Title : Pharmaceutical Water

Version No. : 00
Trainer : Goutam Kumar Sarker
Designation : Manager, Quality Assurance
Date : 27.12.23

Duration : 02 Hours
 Introduction
Water is widely used as
 Raw Material in processing

 Ingredient in formulation

 Solvent in manufacture of
products, APIs & analytical
reagents.
 Types of Water
 There are many different grades
of water used for pharmaceutical
purposes.
 The monographed waters are
divided into two general types:
BULK WATERS
PACKAGED WATERS
 Types of Water
 BULK WATERS
Produced on site where they are
used.
Example – PUW, WFI
 PACKAGED WATERS
Produced, packaged and sterilized to
preserve microbial quality throughout
their packaged shelf life.
Example – Sterile PUW, Sterile WFI
 Types of Water

 The non monographed waters

are divided into two types:

MANUFACTURING WATERS

ANALYTICAL WATERS
 Types of Water
 MANUFACTURING WATERS

Used in pharmaceutical
processing steps such as
cleaning, synthetic steps or a
starting material for further
purification.

Example – Drinking Water

 Types of Water
 This water must comply with the quality
attributes of any of the following:
 U.S. Environmental Protection Agency’s
National Primary Drinking Water
Regulation.
 Drinking Water Regulations of the
European Union or Japan
 WHO Drinking Water Guidelines
 Environmental Laws of Bangladesh
 Types of Water
 ANALYTICAL WATERS

The term WATER clearly stated

in the compendial chapter
REAGENTS, INDICATORS &
SOLUTIONS, without
qualification or other
specification, is indicated for
 Types of Water
 ANALYTICAL WATERS

 The quality of water shall be

Purified Water.

 Example – High Purity Water

Ammonia Free Water

Carbon Dioxide Free

 Types of Water
 POTABLE WATER
 Potable water is derived from an
underground formation or water from
the surface.
 Potable water may be used in the
early stages of -
 Chemical synthesis of excipients
 Sanitation and cleaning of
equipment.
 Types of Water
 POTABLE WATER

 It is the prescribed source of

feed water for the production of
pharmaceutical waters.
 Types of Water
 PURIFIED WATER (PUW)
 PUW is prepared from potable water
as feed water of purifying unit.
 PUW may be used –
 As excipient in the production of
official preparation
 Cleaning of certain equipment
 Preparation of some bulk
pharmaceutical chemicals.
 Types of Water
 PURIFIED WATER (PUW)
PUW may be prepared
 By de-ionization,
 By ion exchange,
 By reverse osmosis (RO)
 By filtration or
 Any other suitable procedure
 Types of Water

 PURIFIED WATER (PUW)

PUW must meet the
requirements-
 For ionic and organic chemical
purity
 Must be protected from microbial
proliferation.
 Types of Water
 STERILE PURIFIED WATER

 Sterile purified water is purified

water that is packaged and
sterilized.
 It is used in the preparation of
non-parenteral compendial
dosage forms.
 Types of Water
 WATER FOR INJECTIONS (WFI)
 Water for injections (WFI) is not
sterile water.
 WFI is prepared by distillation or
reverse osmosis from potable and/or
PUW.
 WFI may be used –
 As excipient in the production of
parenteral product preparations
 For cleaning of certain equipment
coming into contact with parenteral
 Types of Water
 WATER FOR INJECTIONS (WFI)
 For preparation of some bulk
pharmaceutical chemicals.
 For the preparation of sterile,
pyrogen-free steam, if the steam
comes into contact with a
parenteral product or equipment
for preparing parenteral
products.
 Water for cooling autoclaves
should also be WFI grade or
 Types of Water
 WATER FOR INJECTIONS (WFI)
WFI must meet -
 All the chemical requirements for
PUW
 Must be protected from microbial
contamination
 Must meet the requirements
under bacterial endotoxins test.
 Types of Water
 STERILE WATER FOR INJECTIONS
 Sterile WFI is water for injections that
is packaged and sterilized.
 It is used as a diluent for parenteral
products.
 It is distributed in sterile units and
packed in single dose containers not
larger than 1L in size.
 Types of Water
 BACTERIOSTATIC WATER FOR
INJECTIONS
 It is sterile WFI to which has
been added one or more suitable
antimicrobial preservatives and
is packaged and sterilized.
 It is also used as a diluent in the
preparation of parenteral
products.
 Types of Water
 BACTERIOSTATIC WATER FOR
INJECTIONS
 It may be packed in single dose
or multiple dose containers not
larger than 30 ml.
 Types of Water
 STERILE WATER FOR IRRIGATION

 It is sterile WFI that is packaged

and sterilized.
 It is used for irrigation purpose.

 It is packed in single dose

containers larger than 1 L.
 Types of Water
 STERILE WATER FOR INHALATION

 It is sterile WFI that is packaged

and sterilized.
 It is intended for use in
inhalators and in the preparation
of inhalation solutions.
 Design of Water
 The design System
of water system and the
choice of water treatment methods
depends on the-
 Grade of output water required by
pharmacopoeias for pharmaceuticals
under production
 Contamination character and

 Level of input potable or raw water.

