible, and easy to
complete and submit to the NMRA. Instructions on how to complete the form should be
provided, along with a contact for any questions the reporter may have. The case report form
should capture information on:

• The International Non-proprietary Name (INN or generic name) of the medicine

• The trade or brand name
• Name of manufacturer or marketing authorization holder
• Address of manufacturer
• Lot or Batch number ¥
• Expiry Date
• Description of quality issue, including photographs if possible
• Location and/or source
• Reporter name and contact information
• Dates
¥ Note: Two of the most commonly omitted fields are manufacturer and lot or batch number.
However, these are essential to enable NMRAs to investigate possible substandard or
falsified products, and to enable any regulatory action against specific manufacturers of non-
compliant product batches.

In developing or improving national reporting forms, NMRAs may refer to forms used by
other agencies, such as the regional network for pharmacovigilance and post-market

18
surveillance (VIGICARIB),14 or by the World Health Professions Alliance under the Be Aware
– Take Action campaign.15

Sample Collection

Reporters should be instructed to retain samples of the medicine for collection by authorized
sample collectors.

Standard procedures for follow-up, report validation and sample collection should be
implemented by the responsible division of the NMRA (or Ministry of Health). Sample
collectors should follow the procedures recommended to avoid the contamination of
samples. Guidance for sample collection, handling, storage and transportation is provided in
Section II-5.3.

1.2.5 Database Management

As far as possible, staff at the NMRA should follow-up with reporters to confirm the source
and assess the credibility of the information. Questions that may be used to confirm validity
are provided by the WHO Incident Management Guide (Appendix I). Errors in the case report
should be corrected as far as possible to allow for accurate assessment of risk.

Case reports should be entered and stored in a secure information system. Electronic
information systems are recommended as these may be backed-up periodically to a server
to prevent accidental loss. This may be done using an electronic spreadsheet (e.g. Microsoft
Excel®) with key information fields and reporting functions, which may be updated
regularly. On a periodic basis (e.g. monthly, quarterly), summative reports should be
generated and used for system improvement.

1.3 Setting Priorities for Risk-Based Post-Market Surveillance

1.3.1 Determining Priority Medicines for Testing

There is much that can be done to monitor medicines for safety and quality in the market
before resorting to laboratory testing. Laboratory testing is often expensive and frequently
unavailable to small states in the Caribbean, due to the lack of national medicines quality
control laboratories and resources to outsource services. Unfortunately, post-market
surveillance cannot be complete without medicine testing services. Thus, national post-

19
market surveillance programmes must include clear protocols and thresholds for the
conduct of different levels of testing of medicines, including laboratory testing, and to
determine which are technically reliable and financially sustainable.

PMS programmes should have the capacity for routine and emergency testing (even if
sourced to international laboratories), which should be based on the risk to public health.
For example, if there is a cluster of reports related to patients who are receiving an
antimalarial medicine that is not having the intended therapeutic effect, it may be necessary
to send the product for testing of the active ingredient.

The following criteria are recommended to determine priority medicines for testing:

• Medicines frequently used by large populations or public health programmes

• Newly marketed medicines, including innovator products with less characterized
safety profiles
• Medicines with quality issues reported to regulatory authorities
• Medicines with a high prevalence of reports of substandard issues or falsification
within the WHO Global Surveillance and Monitoring System (GSMS), with relevance
to the Caribbean region
• Medicines imported from unregulated and/or poorly regulated markets
• Medicines with dangerous risk profiles, such as narrow therapeutic indices or
complex manufacturing processes.

Medicines recommended for market authorization or registration through partner

organizations (e.g. the Caribbean Regulatory System) that do not meet the above criteria may
be included for monitoring.

Geographic locations (e.g. borders, coastal regions, ports of entry) and clinics that are
vulnerable should also be considered in a post-market surveillance strategy.3

Risk-based sampling also means that certain testing practices may need to be reconsidered
for their usefulness and sustainability. For example, a common practice in the region is to
test all medicines before market authorization (called pre-registration testing). However,
this is quite an expensive process and there are examples of situations where the laboratory
is not able to test and so the country is not able to approve medicines for market
authorization. This compromises regulatory efficiency and more importantly timely access
to medicines for patients. The WHO and other authorities strongly recommend against pre-
registration testing. If manufacturers are in compliance with Good Manufacturing Practices
(GMPs), then quality is built into the process. Testing one sample at one point in time would
not be helpful. NMRAs should focus on how to assure oversight of Good Manufacturing
Practices.

20
1.3.2 Collection sites and sampling methods

The various routes for the distribution of medicines through public, private, or informal
supply chains each pose different risks of entry of substandard, falsified and unregistered
medicines. In developing site selection criteria, NMRAs should consider: local knowledge of
supply chain for target medicines, the availability and accessibility of target medicines, and
information on where patients obtain medicines.16

All medicines outlets (dispensaries) in the sampling area should be mapped out by name and
location.

Sampling may be done using various sampling methods, such as convenience sampling,
random sampling, cluster sampling or lot quality assurance sampling. NMRAs may decide to
also use mystery shoppers (covert) or sample openly (overt) depending on the objectives
and limitations of the study.

For example, where a product that is suspected to be substandard is identified at the central
medical stores, sampling at higher points along the supply chain is not needed. Inspectors
may sample from the central stores, supplier’s warehouse, and any ports and points of entry.
The storage conditions at each location should be clearly documented. For a product that is
suspected to be falsified, which is identified at a health facility, the sample frame should
include the stores of the dispensary, the distributor’s warehouse and any other source of the
product including patient’s own supply. Where applicable, the patient or his/her family
should be interviewed to determine the source of the medicine.

In cases where an illegitimate source is involved, a mystery shopper may be used to approach
the pharmacy or distributor to purchase the sample. Otherwise, overt sampling may be used
where the manager is apprised of the purpose of the visit.

For routine surveillance, where a product is to be sampled from various regions or levels of
distribution in the supply chain to gain a representative view of the quality throughout the
country or district, a cluster sample may be applied. In this case, a random sample of the
product is drawn from each region or level.

In urgent cases, where a medicine is considered high priority or the risk of harm is high (e.g.
use among large numbers of persons, vulnerable populations), and the medicine is widely
distributed e.g. through public health programme, a non-probability sample or convenience
sample may be taken.

Figure 1 outlines the steps recommended for planning national risk-based surveillance
programmes.

21
Figure 1: Steps for Planning Risk-based Surveillance of Medicine Quality

Select Medicines for PMS

• Based on criteria, e.g. novelty, complexity, limited safety data, stability issues,
resistance, high demand, quality, GMP compliance, population exposure

Select Geographical areas for sampling

• Based on criteria, e.g. poor storage, poor access, high disease burden, population,
porous border zone, illicit market, complex supply chain, medicines quality

Select Collection sites

• Consider local knowledge of supply chain (points of entry, virtual outlets),
availability and accessibility, and patient access information

Select Collection methods

• Determine if convenience, random, cluster or lot QA sampling
• Overt sampling or mystery-shoppers

22
2.0 Incident Management, Risk Assessment and
Decision-Making

In addition to planning PMS activities, national medicines regulatory authorities (NMRAs)

will need to:

• Manage incidents with confirmed safety and quality issues

• Assess the potential risk involved, and
• Decide on the approaches need to minimize the risk of harm.

2.1 Handling Reports

The steps for incident management recommended by the WHO provides guidance for the
management for substandard or falsified (SF) medical products reported to NMRAs via its
Aide Memoire (Appendix I).17 Although the guidance is developed for suspected SF products,
the approach may be used in the management of reports of suspected adverse medicine
reactions. The recommended steps for incident management are:

i. Receipt of the report

ii. Establishing the facts
iii. Assessment of risk to public health
iv. Immediate actions to protect public health
v. Field screening and laboratory analysis (if applicable), and
vi. Managing the incident.

Establishing the Facts: For each report of a suspected substandard or falsified medical
product, the NMRA staff should:

1. Contact the reporter

2. Assess the reliability of the source
3. Establish the facts of the case
4. Assess the credibility of the information received
5. Obtain samples of the product and photographs showing batch number and
expiry dates, and
6. Determine if there have been similar reports by regulatory authorities in the
region, and the WHO Global Surveillance and Monitoring System (GSMS)
database. Information on regional reports may be checked through networks
established by the PAHO/WHO.

23
During the process of establishing the facts, staff of the NMRA should submit questions to
the manufacturer to determine:

• If the company manufactured the product

• If the dates on the product are authentic
• If there have been falsified or substandard versions reported previously
• If there have been any complaints about the batch, and
• If there is any other information that the NMRA should be aware of.

The WHO Incident Management Aide Memoire provides questions that NMRA staff may use
to check reliability and validity of reports (Appendix I).

2.2 Risk Assessment and Prioritization

The aim of risk analysis and management should be to evaluate the potential impact of
reports received by NMRAs with respect to substandard or falsified medical products
detected by health professionals, the public, and/or quality control laboratories. NMRAs
should apply a structured risk assessment to determine prioritization of risks and actions to
be taken.18

2.2.1 Risk assessment categories

The following table presents broad categories of risk levels of falsified, unregistered and
substandard products.18

Table 1: Categorization of Risks of Falsified, Unregistered and Substandard Medical Products

Product Type Risk Level Notes

Falsified product High Any case of falsification or suspicion of falsification should be

investigated immediately.
Assess risk to determine priority levels

Unregistered/ High Product has not been evaluated by NMRA and is of unknown origin.
Unlicensed product Check other NMRAs to determine if licensed / in good standing
elsewhere.

Substandard Variable Consider, at minimum:

products Severity of defect / non-compliance
Potential clinical consequences
Potency of medical product or therapeutic index

24
 Product Type Risk Level Notes

Patient population
Route of administration and place of action

All SF products Other factors:

Probable place of deviation occurrence
Exposed population
Frequency of occurrence
Market turnover and expiration date
Single product on market or widely used in public health
Detectability of defect / non-compliance
Adapted from Reference 17

Each NMRA should identify and select the factors to be considered in the evaluation, based
on experience and available information. The selected factors, criteria and steps used in the
assessment of risk for each case should be clearly documented.

2.2.2 Risk classification and prioritization matrix

National medicines regulatory authorities are advised to develop and implement a

procedure or tool to undertake risk assessment for SF products, in order to obtain
standardized and reliable results during evaluation of reports. This will avoid multiple
interpretations of the same event by different personnel. The NMRA may select an
established prioritization matrix, but this should be done after reviewing various types since
the each utilize unique criteria to define priorities.

One possible approach is the development of a matrix to assist in the evaluation. The WHO
guidance provides a suggested method for illustrative purposes only.18 NMRAs may opt to
develop their own tools to aid in risk classification and prioritization.

Principle 1:

Risk factors that compound the evaluation will have different importance for the final result.
That is, some factors are more relevant than others. Relevance levels and rates must be
established by NMRAs individually, taking into account the national and/or regional
circumstances.

Principle 2:

25
The evaluation can be performed individually for each risk factor. The combination of values
will provide a final result, which indicates the severity and the prioritization level for the
case. The findings should be used as a guide, rather than a strict reference.

In developing the matrix, the following four steps are recommended:

 Step 1: Identify the main elements involved in the risk assessment, namely ‘risk
factors’.
 Step 2: Establish the importance level or weight (numerical value) for each risk factor.
 Step 3: Define the different prioritization categories of risk within each risk factor.
For example: low risk (rated as 1); medium risk (rated as 2); and high risk (rated as
3).
 Step 4: Establish groups of prioritization, based on sums generated by the matrix.
Suggested groupings are: low prioritization, medium prioritization and high
prioritization.

Interpreting Results

The results should be reviewed in consideration of risk factors that were not included in the
matrix. The final result should clearly fall into one of the three groups of prioritization. The
higher the index, the higher the severity and importance of the case for public health. After
developing a matrix, the NMRA should proceed to validate it within a specified period of time
or number of reports (or notifications), to confirm it utility before full implementation.

Practical Example:

The example provided is for demonstrative purposes only to show the application of the
matrix to a fictional scenario in a fictional country. Relevance levels and ratings may vary in
different jurisdictions.

Step 1: The NMRA in Country Y has chosen risk assessment factors to be considered in the
evaluation, namely:

- Potential clinical consequences

- Severity of defect or non-compliance
- Recommended patient population, and
- Route of administration / site of action.

26
Step 2: Importance Level – The NMRA has decided that the potential clinical outcomes are
more relevant than the severity of the defect or non-compliance and the recommended
patient population. Route of administration and site of action are the least relevant.

Step 3: Prioritization of Risks – the NMRA has defined the prioritization categories as:

- Sum of 8 – 13: Low priority

- Sum of 14 – 18: Medium priority

- Sum of 19 – 24: High priority

Situation A: Medicine (tablet) used to prevent spina bifida in infants, given to women prior
to conception and during pregnancy was found to have physical contaminant (hair)
embedded in tablet. The contaminant was found in a bottle in the dispensary of a public
health facility.

Risk assessment factor Importance Categories Rate per

Rate
level factor
Severity of defect / non- Low risk
1
compliance Medium risk
2 2 2x3=6
High risk: product
3
contamination
Potential clinical Low risk
consequences Medium risk: bacteria or fungi 1
3 may be destroyed by stomach 2 3x2=6
acid 3
High risk:
Recommended patient Low risk 1
population 2 Medium risk 2 2x3=6
High risk: pregnant women 3
Route of administration, Low risk 1
site of action 1 Medium risk: internal use, oral 2 1x2=2
High risk 3
TOTAL (6+6+6+2) 20
Assessment: High Priority

The information from the risk matrix used to develop recommendations for regulatory
action to minimize risk to the public.

27
28
2.3 Regulatory Decision-Making and Action

2.3.1 Review of Incidents for Regulatory Actions

All alerts, reports and/or results from post-market surveillance activities regarding
substandard, falsified, and unregistered medicines should be assessed by the NMRAs as soon
as possible, with the goal of identifying the cases with the greatest potential to cause serious
damage to public health, which require immediate action.

In order to manage the incident to minimize the risk to public health, staff at the NMRA
should ensure the following are implemented:

i. An Advisory Group or Committee §: A team of relevant regulatory specialists with

a lead person, and any additional relevant external stakeholders should be convened
ii. Documentation: Strict records of meetings and decisions should be maintained
iii. Strategic Plans: The team should focus on developing actions to protect the public
health by mitigating the risk posed and investigating the origin of the product
iv. Verification of the availability of genuine stocks and genuine replacement products
v. Regulatory Actions: Decisions regarding regulatory actions may include: product
recall, communications to health professionals, and the media
vi. A public notice may be necessary
vii. Reporting the incident to regional and global networks, such as the WHO Global
Surveillance and Monitoring System.

Figure 2 outlines a simplified sequence of the stages.

§ Note: For the composition and functions of an advisory committee that oversees the use of
medicines, regulatory authorities may refer to the World Health Organization’s guide for
Drugs and Therapeutics Committees available at:
http://apps.who.int/medicinedocs/en/d/Js4882e/.

29
Figure 2: Overview of Stages of Incident Management by NMRAs

Advisory Group Meetings

Documentation of Decisions

Strategic Planning & Verification

Regulatory Actions

Public Education and Reporting

Based on the public health importance of the survey findings, the NMRA may take various
actions to minimize the risk to public health. This may include requests for additional testing
of samples, contacting manufacturers for further information, clarification or confirmation
of the product, or other appropriate regulatory action including recall.

Focal points in the respective NMRAs in the region are asked to report medicines with
suspected quality issues to the regional network for pharmacovigilance and post-market
surveillance (VIGICARIB) irrespective of status (confirmed or pending). This will serve to
alert other NMRAs in the region about potential threats that are under investigation, and to
improve regional vigilance and regulation of confirmed threats. The guidelines for reporting
incidents of suspected adverse medicines reactions, and substandard/falsified medical
products to VIGICARIB are available via: http://carpha.org/What-We-Do/Caribbean-
Regulatory-System/VigiCarib.14

2.3.2 Taking Regulatory Action

National medicines regulatory authorities should be adequately empowered through

legislation to undertake actions to protect the public from the threat posed by substandard,

30
unregistered and falsified medical products. For the implementation of regulatory action
plans to minimize the distribution of SF products, NMRAs also require sufficient finances
through budgetary allocation for human resources, information technology,
communications and record-keeping. In agencies where staff undertake multiple aspects of
medicines regulation, the NMRA may identify specific personnel (full-time or part-time) to
manage reports on a scheduled basis.

The action plan developed by the NMRA in response to the presence of substandard or
falsified medical products should be flexible and updated based on results obtained. The
actions will vary according to the needs of each case.13

Examples of categories of actions include:

• Immediate actions:
o Characterizing the activity or behaviour through tracing of supply, retention
of samples
o Containing the situation to prevent and reduce risk to public health:
prohibition regulations, market recall, support for patients and relatives,
reporting at international level
o Field actions or inspections
• Short-term actions:
o Communicating and disseminating case information to appropriate parties,
including publication, and reporting to WHO database
o Identifying persons or entities to be held accountable
• Long-term actions:
o Continuity and improvement of monitoring programme
o Continuity with plan for health care community support
o Continuity of collaboration with authorities in charge of the investigation.

For Situation A’s example (contaminated folic acid tablet – High priority), the advisory
committee may decide on the following:

Immediate action:

• Suspension of products with the given batch number

o Notifications sent to public sector dispensaries and private pharmacies to
remove products from shelves
• Contact the manufacturer or market authorization holder
• Send the sample for laboratory testing, if possible to determine nature of
contaminant
• Issue public notice to recall products with given batch number

31
 • Search global database for similar quality issues
Short-term action:

• Notify manufacturer of findings and request investigation into packaging processes

• Discuss remedial actions for affected patients and sanctions / regulatory actions
• Communicate issue to procurement agencies
• Communicate actions to be taken to the public to prevent harm and recurrence

Long-term action:

• Public education campaign on simple visual inspection of medicines, and the need to
report issues including therapeutic failure or contamination
• Implementation of protocols for pharmacy staff to conduct visual inspection of
medicines when receiving inventory
• Education of health professionals to undertake visual inspection of medicines when
receiving inventory and at point of dispensing
• Establish a registry of authorized suppliers and/or donor agencies in the country
• Implementation of policies for procurement of medicines from authorized
distributors, and inspection
• Discontinuation of tender contract for public health supply of folic acid from
supplier/manufacturer
• Revision of laws to include sanctions and penalties for the supply of substandard
medicines in public health.

Note: Each jurisdiction will need to determine the key risk factors, the relevance of each risk
factor, actions related to the various risk levels or priorities, and the appropriate regulatory
actions to be taken to protect the public.

2.4 Strengthening Regional Decision-making and Global Surveillance

2.4.1 Leveraging Key Regional and International Regulatory Programmes

This guide presents key principles and guidance for the development of post-market
surveillance systems in limited resource settings. National medicines regulatory authorities
may undertake these activities on their own, but given resource limits in the Caribbean, it is
highly recommended to consider leveraging available resources where possible. There are a

32
number of regional and global programs that governments may use to augment their post-
market surveillance programmes. These are outlined below.

The Caribbean Regulatory System (CRS) is an initiative of the Caribbean Community and
Common Market (CARICOM) established to assist Caribbean states to perform key
regulatory functions related to pharmaceutical regulation. Similar to the MQCSD, the CRS is
administered by the Caribbean Public Health Agency (CARPHA) and is engaged in two
primary functions:19

• The review of products to make recommendations to Member states for market

authorization (registration), and
• Pharmacovigilance and post-market surveillance of medicines and vaccines in the
region.
The CRS supports the regulatory work of NMRAs through procedural guidance, information
exchange and the formulation of recommendations for product registration and risk
minimization.19 Support for regional pharmacovigilance and post-market surveillance is
provided through the Caribbean network for pharmacovigilance and post-market
surveillance (VIGICARIB). This network was launched in late 2017 to serve as a mechanism
for the receipt and assessment of reports of suspected adverse medicine reactions and
reports of substandard, falsified or unregistered medical products in the region.14 It
facilitates the submission of reports to the global programmes of the World Health
Organization, including the WHO Program for International Drug Monitoring (PIDM), and
the WHO Global Surveillance and Monitoring System (GSMS), on behalf of NMRAs with
membership in the respective systems. As a result, VIGICARIB helps to improve regional and
international monitoring of the quality and safety of medicines, thereby providing countries
with information for regulatory decision-making.

2.4.2 Improving Local, Regional and International Post-Market Surveillance

For CARPHA Member States to benefit from the work of the network, NMRAs will need to
share reports and findings of post-market surveillance and the respective regulatory
decisions. The results may be captured and collated through online databases such as the
WHO’s Global Surveillance and Monitoring System (GSMS), which are accessed by
authorized staff or focal points for individual countries. Data shared in such platforms will
encourage other countries and stakeholders to report and share information on substandard
and falsified medicines to stem the global problem. In addition, this exchange of information
will assist to improve regional and global surveillance of the quality of medicines.

To further strengthen regional vigilance, NMRAs are encouraged to collaborate with other
national and international agencies including:

33
 • Health care providers, such as pharmacists, physicians
• National security agencies (e.g. local police, customs and excise, coast guard)
• Scientists and members of academia
• The Pan American Health Organization (PAHO)/The World Health Organization
(WHO)
• Interpol
• The wider pharmaceutical industry
• Other national governments and regulatory authorities and
• The general public.
Such transparency and information exchange may have a direct impact on the health and
wellbeing of patients and populations, as well as strengthen public confidence in the health
system. In addition, the information from PMS programmes may be used to strengthen the
programmes directly, update national priorities and to improve the PMS activities through
expansion and financing.

2.5 Case Study

The example provided is for demonstrative purposes only to show the application of the
reporting procedures, risk assessment matrix and regulatory decisions to a fictional scenario
in a fictional country (as above). Relevance levels and ratings may vary in different
jurisdictions. It is adapted from the WHO’s recommendations for criteria for risk assessment of
cases involving substandard or falsified or unregistered medical products.18

Step 1: The NMRA in Country Y has chosen risk assessment factors to be considered in the
evaluation, namely: Potential clinical consequences, Severity of defect or non-compliance,
Recommended patient population, and Route of administration / site of action.

Step 2: Importance Level – The NMRA has decided that the potential clinical outcomes are
more relevant than the severity of the defect or non-compliance and the recommended
patient population. Route of administration and site of action are the least relevant.

Step 3: Prioritization of Risks – the NMRA has defined the prioritization categories as:

- Sum of 8 – 13: Low priority

- Sum of 14 – 18: Medium priority
- Sum of 19 – 24: High priority
Situation B: Medicine (tablet) used as the main treatment for breast cancer.

Steps involved:

34
 i. Staff at the NMRA received a case report of therapeutic failure from a private
hospital. A patient had brought her own supply of medicines for breast cancer
treatment, but over the past three months, her condition worsened.
ii. The NMRA staff contacted the reporter and arranged to collect the sample of the
medicine from the hospital pharmacy.
iii. Visual and physical inspection of the sample did not reveal any anomalies. The
product is authorized for sale on the local market.
iv. The sample collected was sent to the quality control laboratory for testing to
determine the quantity of active ingredient within.
v. While waiting for test results, the staff at the NMRA contacted the manufacturer to
confirm the source. The marketing authorization holder indicated that this was not
from their inventory.
vi. The NMRA staff searched the WHO GSMS database and found there had been 5
similar incidents reported of low active pharmaceutical ingredient (API) in the
products, which had not been produced by the manufacturer (falsified). Case
reports submitted to regional network and international system, with note
regarding pending test results and regulatory decision-making.
vii. A preliminary report was submitted to the advisory committee, which included the
following risk assessment matrix and information found during searches of
external databases.

Risk Assessment Matrix

Risk assessment factor Importance Categories Rate per
Rate
level factor
Severity of defect / non- Low risk
1
compliance Medium risk
2 2 2x3=6
High risk: assay below
3
specification
Potential clinical Low risk
1
consequences Medium risk
3 2 3x3=9
High risk: medicine used in
3
breast cancer
Recommended patient Low risk
population Medium risk 1
2 High risk: 2 3x2=6
immunocompromised 3
patients
Route of administration, Low risk 1
site of action 1 Medium risk: internal use, oral 2 1x2=2
High risk 3
TOTAL (6+9+6+2) 23
Assessment: High Priority

35
 Lab Result:
Compendial testing confirmed that the samples of the product contained 30-50% (average
of 40%) of the active pharmaceutical ingredient. The quality issue is classified as
substandard – low API.

Regulatory Decisions / Actions to be taken:

Immediate:
- Notices to distributor(s) and pharmacies to suspend sale and distribution of
product with given batch number
- Public notices were issued to advise the public to discontinue use of the product
with given batch number, and to report these to the NMRA for further investigation
- Updates to case report submitted to regional and/or international network

Short-term:
- Investigation into sources of substandard medicine
- Public education activities to increase awareness about purchase of medicines from
unauthorized suppliers
- Referral to law enforcement agencies for application of penalties to unauthorized
distributors as per local laws

Long-term:
- Assessment of supply chain vulnerabilities to reduce stock-outs;
- Review and/or updating of national treatment protocols for breast cancer to
support sustainable supply.

1.3.3 USP’s Risk-Based PMS Tool

The USP’s Promoting the Quality of Medicines (PQM) programme has developed a risk-based
post-market surveillance tool, called MedRS that may be used to assist to develop a risk-
based surveillance plan. It applies information related to the three dimensions of risk:
medicines, geographic area and supply chain, to develop cluster sampling of facilities based
on their risk profile. It may also be used for less rigorous methods, such as convenience
sampling. The tool may assist NMRAs to identify the most susceptible medicines, determine
the number of samples required, and prioritize sampling at the most vulnerable locations. A
pilot version of the tool is available at:
https://drive.google.com/file/d/0B6mAAO0Fp82fa2xwMEMyZFF1ZVE/view.1

36
SECTION II: GUIDANCE FOR QUALITY
TESTING OF MEDICINES

37
3.0 Guiding Principles for Risk-Based Testing

Post-market surveillance for the protection of public health may extend beyond identifying
substandard medicinal products, to include the identification of falsified and unregistered
medical products. The inclusion of the latter categories depends on the needs of the country
and the purpose of the surveillance activities, which may vary based on the types of product
issues reported by users. For example, Country A may experience several reports of adverse
medicine reactions, while Country B may be challenged by reports of therapeutic failure or
inappropriate packaging.

In general, the steps involved in planning quality surveys for risk-based post-market
surveillance include:

1. Identification of objectives of the quality survey

 These may be informed by product complaints, adverse reaction reports, and
pharmaceutical assessment activities
2. Identification of medicines and/or geographical areas at high-risk
3. Determining priorities and criteria for selection of medicines to be tested and
sample collection sites
4. Application of a tiered approach to risk-based sampling and testing (Levels 1-3).
5. Development of a sampling plan that is appropriate for the post-market
surveillance (PMS) programme objectives and types of facilities involved
6. Recruitment and training of sample collectors
7. Undertaking sample collection and field testing, using appropriate documentation
8. Submission of samples for Level 3 testing to qualified quality control (QC)
laboratory, where applicable
9. Reporting of findings to an advisory committee

Additional steps or actions may be included, and some steps may be omitted based on the
objectives and testing priorities of national surveys.

3.1 Applying a Risk-Based Approach to Testing

In a tiered (three-level) approach to testing of medicines quality, the number of samples

required and the types of tests are reduced without compromising the quality of the post-
market surveillance. For example, where the objective of sampling and testing activities is to
assess the stability of medicines at different levels of supply chain, it may not be necessary
to conduct full compendial testing at each level of the system. If product identification,

38
disintegration and dissolution were done on samples at the central level, samples at the
district level may only benefit from testing related substances. On the other hand, if the
initial screening of the sample from the district level showed discoloration, it may not be
necessary to conduct compendial testing of the sample.1,12

NMRAs may refer to the Three-Level Approach used by the USP’s Promoting Quality of
Medicines (PQM) programme for quality testing, which are:1

1) In the field through visual and physical inspection

2) Field-based tests using field screening tools, and
3) At the laboratory as needed, using compendial or other methods.

This approach enables NMRAs to screen a large number of samples across geographical
areas at limited cost. The use of basic analytical (screening) tests in the field could reduce
the number of units required per sample, as only a subset of medicines would be tested in
QC laboratories using compendial methods.

Several falsely-labelled and unregistered medicines may be detected and removed from
circulation through the use of visual inspection and field-based screening in sampling and
collection activities. Level 1 screening may be undertaken at staff at various points
throughout the supply chain, and by patients.

A national medicines registration database inclusive of photos of labels of registered

medicines is recommended to provide information to health professionals and patients and
thereby improve the detection of falsified and unregistered medical products.

Table 2 presents the various tests that may be done using three-level approach. For the
CARPHA Member States, the CARPHA MQCSD may provide testing at Levels 2 and 3 on behalf
of NMRAs for selected medicines.

39
 Table 2: Three-Level Approach to Medicines Quality Control
Level Type of Analysis Type of Test Purpose / Possible product quality issue Personnel Responsible /
Resources
1 Visual and Labelling and packaging
- Identify falsified medicines and/or Staff at each stage of
Physical properties medicines with insufficient, erroneous supply chain, and patients
inspection - Appearance, conditions and/or fraudulent information;
and physical damage to packaging; damage and/or
characteristics of alterations to condition of medicine;
medicine Unregistered medicines
2 Simple, Rapid and - Thin-layer Identify medicines deficient in at least - Personnel trained in
Cost-Effective chromatography (TLC) four critical quality attributes Screening Tests
Screening Tests - Disintegration (identity, content, impurities, and - Medicines Quality
- Colorimetric reactions disintegration for solid dosage forms) Control Lab
(alternate to TLC)
- Spectroscopy based
technologies
3 Pharmacopoeial or According to registration Assessment of all critical quality Medicines Quality Control
Manufacturer’s specifications attributes of the medicine Lab
Validated Tests
Source: Pribluda et al, 2014 12
3.1.1 Guidance for Visual and Field-based Screening (Levels 1 and 2)

Physical and Visual Inspection (Level 1)

Simple visual and physical inspections may identify poor-quality medicines, either by
identifying anomalies in important characteristics (e.g. registration status, expiry date,
and packaging) or by identifying issues with physical characteristics of the dosage form
(e.g. presentation, colour, texture, viscosity). Visual and physical inspections may be
conducted by health professionals who suspect a medical product is substandard or
falsified. Patients and/or caregivers may be instructed to routinely screen medicines and
report anomalies to health professionals and/or the national regulatory authority. Figure
3 presents the flowchart of steps recommended for visual inspection (Level 1), which
includes an assessment of the product label, packaging and presentation.

Checklists and guides by The World Health Professionals Alliance (Appendix II)15 and the
World Health Organization (Appendix III)17 may be used during Level 1 screening to
facilitate inspection of packaging and physical characteristics of the medicine. These tools
highlight questions that may be asked to identify anomalies of therapeutic effect,
packaging, supply source and other factors, such as smell and storage.

After A Problem Is Identified at Level 1:

On the identification of a quality problem during Level 1 inspection, the product should
be reported to the NMRA to determine the next steps with respect to incident
management and regulatory action. Reporters should be instructed to retain the sample
for collection by inspectors. The NMRA may decide to seek clarification from the
manufacturer and/or distributor, proceed with other levels of testing, or take other
regulatory actions based on the findings. Guidance for the management of incidents
involving suspected substandard or falsified products is provided in Section I-2.0.

Level 2 testing is not required if:

i. The product is not registered with the NMRA (report as unregistered)

ii. The product is expired, or
iii. There are physical issues or anomalies related to: labelling, batch number,
scientific name, company’s logo, number of units per container, dosage form,
strength, manufacturer’s address, package insert, or damage to packaging.

If the product passes visual inspection or if a determination cannot be made, the product
should proceed to testing at Level 2.

41
 Figure 3: Flowchart for Visual and Physical Screening (Level 1) 1

Level 1:
Start
Visual inspection 1

STOP: No
Is product
No additional testing
registered?
needed.

Yes

STOP: No
Is product
Yes additional testing
expired?
needed.

No

Did product STOP: No

fail other Yes additional testing
aspects of L1 needed.

No/Questionable

Level 2:
Field-based Screening

Footnote:

1 – Level 1: Visual inspection to include assessment of registration status, expiration date, labelling, batch number,
scientific name, company logo, number of units per container, dosage form, strength, manufacturer’s address, presence of
package insert, damage to packaging.

Report suspected substandard / falsified medical products to NMRA as per country regulations and protocols.

42
Field-based Screening (Level 2)

At Level 2, analytical testing of product quality using field-based screening technologies

may identify potential product issues that may not be apparent at Level 1.1

Suspicious samples identified by visual inspection may be further screened using one or
more advanced screening tests, such as:

• Thin-layer chromatography (TLC)

• Colorimetric methods
• Disintegration tests and
• Spectroscopy: Raman and/or near infrared (NIR) spectroscopy.
These tests may range from qualitative to semi-quantitative, according to the capability
of the screening technology used. The tests may be used to identify the presence of the
active ingredient, possible degradation and/or impurities. NMRAs should assess the
various screening tests available prior to procurement and compare the features to
source the product that best meets their needs.

Based on the objectives of the study, a product that passes identification and other field-
based tests usually provides sufficient information to eliminate the need for further
testing. However, based on the screening tools used and the tests done, the regulatory
authority may decide to send a portion of the passed samples for compendial testing
(Level 3) to confirm the results. Figure 4 describes the steps involved when testing
medicines at Level 2.

Where a product is confirmed as substandard at Level 2, a report should be submitted to

the responsible division of the NMRA as soon as possible. The WHO guidance provided
for management of incidents where substandard or falsified products are identified
should be followed to facilitate confirmation of source(s) and credibility of the
information (Appendix I).17 Staff of NMRAs may use the guides to develop checklists.
Based on the NMRAs protocols for incident management, the findings should be
disseminated to the relevant committees or units of public health authorities for
regulatory action.

43
 Figure 4: Guidance for Field-based Screening (Level 2) 1

Level 2:
Field-based
Screening1

No API
detected
Does product STOP: No need
pass ID? to verify at Level
3

Yes

Pass Conduct other

A portion of
samples may screening
STOP go on to L3 to tests as
confirm results

Fail

Move to Level 3
Testing

Footnotes:

1: Level 2: Field-based screening may include assessment of a product’s identity (ID) and other screening tests as
applicable.

2: If a product passes identification, additional tests should be prioritized in the following order: content, disintegration,
and impurities.

44
3.1.2 Prioritizing for Compendial Testing (Level 3)

Compendial testing provides the most extensive information on the quality of medicines,
but is complex, expensive and time-consuming. Compendial testing should be done on
the following:

(i) Suspected samples that fail field-based screening tests, and

(ii) A portion of samples to confirm Level 2 results, according to study protocol.
Figure 5 presents steps for prioritizing compendial testing.1

If product fails a test at Level 2, the same test should be done at Level 3 before initiating
tests for other product quality attributes.

If the result from Level 2 is confirmed as ‘Fail’ at Level 3, no further testing is needed.

If the result from Level 2 is not confirmed as ‘Fail’ at Level 3, the analysts should proceed
with the recommended prioritization of compendial tests as shown in Figure 5.

The recommended steps in Figure 5 should be used together with the applicable
pharmacopoeial requirements for the product.

Adjustments to the sequence of testing may be necessary based on the dosage form,
formulation or other considerations. Some products may require additional tests not
shown in Figure 5. The flow diagram is not intended as a list of required tests and
does not apply to every testing scenario. Instead, the flow diagram illustrates the
prioritization of analytical tests to guide the sequence for testing the majority of samples,
as applicable.

Depending on the dosage form involved, appropriate adjustments to the sequence may
be needed. For example, injectable liquid dosage forms would not undergo disintegration
and dissolution tests. For products procured by the funding or donor organizations with
sound quality assurance measures in place, a selection of appropriate compendial tests
may be considered based on where in the supply chain samples were collected.

45
 Figure 5: Recommended Prioritization for Compendial Testing (Level 3) 1 ¥

Did product
START N
fail at Level Fail
Disintegratio STOP ¤
n

Yes Pas
Pass

Confirm Fail
Fail
failed result Identificatio STOP ¤
n

Pass
Fail
Fail
STOP ¤ Assay STOP ¤

Pass

Fail
Dissolutio STOP ¤
n

Pass

Fail
Uniformity STOP ¤
of units

Pass

Fail
Related STOP ¤
substances

Pass

Fail
Sterility STOP ¤

Pass

Fail
Other STOP ¤
tests
Legend:

¥ For injectable products, basic tests such Pass

as pH should be confirmed before starting
Level 3 testing. STOP. Product
passed quality
¤ No further testing required. testing

46
4.0 Medicines Quality Testing at The MQCSD

4.1 Services at the Medicines Quality Control and Surveillance

Department (MQCSD)

The Caribbean Regional Drug Testing Laboratory (CRDTL), was established in 1975 by
CARICOM Governments as a regional institution to provide laboratory services to support
the evaluation of the quality of pharmaceutical products. In 2011, the CRDTL was among
regional health institutes and entities that were brought under the umbrella of the
Caribbean Public Health Agency (CARPHA). In its strategic plan 2018-2020, under
Strategic Priority 1, the agency aims to: “strengthen CARPHA Member States’ Health
systems through training, policies, standards and guidelines, access to laboratory
services and essential medicines through the Caribbean Regulatory System.”20 Towards
this objective, the CRDTL was restructured and renamed CARPHA Medicines Quality
Control and Surveillance Department (MQCSD).

The primary goal of the MQCSD is to support CARPHA Member States in the assurance of
the quality of medicines towards the preservation of public health, by verifying that
medicines used in the region are reliable and of good quality. The core functions of the
department are:

1. Performance of analyses of pharmaceutical products and evaluate the technical

data for CARPHA Member States on request.

2. Provision of information and advisory services to CARPHA Member States on

issues pertinent to medicinal quality.

3. Facilitation of training in analytical techniques for pharmaceutical quality control

laboratories.

In addition, the MQCSD will offer educational materials and training to regulatory
personnel in the region to develop capacity within the national medicines regulatory
authorities (NMRAs) post-market surveillance activities.

For products that require compendial testing for market authorization of products, or for
routine or spontaneous post-market surveillance of the quality of medicines, NMRAs may
request the services of the CARPHA Medicines Quality Control and Surveillance
Department.11

The application for testing may include requests for:

 Verification of pharmaceutical identity, and

 Complete or partial pharmacopoeial testing.

47
4.1.1 Testing Services and Accreditation

The MQCSD offers the following testing services for finished pharmaceutical products:
CHEMICAL AND PHYSICO-CHEMICAL ANALYSIS
• Disintegration • Dissolution
• Loss on Drying • pH
• Water content • Thin Layer Chromatography
• Qualitative Identifications (colour reactions, • Uniformity of Dosage Units (mass,
precipitation and other tests) content)
• Titration • Specific Gravity/Weight per mL
• Potentiometry
INSTRUMENTAL ANALYSIS
• High Performance Liquid Chromatography • Spectrophotometry: Ultraviolet-Visible
(Ultraviolet-Visible (UV-VIS) (UV-VIS) and Infrared (IR)

In September 2017, the CARPHA Medicines Quality Control and Surveillance Department
was awarded accreditation through the Jamaica National Agency for Accreditation
(JANAAC) to the international ISO standard 17025 “General requirements for the
competence of testing and calibration laboratories”.

The Department has been accredited to the ISO/IEC 17025 for the following tests:

 High Performance Liquid Chromatography:

o Assay, dissolution, identification, content uniformity
 Ultraviolet-Visible Spectrophotometry
o Assay, dissolution, identification, content uniformity
 Disintegration
 pH
 Uniformity of weight

To verify the maintenance of the scope of accreditation, the Jamaica National Agency for
Accreditation (JANAAC) will conduct annual surveillance visits during a four-year
accreditation cycle, with a full reassessment in the fourth year.

Sterility tests are not performed at the MQCSD at this time and will not be part of the
MQCSD’s post-market surveillance programme. The staff of the MQCSD will advise focal
points regarding the recommended tests for the product based on the dosage form and
the quality issue.

48
4.1.2 Medicines Tested by the MQCSD

The current list of medicines with accredited tests that can be tested by the MQCSD is
available in Appendix IV. This list may be updated periodically based on the department’s
capacity. This list may be used as a reference for NMRAs or other partners seeking to
submit requests for testing of medicines as part of medicine quality surveys.

Regulators with requests for testing outside of the Department’s schedule, or for testing
of unlisted medicines should submit information about the product to the Head of the
MQCSD for technical review and to determine feasibility based on the Department’s
capacity to test.

4.2 The MQCSD Post-Market Surveillance Programme

In June 2018, MQCSD established a post-market surveillance programme with an

introductory phase to be conducted in the first two years. Through this programme,
MQCSD undertakes the monitoring the quality of selected medicines circulating in the
pharmaceutical markets of participating CARPHA Member States.

The objectives of the programme are to:

1. Develop risk-based criteria for the selection of medicines to be tested, in order to

prioritize those that pose risks to public health.
2. Proactively monitor selected medicines on the Caribbean market for quality,
safety and efficacy.
3. Develop competencies to enable sampling and testing of medicines on the market,
as routine surveillance of the quality of medicines.
4. Collaborate with the CARPHA CRS, TECHPHARM, and national focal points to
select medicines for annual post-market surveillance, including drawing on the
CARPHA CRS regional network for pharmacovigilance and post-market
surveillance.

All CARPHA Member States are eligible to participate. The activities of the programme
will involve:

 Identification of priority medicines by focal points for compendial testing, based

on risk-based criteria
 Sampling of medicines by assigned personnel of the NMRA
 Shipping of samples to the MQCSD with appropriate permits and documentation;
 Testing of samples
 Communication of results to NMRAs, and
 Annual reporting of programme activities to CARPHA Member States.

49
A pre-determined list of medicines will be selected and revised annually, in collaboration
with regional NMRAs, CRS and TECHPHARM. The procedures of the programme are
subject to review during the annual evaluation of the programme. An overview of the
sequence of activities involved in the MQCSD post-market surveillance programme is
shown in Figure 6.

Figure 6: MQCSD Post-Market Surveillance Programme Sequence

•NMRA selects
priority
Selection medicines
from MQCSD
list

•NMRA staff
Sampling samples
medicines

•NMRA ships
Submission samples to
MQCSD

•MQCSD
Testing tests
samples

•MQCSD
submits
Results results to
NMRA

Key: MQCSD – Medicines Quality Control and Surveillance Department; NMRA – national
medicines regulatory authority

50
4.2.1 Risk-based Criteria used in Selection of Medicines

The following criteria will be used to select the medicines for the post-market
surveillance programme:

1. Medicines/manufacturers reported by NMRA/Ministry of Health, procurement

agencies, MQCSD for quality/substandard/falsification issues

2. Medicines produced by countries with limited regulated systems

3. Medicines with limited time on market (less than 5 years on the market of a
stringent regulatory authority)

4. Medicines listed on recognized standard guidelines and used in high volume/wide

regional distribution such as the WHO Essential Medicine List, National Institute
for Health and Care Excellence, Joint National Committee 8 Guidelines, National
Guidelines, CRS recommended medicines.

5. Medicines with narrow therapeutic index/drug therapeutic monitoring

6. Medicines with formulation challenges/ complex production processes

The criteria were finalized at a meeting on post-market surveillance and the Caribbean
Pharmaceutical Policy held by the Department in March 2019, with the assistance of
TECHPHARM and the national focal points of the Caribbean Regulatory System.

51
5.0 SAMPLING PLANS AND PROCEDURES

5.1 Developing Sampling Plans

National medicines regulatory authorities are responsible for developing quality surveys
for post-market surveillance, including the identification of medicines to be surveyed,
geographic areas, collection sites and methods. The specific objectives of the survey,
sampling priorities and methods should be used to guide the development of subsequent
sampling plans. The NMRA should clearly identify roles of collaborators or affiliates (e.g.
importers) that would be involved in facilitating sample collection.

Plans should be prepared for each area, region or country involved in the survey and
should comply with requirements identified in the survey protocol.

The following should be specified in the sampling plans:

1. The individual sites where collectors should collect samples (by facility type and
address)
2. Medicines to be sampled (by active pharmaceutical ingredients, dosage form,
strength, and if needed, by package size)
3. The sampling method: cluster, simple random or convenience sampling
4. The minimum number of dosage units to be collected per sample
5. The number of samples to be collected per medicine
6. Total number of samples to be collected in the relevant area, region or country.

In addition, plans should include clear instructions for sample collectors.

The MQCSD does not undertake sampling directly but will work with NMRAs to confirm
the requirements for submission of samples that are eligible for compendial (Level 3)
testing.

5.2 Sampling Preparation

5.2.1 Training of Sample Collectors

Sample collectors should be trained in:

• Procedures for sample collection and handling

• Documentation of samples
• The use of field-based screening devices, where applicable.

The completion of training should be documented in the individual’s training records.

52
5.2.2 Preparing for Sample Collection

Prior to sampling activities, field inspectors or sample collectors should be familiar with:

1. The objectives of the quality survey

2. The individual sites for sample collection (by facility type and address)
3. The medicines to be sampled (active pharmaceutical ingredients, dosage form,
strength, and if needed, package size)
4. The minimum number of dosage units to be collected per sample
5. The number of samples to be collected per medicine
6. Total number of samples to be collected in the relevant area, region or country
7. The tools and equipment required, including personal protective equipment
8. The procedures for sample collection, handling, storage and transportation.

Screening Devices: Where field-based screening devices are available, sample collectors
should review instructions for their use according to the survey protocol.
Documentation: Ensure that sufficient copies of the Sample Collection Form are available
for the site (Appendix V for example of a Sample Collection Form).

If photos of the product package labels are available, use these to verify the product being
sampled.

Tools: Before and after using collection tools (e.g. scoops), collectors should ensure they
are thoroughly washed and rinsed with water or suitable solvent, and dried. Tools should
be stored under clean conditions.
Vigilance: Sample collectors should be meticulous, paying close attention to details and
cleanliness. He or she should remain alert to any signs of contamination, deterioration or
tampering. Where the finished product is to be sampled from a storage container,
collectors should check to ensure that the exterior and opening of the container is clean
before sampling. If necessary, sample collectors may need to clean the exterior of the
storage container or its opening to remove dust or dirt.
Distributors, pharmacists and/or inventory managers at health facilitates should be
familiar with the conditions required to facilitate clean collection of samples.

5.2.3 Sampling Facilities

Sampling facilities should be designed or maintained to:

• Prevent contamination of opened containers, the products and the handler

• Prevent cross-contamination by other materials, products and the environment
and
• Protect the individual who samples (sample collector) during the sampling
procedure.

The site from where the sample is taken, and its conditions should be recorded in the
sampling record. A log should be kept of all products sampled from a site.

53
5.2.4 Health and Safety

In preparing for sampling from a site, the following should be ensured:

• Safe access to and egress from the site by sample collectors

• Pathways should be unobstructed to avoid spills
• Storage areas should be adequately lit and ventilated, to enable reading of labels
and to ensure safety.

Sample collectors should:

• Read the relevant health and safety information before sampling the product;
• Wear appropriate protective clothing, such as a laboratory coat and gloves during
sample collection;
• Be trained in the use, and use equipment required for special precautions, where
applicable.

5.2.5 Minimum Number of Sample Units

The number of units to collect per sample depends on:

• the objectives of the sampling and testing activity

• the type of medicine
• the planned tests, and
• the approved medicine specification.

The number of dosage units per sample should allow:

• The planned tests to be conducted

• Investigation and confirmatory testing of samples found to be out-of-specification,
and
• Sufficient retention samples to be used in case of dispute.

Tests of unit dosage forms for uniformity of weight, volume or content may require a
considerable number of units.

54
For samples of products to be submitted to the MQCSD, the following minimum quantities
are required for testing:21

I. For Complete Pharmacopoeial Analysis:

Dosage Form Number of Units
Tablets and Capsules (> 5mg) 100

Oral solutions (bottles >200mL each) 5 bottles

Ointments and Creams (tubes >5g or >5mL)
5 tubes
- For tubes <5g or <5mL contact the lab
Note: For products (tablets, capsules or oral solutions) containing 5mg or less of the active pharmaceutical ingredient,
and for tubes containing less than 5g or less than 5 ml of medicine, contact the department for guidance.

II. For Individual Tests:

Test Notes Quantity

Performed on tablets, capsules, solids in

single unit containers and solids for
Weight Variation parenteral use, where average weight is 30
>25mg or >25% of active ingredients by
mass
Tablets, capsules or Other dosage forms, e.g.
Assays creams, parenterals – depends on type of TBD
assay
Identification/Related
Tablets, capsules or Other forms – depends
substances/Breakdown TBD
on method of analysis
products
Dissolution/Disintegration Performed on tablets or capsules 24
Uniformity of Content Performed on tablets or capsules 30
Key: TBD – to be determined

5.3 Sample Collection Procedures

The principles should be stated in instructions for collectors regarding target medicines,
drawing samples, handling samples, storage and transportation.

55
5.3.1 Target Medicines

For the sampling of target medicines:

• The target medicines, their dosage forms, strengths and package sizes should be
defined.
• The minimum number of dosage units per sample and number of batches to be
collected from each collection site for each medicine in the sampling plan should
be adhered to.
• All units of one sample should have the same batch number.
• Samples should have at least six months remaining before expiry.
• Each sample should be recorded separately using the sample collection form. Note
any abnormalities including missing information, missing leaflets or product
abnormalities.
• Each sample should be identified by a unique sample code, defined on the sample
collection form and specified on all original packages belonging to the respective
sample.
• Sampling records should clearly indicate the date of sampling, the sampled
container and the identity of the person who sampled the batch. A copy of the
Sample Collection Form may be included in the sampling record (Appendix V
Sample Collection Form).
• The sample collection form should always be kept with the collected sample.
• The manufacturer’s batch certificates of analysis should be collected with the
samples, if available, and kept with the sample collection form.

Where Level 2 or 3 testing is required, sampling units should consist of whole packs.
Individual packs should not be broken open for sampling.

5.3.2 Drawing Samples

If the consignment consists of one very large batch, or if there has been little experience
with the product, two independent analyses may be done. The two independent samples
should be taken from different sampling units.

If a consignment is composed of two or three batches from the same manufacturer, a

single sample taken from each batch may be adequate, provided that there is evidence
from the expiry date, or other information that the batches were produced at
approximately the same time.

56
During or prior to sampling the following steps may be applied:

1. Check condition of containers for integrity of packaging material.

2. Check for cleanliness of containers.
3. Check condition of containers for shape and colour.
4. Check the labelling of containers for damage.
5. Check the labels for spelling mistakes.
6. Check the labels for manufacturing and expiry dates.
7. Check the product registration to confirm market authorization
8. Count, categorize and record the number of defects.
9. Check the supplier certificate against the specifications, if applicable.
Note: When sampling finished products, packaging materials may be retained for testing.

5.3.3 Packaging Materials (primary and secondary)

To avoid mixing up printed packaging materials during the sampling operations, only one
material should be handled at a time.

Samples of packaging materials should never be returned to the consignment. Primary

packaging materials should be adequately protected during the sampling operation to
avoid environmental contamination.

5.3.4 Labelling

Closures and labels should be such that unauthorized opening can be detected.

Labelling of samples should provide appropriate details (below). Identification should be

provided for the sample (labelling) to avoid mixing or damage.

Labels should be applied at the time of sampling, and the container used to store the
sample should be properly labelled with appropriate details, such as:

1. Product description: name, dosage form, strength

2. Identification code, batch/lot number
3. Quantity
4. Date sampled
5. Storage conditions, handling precautions and
6. Assigned container number.

When a container is sampled from, the following precautions should be taken:

• If a tamper-proof seal is broken, the consignee should be informed and the

container resealed with an appropriate seal.
• If a bag has been punctured, the hole should be appropriately closed and identified
as a sampling hole made by an authorized sample collector.

57
 • Sampled containers should be identified, as they no longer contain the quantity
stated on the label. Exceptions may include products under investigation for
falsification or adulteration.

5.3.5 Handling

The medicine samples should not be removed from the original primary and secondary
packaging, as far as possible.

• For loose tablets or capsules packaged in large volume containers (e.g. >1000), the
sample may be collected in plastic bottles with snap-caps or screw-tops.
• Containers such as bottles and vials should not be opened. Seals should remain
intact.
• Do not remove or allow damage to medicine labels or package leaflets. Where
medicines are supplied without package leaflets, or in unlabelled plastic bags from
larger containers (repackaged), or as individual dosage forms, this should be
recorded.
• Keep a sample collection form and all packages belonging to one sample together.
• Do not return samples to bulk.

5.3.6 Visual and Physical Inspection

During sampling, attention should be paid to any signs of nonconformity of the product,
such as:

• Differences in physical characteristics of tablets/capsules:

o Uniformity of shape, size, texture and colour; markings; breaks, crack
or splits; embedded surface spots or contamination; presence of empty
capsules and smell
• Moist crusts on hygroscopic substances; Deposits of solid product in liquid or
semi-liquid products
• Stratification of liquid products and
• Tampering, damage or anomalies of the packaging: container, label, leaflet or
package insert.

Sample collectors may refer to the checklists by the World Health Professionals Alliance’s
Tool for Visual Inspection of Medicines to guide the inspection process (Appendix II),15
or the World Health Organization’s guide for identifying suspect substandard and
falsified medical products (Appendix III).

58
Sample collectors should have access to a medicines registry, and photos or samples of
the product packages to allow identification of any falsified products during Level 1
testing.

The following should also be reviewed by sample collectors:

• Batch number
• Scientific name
• Company logo
• Manufacturer address
• Number of units per container
Any suspicious signs of contamination, deterioration or tampering should be recorded.

Sample collectors should avoid pooling of samples from different portions (non-
homogenous), as this can mask contamination, low potency or other quality problems.

Where available, sample collectors should utilize field-based (mobile) screening

equipment to identify the presence of active pharmaceutical ingredients (APIs). The tests
should be applied as per on guidance for Level 2 testing shown in Figure 5, Section 2.

In the event that substandard or falsified products are identified during sampling, with
confirmation via visual or physical inspection or Level 2 testing, a report should be
immediately sent to the NMRA.

5.3.7 Site Storage Conditions

Storage conditions at the site (temperature, humidity, access of light and other
observations) should be described in the sample collection form. When overt sampling is
used, collectors can measure the temperature if it is not controlled at the site.

• Samples should be collected and kept under controlled conditions in line with
product requirements. The cold chain must be maintained where needed.
• Samples should be protected from light, excessive moisture or dryness.
• Ensure safety measures are in place to secure samples. Packages should be kept
in a locked area.
• The period within which samples should be collected and the deadline for sending
the last sample to the testing laboratory should be clearly indicated and adhered
to.

5.3.8 Storage Containers and Transportation of Samples

Storage and transportation of samples to the testing laboratory should be done according
to the requirement set out in the WHO Guidelines for sampling of pharmaceutical
products and related materials:6

59
• Containers used to store samples should not interact with the sampled
material or allow contamination. They should protect samples from light, air
and moisture. Containers should be sealed and preferably tamper-evident.
• Samples of loose products (solid or liquid) should be placed in clean
containers. Liquids should be transported in suitable bottles closed by screw
tops with inert liners that provide a vapour-proof seal for the contents.
• Light sensitive materials should be protected by using amber glass containers
or by wrapping colourless glass containers in foil or dark-coloured paper.
Head-space should be kept to a minimum to minimize any possible
degradation.
• Solid dosage forms should be protected during transit, either by totally filling
the container with the product or by filling any residual space with a suitable
material, such as sterile cotton.
• For all containers that come apart (e.g. screw-capped jars) precautions should
be taken to avoid any mix-up when they are opened for examination, e.g. all
components should be labelled (jars and covers).
• Transportation should be prompt and as direct as possible to avoid
jeopardizing the quality of the collected samples.
• The samples should be kept in their original packaging and stored under the
conditions specified on the label. Avoid freezing, and maintain the cold chain
where required.
• For transport, all samples should be packaged adequately and transported in
such a way as to avoid breakage and contamination. Any residual space in the
container should be filled with a suitable material.
• For temperature-sensitive medicines, temperature monitors may be included
with shipments to document maintenance of an appropriate temperature
during prolonged transit.
• A covering letter, sample collection forms and if available, the manufacturer’s
certificate of analysis should accompany the samples.

60
6.0 SUBMITTING PRODUCTS FOR TESTING TO THE
MQCSD

6.1 The Medicines Quality Testing Process at the MQCSD

6.1.1 Process for MQCSD’s Post-Market Surveillance Programme

For the MQCSD’s post-market surveillance programme, the list of products will be issued
with an invitation to NMRAs to participate in the surveillance activity. Once regulators
confirm interest, the number of products to be submitted and feasibility, the MQCSD
begins preparations to acquire import permits.

Ad hoc testing of products is discouraged as tests and reagents are limited. Instead,
NMRAs are encouraged to apply risk-based approaches to post-market surveillance to
reduce costs and to improve efficiency of monitoring the quality of medicines.

The steps involved in the MQCSD PMS quality testing process are as follows:

Step Mode/Documents
1. Regulator or NMRA is informed of proposed quality Email
survey and list of products List of medicines
2. NMRA confirms acceptance of proposed tests and Email
the estimated costs (where applicable). NMRA staff Request Form
returns form to lab via email. Product documentation
3. Reagents and reference standards are procured by
Procurement process
lab, if needed. Import permits submitted
4. MQCSD staff will notify NMRA regarding when to
Email
ship medicine sample

5. NMRA staff acquires required number of units for Physical sampling

testing from local site(s) Sample Collection Form
Product Submission Form
6. NMRA staff completes Product Submission Form
Sample Collection Form
(MQCSD-Guide-01 Form 2) and prepares supporting
Manufacturer’s COA
documents

Packaging
Documents
7.NMRA staff packages sample with supporting
Letter from NMRA
documents and sends to shipper or courier
Invoice of minimum amount
Courier

61
 Step Mode/Documents
8. Reagents and reference standards received by
MQCSD Suppliers

9. Sample is received by MQCSD and verified against

product submission form. Any discrepancies with the Courier
sample or documentation must be resolved before MQCSD staff
registration of the sample for testing.
10. Sample is tested, and results are reviewed by
MQCSD staff
Chemist
Report

11. Results are sent to Senior Chemist for secondary

review and confirmation of validity of results. Final Report
Anomalies are addressed, if needed.
12. Results are sent to Head of MQCSD for preparation Final Report
and submission of COA. MQCSD COA
Email and via post
13. COA is sent to requestor via email and post.
Final report
Key: COA – certificate of analysis, NMRA – national medicines regulatory authority

6.1.2 Process for Requests for Standard Product Testing

For NMRAs with requests for quality testing of medicines based on national surveys, the
steps involved in the standard quality testing process are as follows:

Step a Mode/Documents

1. Requestor completes and submits the Request for Email

Analysis Form (MQCSD-Guide-01 Form 1) to the lab. Request Form

2. MQCSD staff conducts technical review of request MQCSD staff

to determine ability to test. Product documentation
3. Requestor is informed of MQCSD’s ability to test, Email
proposed tests, proposed schedule, and estimated
Request Form
costs, where applicable (budget).
4. Requestor confirms acceptance of proposed tests, Email
including proposed deviations from test methods, Request Form
and estimated costs. Requestor returns form to
MQCSD via email. Product documentation
5. Reagents and reference standards are procured Procurement process
by MQCSD, if needed. Import permits submitted.

62
 Step a Mode/Documents

6. MQCSD submits applications for import permits to

Import permit application
Ministry of Health, Jamaica.

7. MQCSD staff notify requestor regarding when to

Email
ship medicine sample.
8. Requestor acquires required number of units for Physical sampling
testing from local site(s). Sample Collection Form
Product Submission Form
9. Requestor completes Product Submission Form
Sample Collection Form
(MQCSD-Guide-01 Form 2) and prepares supporting
Manufacturer’s method and
documents.
COA
Packaging
Documents
10. Requestor packages sample with supporting
Letter from NMRA
documents and sends to shipper/courier.
Invoice of minimum amount
Courier
11. Reagents and reference standards received by
MQCSD. Suppliers

12. Sample received by lab and verified against

product submission form. Any discrepancies with Courier
the sample or documentation must be resolved MQCSD staff
before registration of the sample for testing.
13. Sample is tested and results are reviewed by
MQCSD staff
Chemist.
Report

14. Results are sent to Senior Chemist for secondary

review and confirmation of validity of results. Final Report
Anomalies are addressed, if needed.
14. Results are sent to Head of MQCSD for Final Report
preparation and submission of COA. MQCSD COA
Email and via post
15. COA is sent to requestor via email and post.
Final report
Key: a. Steps 1-4, 7-9, 11-14 are part of routine testing sequence.
COA – certificate of analysis, NMRA – national medicines regulatory authority

63
Procedural delays may occur in the event that there is a need to procure reagents and/or
reference standards or where the lab has to acquire import permits. Delays in sample
analysis may occur where method verification or system suitability requirements are not
met. The MQCSD staff will inform customers in writing of all events that may delay sample
submission and analysis.

6.2 Submitting a Request for Testing of Samples

To submit a request for testing of the quality of medicinal products, the Request for
Analysis form (MQCSD-Guide-01 Form 1) must be completed and submitted to the
MQCSD. The forms may be downloaded from the website at http://carpha.org/What-
We-Do/Medicines-Quality-Control-and-Surveillance/Testing-and-Customer-Service for
completion by direct entry and submission via email to [email protected]

Note: Testing for manufacturers will only be conducted with the approval of the relevant
national medicines regulatory authority.

Staff at NMRAs should complete the Request for Analysis form provided by indicating:

• Administrative Information:
o Name of Submitting Agency
o Name of person making request, Designation, Telephone number, Email
address
o Date of request
• Product Information:
o Generic name of product (International Non-proprietary Name or INN)
o Dosage Form
o Specification: British Pharmacopoeia (BP), United States Pharmacopoeia
(USP), manufacturer’s method, Other
• Acceptance: When the lab returns the form identifying the tests to be done, the
requestor indicates acceptance or agreement (Yes or No) in column 5. Where the
Department advises the requestor of the need for deviation from a test method for
a product, the requestor must give approval in writing for testing to proceed.

For products where there is no official specification or reference standard provided, the
manufacturer’s method, specification, reference standard and Certificate of Analysis
(COA) are required.

64
6.3 Submitting Samples for Testing

Each sample submission must be accompanied by a completed Product Submission Form

(MQCSD-Guide-01 Form 2), a copy of the Sample Collection Form, a Cover letter and the
manufacturer’s batch certificate of analysis, if available.

The requestor must complete the Product Submission Form by indicating:

I. Administrative Information:
a. The submitting agency
b. Name and address of contact

II. Reason for submission

III. Manufacturer’s Information:

a. Name, address

IV. Product Information:

a. Brand name, generic name (INN)
b. Labelled claim
c. Expiry date
d. Lot/batch number

The MQCSD staff will add the following information:

a. Assigned sample number, number of sampled units, condition of sample

b. Persons registering and checking the sample
c. Dates
d. Comments

6.3.1 Sending Samples by Courier

Where collectors do not transport samples directly to the laboratory, samples and
documents should be sent by a courier service.

Confirm terms of use with couriers or shipping agents. Ensure they can maintain storage
conditions and requirements for handling and packaging. Give clear instructions to
shipping agent regarding storage and handling.

The documentation with each shipment should indicate the following:

• The samples are being sent for laboratory testing purposes only
• The samples will not be used on humans or animals
• The samples have no commercial value and will not be placed on the market.

65
Include sample details on the courier invoice and shipping label. Where possible, include
a letter from the NMRA describing the purpose for shipping the sample.

Import permits are required before samples can be shipped to the MQCSD. The permit
should be given to the courier service prior to shipping. The samples submitted to the
department must match the import permit to avoid penalties to the department incurred
by the Collector of Customs, Jamaica.

Once approval to ship the samples is acquired and the samples are shipped, the MQCSD
should be informed of the shipment details, including the tracking number assigned by
the courier service to enable them to follow the shipment and arrange prompt collection
of samples. Scanned copies of the enclosed documents (Cover letter, Sample Collection
Form, Product Submission Form, Import Permit) should also be sent to the department
prior to shipping.

6.4 Communication with the MQCSD

The MQCSD will provide requestors with periodic updates on medicines submitted for
testing by email and on request, including any unexpected delays in testing. The results
of tests will be communicated to the respective requestor. In the event product testing
identifies a substandard or falsified medicine, the department will submit a report to the
requestor, and/or the national focal point for further action and decision-making. Where
product testing is conducted on request from manufacturers, only information pertinent
to their product will be made available to the requestor.

Note: Testing for manufacturers will be conducted only with the approval of the relevant
national medicine regulatory authority.

6.4.1 Estimated response times for requests for analysis

The estimated response times from the MQCSD for requests varies with the type of testing
or requests as follows:

• Routine testing: within 5 working days after receiving the request

• Emergency requests: within 24 to 48 hours of receiving the request

• Post-market surveillance: response will be based on PMS schedule.

66
The MQCSD may be contacted by:

Mail: CARPHA Medicines Quality Control and Surveillance Department

Hope Gardens
Kingston 6
Jamaica

Tel: +1-876: 977-3540; 702-4235

Fax: +1-876: 977-0974

Email: [email protected]

Website: http://carpha.org/

6.4.2 Communication of Results

The average turn-around time for routine testing at the MQCSD from receipt of sample to
communication of result is between 30 to 45 working days.

For the PMS programme, the results will be communicated based on an agreed schedule.

Results from the laboratory testing of products will be reviewed and approved by the
Head of the MQCSD. These will be presented as a certificate of analysis and will be sent to
the customer via email. In addition, the original certificate of analysis will be dispatched
via post to the customer.

The certificate of analysis will include:23

i. The name and address of the Department

ii. The name and address of the customer who requested the analysis
iii. Unique identification of the COA chronological numbering starting with
001/YEAR, e.g. 001/2018
iv. Page number and identification on each page
v. Lab identifier (ID) of the sample
vi. The name, description, condition, expiration date, date of manufacture and lot
number of the sample
vii. The date the certificate is issued
viii. The date of receipt of the test item
ix. The tests performed and the results with the units of measurement where
appropriate
x. The specifications and test methods used to analyse the sample
xi. The limits of the specifications
xii. Whether the sample meets specifications
xiii. Name and address of original manufacturer, or name and address of distributor
or re-packaging plant

67
xiv. Submitter’s code if available
xv. Name and signature of the Head of MQCSD or designate, authorizing the COA
xvi. A statement that the COA shall not be reproduced, except in full, without the
written approval of the laboratory
xvii. Deviations from official test methods.

The Senior Chemist or designate will record the date of issue of the certificate of analysis
for the sample in the Sample Register.

Amendments and Reissue of COAs:

When amendments (e.g. corrections) to a COA are required, a new COA will be prepared.
The statement “Reissue of Certificate of Analysis No. X Dated Y” will be placed on the COA.
Date ‘Y’ will reflect the issue date of the original COA. An “R” is placed beside the COA
number to indicate that the new COA is a reissue, e.g. 001/2018R.

Queries about the findings may be communicated via email to the department at
[email protected] or via telephone.

68
APPENDIX I: WHO Suspected SF Products Incident
Management – Aide Memoire

1 Receipt of
• Report of SF medical product received by NMRA
Report

•Contact the source of the information

•Assess the reliability of the source (see textbox)
•Establish the facts
2 Establish •Assess the credibility of the information received (see textbox)
Facts •Obtain samples of the product and photographs showing batch number and expiry dates
•NATIONAL FOCAL POINT SHOULD IMMEDIATELY SEARCH THE WHO GSMS DATABASE TO CHECK IF THE PRODUCT
IS KNOWN

•Is the suspected SF product available in hospitals, clinics, pharmacies, health centres?
•Is the product available in illegal markets, or through internt sites or smartphone applications?
•Have any adverse reactions been reported? Check with national PV centre.
3 Assess Risk •What quantities of suspected SF products have been discovered?
to public
health •Is there evidence that the suspected SF medical product is in recent circulation?
•Is the suspected SF product in wide circulation within your country, or neighbouring countries?
•Is this product in strong demand, or in short supply?
•Consult with stated manufacturer of the reported product (see textbox)

•Quarantine or seize any suspected medical product dependent on risk

4 Immediate •Ensure the product is stored securely and in compliance with storage conditions
Actions •Ensure appropriate treatment is available to affected patients

•If product is suspected of causing adverse reactions, send directly to the lab
•Screen suspected SF product with handheld equipment or other field-testing equipment if available
5 Field •Secure up to 100 samples for testing, if not, as many samples from from same source as reported product as
Screening / possible and store in controlled conditions
Lab analysis
•Request sample from genuine manufacturer for comparison purposes
•Arrange for testing as a priority dependent on risk to public health

•Establish a team of relevant regulatory specialists, appoint a lead person and invite relevant external stakeholders
/ experts
•Keep strict records of all meetings and all decisions that are made
•Focus on protecting the public health, mitigating risk posted by the product and investigating the origin
6 Managing
an Incident •Consider a recall of the medical product and associated communications and media messages
•Verify stocks / availability of genuine replacement product
•Consider an alert or public notice
•REPORT TO THE WHO GLOBAL SURVEILLANCE AND MONITORING SYSTEM FOR SUBSTANDARD AND FALSIFIED
MEDICAL PRODUCTS

69
Supplementary Questions Textbox

REMEMBER, these incidents attract a lot of attention, unnecessary delays are difficult
to explain, public health and the reputation of your organization may be at risk.

National Focal Points are strongly advised to conduct a search of the WHO database
when dealing with a suspected SF medical product at the earliest opportunity.
Irrespective of whether you receive a match with other products in the database you
should report the suspected or confirmed medical product to WHO as soon as possible.
Other Member States may be seeing the same product in circulation and your report
will assist them. It should be remembered searches can yield matches with your
product on a separate continent or in another region. This information can help you
assess risk, manage and respond to your case more efficiently and effectively and in
serious cases save lives.
Assessing the Reliability of a Source
• Anonymous information should be treated with caution
• Is the source a whistle blower or a current or ex-employee of a company that they are
providing information about?
• What is the motivation for supplying the information?
• Is the source easily contactable?
• If contact details are supplied are they accurate (dialling codes, telephone numbers,
email addresses, physical addresses)?
• Has information been received from the same source previously? If so, was the
information accurate?
• Is the source willing to be contacted, met, or supply further information?
Assessing the Credibility of the Information
• Has any similar information been received from different sources?
• Are there any other sources that can corroborate the information provided?
• Are there any obvious inaccuracies in the information?
Questions to Manufacturers?
 Did you manufacture this product?
Does the product and packaging look genuine? – Photographs and samples will be provided if available
 Are the manufacturing / batch / expiry dates authentic?
If the batch number is genuine, where, and when was it distributed?
 Have you had falsified or substandard versions of this batch reported previously?
If so, when and where?
 Have you received any complaints about this batch?
If so, from whom, where, and when?
 Have you received any reports of unexpected adverse reactions relating to this product or batch?
Is so, when, where, numbers, and severity?
 Is there any other information we should be aware of?

70
APPENDIX II: Tool for Visual Inspection of Medicines
Source: World Health Professions Alliance 15

This tool is designed to help health professionals carry out a visual inspection of medicines for signs of
falsification (counterfeiting) such as improper packaging, labelling, description of dosage, etc. All suspicious
medicines with incorrect labels, missing information about the strength, dosage or expiration date should be
reported to the appropriate authority. The term ‘drug’ has been replaced with ‘medicine’ and the term
‘counterfeit’ has been replace with ‘falsified’ from the original version.

1. Packaging
Any medicine should be packaged in a container, which can be anything from a glass bottle to a blister pack,
to a tube of glass, plastic or metal. A folding carton bearing the label very often protects the container.
Check the type of packaging and compare it to known containers for the same medicine from the same
manufacturer. The packaging and labelling of pharmaceutical products is a very complex and expensive
business. Thus, the process and the quality of packaging material are very difficult to falsify. This is why a
thorough visual inspection could be an important screening step for medicines quality control. However,
producers of falsified products are quick to copy special labelling and holograms.
Yes No Other observations
1.1 Container and closure
Do the container and closure protect the medicine from the
outside environment e.g. properly sealed?
Do they assure that the medicine will meet the proper
specifications throughout its shelf life?
Are the container and the closure appropriate for the
medicine inside?
Is the container safely sealed?

1.2 Label The information written on the label is very important. The information can be printed on a
label adhered to the container, or printed directly onto the container itself, but all information must be
legible and indelible.
If there is a carton protecting the container, does the label
on the carton match the label on the container?
Is all information on the label legible and indelible?

1.2.1 The trade name

Is the trade name spelled correctly?
Is the medicine (trade name) registered in the country by
the NMRA (national regulatory authority)?
Is the medicine legally sold in the country?
Does the symbol ® follow the trade name?

1.2.2 The active ingredient name (scientific name)

Is the active ingredient name spelled correctly?
Do the trade name and the active ingredient name
correspond to the registered medicine?

1.2.3 The manufacturer’s name and logo

Are the manufacturer’s name and logo legible and correct?
Does the logo or hologram (if applicable) look authentic?

Does it change colour when viewed from different angles?

71
 Yes No Other observations
1.2.4 The manufacturer’s full address All manufacturers are required by international law to print
their complete address on the label. Many companies making substandard or falsified medicines do not
have traceable address on the label.
Is the manufacturer’s full address legible and correct?
Has the company or its agent registered the medicine in the
country?

1.2.5 The medicine’s strength (mg/unit)

Is the strength – the amount of active ingredient per unit –
clearly stated on the label?

1.2.6 The dosage form (e.g. tablet / capsule)

Is the dosage clearly indicated?
Is the indicated medicine under this dosage form
registered and authorized for sale in the country?

1.2.7 The number of units per container?

Does the number of tablets or capsules listed on the label
match the number stated on the container?

1.2.8 The batch (or lot) number. Medicines under the same batch/lot number are expected to be
equivalent. In a continuous process, a batch corresponds to a defined portion of the production, based
on time or quantity. Medicines from the same batch number should have the same history of
manufacturing, processing, packing, and coding. All medicine quality control testing should be based on
batch/lot numbers.
Does the numbering system on the package correspond to
that of the producing company?

1.2.9 The date of manufacture and the expiry date. An expired medicine should not be sold under any
circumstances.
Are the manufacture and expiry dates clearly indicated on
the label?

1.3 Leaflet or package insert. All product packages should contain a leaflet explaining dosage, the
product content, the adverse effects, the medicine’s actions, and how the medicine should be taken. The
only exceptions are where the packaging includes all the information that would otherwise by in the
leaflet.
Is the package insert printed on the same coloured or same
quality paper as the original?
Is the ink on the package insert or packaging smudge-
proof?

72
2. Physical characteristics of tablets/ capsules
All types of medicine can be and have been falsified from cough syrups to injections. As mentioned in
Section 1, it is important to check the packaging of these products. Additionally, medicines in the form of
tablets or capsules can be checked for signs of moisture, dirty marks, abrasion erosion, cracks, or any other
adulteration.
Yes No Other observations
2.1 Uniformity of shape
Are the tablets / capsules uniform in shape?

2.2 Uniformity of size

Are the tablets/ capsules uniform in size?

2.3 Uniformity of colour

Are the tablets / capsules uniform in colour?

2.4 Uniformity of texture Tablets can be film-coated, sugar-coated or enteric-coated

Do the tablets have a uniform coating?
Is the base of the tablets fully covered?
Are the tablets uniformly polished, free of powder, and
non-sticking?

2.5 Markings (scoring, letters, etc.)

Are marking uniform and identical?

2.6 Breaks, Cracks and Splits

Are the tablets / capsules free of breaks, cracks, splits or
pinholes?

2.7 Embedded surface spots or contamination

Are the tablets / capsules free of embedded surface spots
and foreign particle contamination?

2.8 Presence of empty capsules in the case of a sample of capsules

Is the sample examined free of empty capsules?

2.9 Smell
Does the medicine smell the same as the original?

73
APPENDIX III: WHO Tool - Identifying Substandard and
Falsified Medical Products
IDENTIFYING SUSPECT SUBSTANDARD AND FALSIFIED MEDICAL PRODUCTS

Some substandard and falsified medical products are almost visually identical to the
genuine product and very difficult to detect. The following signs should raise your
suspicion.
Please note that this guide is a non-exhaustive list

▪ Patients report that it is not working properly (unexpected lack of

THERAPEUTIC
efficacy), or
EFFECT
▪ Patients suffer unexpected adverse reaction(s)

▪ Packaging is not in good condition, or

OUTER
▪ Manufacturers details are not clearly stated, or
(SECONDARY)
▪ Incorrect language, grammatical and spelling errors, or
PACKAGING
▪ Batch numbers and expiry dates appear altered

INNER ▪ Batch numbers, manufacturing and expiry dates on inner

(PRIMARY) packaging (e.g. blister) are different to outer packaging, or
PACKAGING ▪ Patient information leaflet is in the wrong language

▪ Any suspicion on the source, price, or authenticity of

accompanying documents, or
SUPPLY SOURCE ▪ Any suspicion on quantities available, for example products that
are usually in short supply are suddenly available very regularly or
in large quantities

▪ Product does not look, smell, taste and feel correct, or

OTHER FACTORS ▪ Packaging components are empty or separated
▪ Product was not properly stored

IF IN DOUBT, VERIFY THE TO THE GLOBAL SURVEILLANCE AND MONITORING SYSTEM

PORTAL AND REPORT PRODUCT OR CONTACT [email protected]

FOLLOW GUIDANCE PROVIDED IN THE AIDE-MEMOIRE ON HOW TO MANAGE AN

INCIDENT OF AN SF MEDICAL PRODUCT.

74
 GUIDE FOR HEALTHCARE PROFESSIONALS
Therapeutic Failure
▪ Is there an unexpected lack of efficacy? Often the product will not cause a toxic reaction, but will
fail to treat the condition for which it was intended, with potentially devastating consequences. For
example, a patient failing to respond to their anti-malarial will rarely consider that the cause of the
problem may be their medicine.
▪ Is there an unexpected adverse reaction? Some substandard and falsified medical products do
cause adverse reactions and sometimes fatalities. A patient may experience an unexpected or unusual
worsening of their medical condition.
Outer (Secondary) Packaging and Inner (Primary) Packaging
▪ Is the packaging in good condition? The container should appropriately protect the medical product
inside (e.g. properly sealed, airtight, etc.).
▪ Are the manufacturer’s details clearly stated and in correct language? The manufacturer’s details
(name, logo, hologram, full address, registration number, etc.) should be correct and in the appropriate
language for the market/country in which the product is distributed.
▪ Are there any spelling or grammatical errors? There should be no spelling or grammatical errors,
particularly for the trade (brand) name and active ingredient(s).
• Are the batch/lot numbers and manufacturing and expiry dates altered? They should be clearly
indicated, should not be possible to erase, be easily readable, and there should be no irregularity in the
embossing, impressing or imprinting.
▪ Is the dosage form or medicine strength clearly indicated on the label? They should be the
appropriate strength and dosage form for the medicine and be the same on all parts of the packaging.
▪ Is the information the same on the inner and outer packaging? This information should be the
same on all parts of the packaging (with no signs of alteration and discrepancies).
▪ Is there a patient information leaflet and is it in the correct language? The information on the
patient information leaflet should be clearly indicated and should match the information on other parts
of the packaging and product container. There should be no irregularity in how it is printed and the
quality of the colour, shape, texture, and size of paper (e.g. ink should not be smudged, paper is not too
rough, etc.).
Source of Supply
▪ Is there any suspicion of the source, price, quantities available, regularity of products that are
usually in short supply or authenticity of accompanying documents? Those engaged in the
manufacture, distribution and supply of substandard and falsified medical products have shown they
respond quickly to demand, thoroughly understanding the market and are fast to exploit opportunities.
Most commonly, substandard and falsified medical products enter the legal supply chain at distribution
level through hospitals, clinics, pharmacies and wholesalers, who have obtained medical products from
unknown sources and intermediaries without checking their credentials or conducting any due
diligence. For example, products whose price appears unusually low, or which are available in unusually
large quantities should raise suspicions and further checks should be conducted.
Other Factors
▪ Did the patient (or did you) notice that the medical product looks, tastes, smells or feels
different? Any irregularity in the uniformity of appearance (colour, shape, texture, size, clarity), flavour,
and odour should raise suspicion. For example, the product is discoloured or degraded.
▪ Are there any empty or separated packaging components (bottle caps, spoons, bottles, flat
packs, capsules)? Signs of empty or separated packaging components may indicate signs of smuggling
or tampering.
▪ Was the product properly stored? Storage conditions (temperature, humidity, etc.) should be stated
on the label and maintained. Signs of degradation may include leakage, discoloration, etc.

75
APPENDIX IV: MQCSD List of Pharmaceutical Products
with Accredited Tests

No. NAME OF PRODUCTS SPECIFICATIONS TESTS

Acetaminophen Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
1
Paracetamol Tablets BP Dissolution: Apparatus 2 (UV); Assay
(UV)
Aciclovir Tablets BP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
2
Acyclovir Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
3 Amlodipine Besylate Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Amoxicillin Capsules BP Assay (HPLC)
4 Amoxicillin Capsules USP Dissolution: Apparatus 1 & 2 (UV); Assay
(HPLC); Uniformity of Content (HPLC)
5 Amoxicillin for Oral Suspension BP & USP pH; Assay (HPLC)
Atenolol Tablets BP Disintegration: Assay (UV)
Atenolol Tablets USP Dissolution: Apparatus 2 (HPLC);
6
Uniformity of Content (HPLC); Assay
(HPLC)
Bendroflumethiazide Tablets BP Assay (UV)
7 Bendroflumethiazide Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Captopril Tablets BP Assay (HPLC)
8 Captopril Tablets USP Dissolution: Apparatus 1 (UV); Assay
(HPLC)
9 Carbamazepine Tablets BP Assay (HPLC)
Carbamazepine Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
10 Chlorpromazine Tablets BP Assay (UV)
10 Chlorpromazine Hydrochloride USP Dissolution: Apparatus 1 (UV); Assay
Tablets (UV)
Chlorpropamide Tablets BP Dissolution: Apparatus 1 (UV); Assay
(UV)
11
Chlorpropamide Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Chlortalidone Tablets BP Disintegration; Assay (UV)
12 Chlorthalidone Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
13 Ciprofloxacin Tablets BP & USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
14 Clotrimazole Cream BP & USP Assay (HPLC)
Diazepam Tablets BP Assay (UV)
15 Diazepam Tablets USP Dissolution: Apparatus 1 (UV); Assay
(HPLC)
16 Diclofenac Tablets (Gastro- BP Assay (HPLC)
resistant)
17 Enalapril Maleate Tablets USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)

76
No. NAME OF PRODUCTS SPECIFICATIONS TESTS
Furosemide Tablets BP Dissolution: Apparatus 2 (UV); Assay
(UV)
18
Furosemide Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Glibenclamide Tablets BP Dissolution: Apparatus 2 (HPLC); Assay
(HPLC)
19
Glyburide Tablets USP Dissolution: Apparatus 1 & 2 (HPLC);
Assay (HPLC)
20 Ibuprofen Tablets BP Disintegration; Assay (HPLC)
Lamivudine Tablets BP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
21
Lamivudine Tablets USP Dissolution: Apparatus 2 (UV & HPLC);
Assay (HPLC)
22 Levofloxacin Oral Solution USP pH; Assay (HPLC)
23 Levofloxacin Tablets USP Dissolution: Apparatus 1 & 2 (UV); Assay
(HPLC)
Levothyroxine Tablets BP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
24
Levothyroxine Sodium Tablets USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
Lisinopril Tablets BP Dissolution: Apparatus 2 (HPLC); Assay
(HPLC)
25 Lisinopril Tablets USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
Loratadine Tablets BP Disintegration; Assay (HPLC)
26 Loratadine Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
27 Loratadine Oral Solution USP pH; Assay (HPLC)
Losartan Potassium Tablets BP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
28 Losartan Potassium Tablets USP Dissolution: Apparatus 1 & 2 (UV &
HPLC); Uniformity of Content (HPLC);
Assay (HPLC)
Metformin Tablets BP Dissolution: Apparatus 1 (UV); Assay
(UV)
29
Metformin Tablets USP Dissolution: Apparatus 1 & 2 (UV); Assay
(UV)
30 Metronidazole USP Dissolution: Apparatus 1 (UV);
Uniformity of Content (UV); Assay
(HPLC)
31 Mycophenolate Mofetil Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
32 Omeprazole Delayed-Release USP Dissolution: Apparatus 2 (HPLC); Assay
Capsules (HPLC)
Prednisolone Tablets BP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
33
Prednisolone Tablets USP Dissolution: Apparatus 2 (UV);
Uniformity of Content (HPLC); Assay
(HPLC)
34 Prednisone Tablets USP Dissolution: Apparatus 2 (UV);
Uniformity of Content (HPLC); Assay
(HPLC)
35 Propranolol Tablets BP Disintegration; Assay (UV)

77
No. NAME OF PRODUCTS SPECIFICATIONS TESTS
35 Propranolol Hydrochloride USP Dissolution: Apparatus 1 (UV);
Tablets Uniformity of Content (UV); Assay
(HPLC)
Pyrazinamide Tablets BP Disintegration; Assay (UV)
36 Pyrazinamide Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Ramipril Capsules BP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
37
Ramipril Capsules USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
Ranitidine Tablets BP Disintegration; Assay (HPLC)
38 Ranitidine Tablets USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
39 Risperidone Tablets BP & USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)
40 Terbinafine Tablets BP & USP Dissolution: Apparatus 2 (UV); Assay
(HPLC)
Warfarin Tablets BP Dissolution: Apparatus 1 (UV);
Uniformity of Content (HPLC); Assay
(HPLC)
41
Warfarin Sodium Tablets USP Dissolution: Apparatus 2 (HPLC);
Uniformity of Content (HPLC); Assay
(HPLC)

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APPENDIX V: Sample Collection Form

Survey Title
Area / Region /
Country
Sampling Location /
Site
Address
Sample Code
Date of Sampling
1.
Name(s) of Samplers
2.
Product Name of
sample
Name of APIs (INN)
and strength
Dosage form Package Size:
Batch / Lot Number Expiry Date:
Date of Manufacture
Name and Address of
Manufacturer
Date received at
location
Quantity collected
Brief physical description / Appearance of sample

Temperature and Controlled conditions? Yes No

Humidity
Comments on suitability of premises, abnormalities, or observations

1.
Signatures of Samplers
2.
Key: API – active pharmaceutical ingredient, INN – International Nonproprietary Name

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REFERENCES

1. Nkansah P, Smine K, Pribluda V, et al. Guidance for Implementing Risk-based

Post-marketing Quality Surveillance in Low- and Middle-income Countries.
Rockville, Maryland: U.S. Pharmacopoeial Convention. The Promoting the Quality
of Medicines Program; 2017: https://www.usp-
pqm.org/sites/default/files/pqms/article/risk-based-post-marketing-
surveillance-feb-2018.pdf. Accessed 5th September, 2018.
2. World Health Organization. Quality assurance of pharmaceuticals: A compendium
of guidelines and related materials. Good manufacturing practices and inspection.
Vol 2: World Health Organization; 2007.
3. World Health Organization. The importance of pharmacovigilance. Geneva: World
Health Organization; 2002.
4. World Health Organization. Small Island Developing States Health and WHO:
Country Presence Profile. In: System DoCCaCwtUN, ed. WHO/CCU/17.08 ed.
Geneva2017.
5. Management Sciences for Health. Quality Assurance for Pharmaceuticals. MDS-3
Managing Access to Medicines and Health Technologies. Arlington, VA:
Management Sciences for Health; 2012.
6. World Health Organization. Regulation of vaccines: Buidling on existing drug
regulatory authorities. In: Biologicals DoVaO, ed. Geneva1999.
7. World Health Organization. WHO Global Benchmarking Tool (GBT) for Evaluation
of National Regulatory Systems. Geneva: World Health Organization; 2018:
https://www.who.int/medicines/regulation/benchmarking_tool/en/. Accessed
20th October, 2018.
8. Pan American Health Organization, World Health Organization. Resolution
CD50.R9. Washington, D.C.2010.
9. World Health Assembly. Regulatory system strengthening for medical products.
2014.
10. Pan American Health Organization, Caribbean Community. Caribbean
Pharmaceutical Policy. Washington, D.C.: PAHO/WHO; 2013:
https://www.paho.org/hq/index.php?option=com_content&view=article&id=91
98:2013-caribbean-pharmaceutical-policy-2013&Itemid=3562&lang=en.
11. Medicines Quality Control and Surveillance Department. About MQCSD. 2018;
http://carpha.org/What-We-Do/Medicines-Quality-Control-and-
Surveillance/About-MQCSD. Accessed 23rd August, 2018.
12. Pribluda V, Barojas A, Coignez V, et al. The three-level approach: a framework for
ensuring medicines quality in limited-resource countries. Pharmaceut Reg Affairs.
2014;3(1):117.
13. WHO Member State Mechanism. Annex 1 Recommendations for Health
Authorities to Detect and Deal with Actions, Activities and Behaviours that Result
in Substandard / Spurious / Falsely-labelled / Falsified / Counterfeit Medical
Products: A68/33. . Geneva: World Health Organization; 2015:
http://www.who.int/medicines/regulation/ssffc/mechanism/A68_33-en.7-
15.pdf. Accessed 12th October, 2018.
14. Caribbean Public Health Agency. VIGICARIB. 2018; http://carpha.org/What-We-
Do/Caribbean-Regulatory-System/VigiCarib. Accessed 5th September, 2018.

80
15. World Health Professions Alliance. The Be Aware. Take Action Toolkit. In: Alliance
WHP, ed. Ferney Voltaire: WHPA Secretariat; 2011:
http://www.whpa.org/pubs.htm.
16. World Health Organization. Annex 7 WHO Guidelines on the Conduct of Surveys of
the Quality of Medicines. Technical Report Series No. 996. Geneva: World Health
Organization;2016.
17. WHO SF Medical Products Group. Substandard and Falsified Medical Products
Incident Management - Aide Memoire. Geneva: World Health Organization; 2014.
18. WHO Member State Mechanism. Recommendations for Health Authorities on
Criteria for Risk Assessment and Prioritization of Cases of Unregistered
/Unlicensed, Substandard and Falsified Medical Products. Geneva: World Health
Organization; 2017:
https://www.who.int/medicines/regulation/ssffc/mechanism/en/. Accessed
4th October, 2018.
19. Caribbean Public Health Agency. The Caribbean Regulatory System (CRS). 2017;
http://carpha.org/What-We-Do/Laboratory-Services-and-Networks/CRS.
Accessed 5th September, 2018.
20. Caribbean Public Health Agency. Pathway to 2025: Strategic Plan 2018-2020.
Trinidad and Tobago: CARPHA; 2018.
21. Medicines Quality Control and Surveillance Department. Product Submission
Guidelines. Kingston, Jamaica: Caribbean Public Health Agency; 2017.
22. Medicines Quality Control and Surveillance Department. Testing and Customer
Service. 2018; http://carpha.org/What-We-Do/Medicines-Quality-Control-and-
Surveillance/Testing-and-Customer-Service. Accessed 23rd August, 2018.
23. Medicines Quality Control and Surveillance Department. Quality Manual.
Kingston, Jamaica: Caribbean Public Health Agency; 2017.

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