 Design of Water
 System
The choice of water purification
method depends on final
production quality requirements
specified in the pharmaceutical
product dossier.
 Other aspects that should be
considered include engineering,
production and quality control.
 Design of Water

System
All construction material of storage
tanks and distribution configuration,
including pumps, pipelines and joints,
should be of high quality stainless
steel 316L compliance.
 Fully automatic orbital welding
techniques will ensure a high quality
weld and are recommended where
pipes need to be welded.
 Design of Water

System
All pipe works, valves, fittings,
connections should be easy to clean.
 The system elements should be
designed to prevent sites for
microbial growth. The gasket should
be designed to provide perfect
alignment of pipes, no crevices that
will allow bacterial attachment, short
outlet tee piece, and short outlet with
minimum dead leg.
 Design of Water
 System
It is generally agreed and
recommended that A dead leg in
the pipe work should be minimized
through appropriate design, and as
a guide should not significantly
exceed three times the branch
diameter as measured from the ID
pipe wall to centre line of the point
 Design of Water
System
FDA Guide to Inspections of high purity water systems in 1993 - only
now it was called 6D rule.
WHO TRS 970 2012 Annex 2 Water for pharmaceutical use talk about
the 3D rule.

WHO TRS 1033 2021 Annex 3 Good manufacturing practices: water

for pharmaceutical use – zero dead leg diaphragm valves , minimizing
dead legs elsewhere
 Design of Water

System
Sloping of the pipes should be in such a way that
water does not pool and can drain easily. The ratio
of the slope to the length of pipe should not be
more than 1:100.
 Sanitary pumps should be used for the final water
treatment steps. Sanitary pumps should have a
mechanical seal around the shaft.
 Special clamps should be used for pump joints to
pipes and suitable “O” ring fittings should be
used. Threaded fittings should be avoided.
 Design of Water System
• Welding Inspection
• All weld joints in the system should be
thoroughly checked for the following
parameters
 Stainless steel oxidation
 Pinholes must be absent
products must be absent
Weld bead appearance must be Welded tubing sections must be
regular and uniform. aligned properly
Thermal cracking must be absent Weld shape must be noticeably
Weld seam color must be absent
convex
Weld thickness must not be more
than 20% of the tube thickness
Inspection: 100% of manual welds, 10% of orbital welds
 Design of Water System

• Passivation
 This test is performed to remove all oxidizable
matters from the system.

 Water Velocity Test

 The flow velocity should not be less than 1.5 m/sec.
 Design of Water
 Ball valves are not
1. Ball
System
valves are
recommended.
unacceptable
2. Bacteria can grow
when
the valve is closed
3. The water is
contaminated as it Stagnant
passes through the water
valve
inside valve
 Design of Water
 System
In case of long pipe to outlet without
circulation, there should be a
procedure in place that allows the
pipe work to be completely drained
and left dry daily.
 These pipeline outlets should be
included in the control procedure, and
special attention concerning sampling
and testing frequency for microbial
counts should be indicated.
 Design of Water
 System
Heat exchangers (HE) should
have double shell or double
tubing because pinholes may
allow heating or cooling liquid to
contaminate the purified water.
 Single plate heat exchangers
should be under continuous
monitoring of pressure
differentials across the plates.
 Design of Water
 System
Side arm level measuring devices
on the WFI storage tanks/vessels
are not recommended because
the water in these measuring
pipes and devices is still and
may become a harbour of
biological contaminants.
 Design of Water
 System
In case of water systems, the qualification process entails a three-phase
approach in order to satisfy the objective of demonstrating the reliability

and robustness of the system in service over an extended period .

 Unit Operations
 Concerns
Pre-filtration
 Referred as initial, coarse or
depth filtration.
 Removes solid contaminants
down to a size of 7 to 10 µm
from the incoming source water
and protect downstream system
components.
 Unit Operations
 Concerns
Pre-filtration
 Filtration unit ranges from
granular bed filters (sand filters)
to depth cartridges (multi-gravel
filter).
 Concerns
Channelling of the filter
media.
Blockage from slit, microbial
growth.
 Unit Operations
 Concerns
Pre-filtration
 Control Measures
Pressure and flow monitoring
during using and backwashing.
Sanitizing.
Replacing filtering media.
Proper sizing of the filter.
 Unit Operations
 Concerns
Softeners
 Softeners utilize sodium based
cation exchange resins to
remove water hardness ions
such as calcium and magnesium.
 Water hardness affects the
performance of RO membrane,
de-ionization devices and
distillation units.
 Unit Operations
Concerns
 Softeners
Softeners

 Water softener resin beds are

regenerated with concentrated
sodium chloride solution (brine).
 Unit Operations
 Softeners Concerns
 Concerns
Micro-organism proliferation.
Channelling due to
agglomeration of resin particles.
Ion-exchange capacity.
Organic and particulate resin
fouling.
 Unit Operations
 Softeners Concerns
 Concern
Leaching from new resins.
Fracture of resin beds.
Resin degradation caused by
excess chlorine water.
Contamination from brine
solution.
 Unit Operations
 Softeners Concerns
 Control Measures
Recirculation during low water
use.
Sanitization of the resin and
brine system.
Use of microbial control device
(chlorine).
Appropriate regeneration
frequency.
Effluent chemical monitoring
(e.g. hardness ions).
 Unit Operations
 Concerns
Activated Carbon Filter
 Activated carbon is used for
dechlorination and depyrogenation
purpose as it adsorbs low
molecular weight organic material
and oxidizing additives.
 The origin and source of an
activated carbon supply should be
checked. Charcoal from petroleum
sources is preferable to vegetable
carbon because vegetable carbon
has high levels of heavy metals.
 Unit Operations
 Activated Concerns
Carbon Filter
 Concern
Creates a nutrient-rich
environment for micro-organism
growth on the surface.
Hydraulic channelling.
Organic adsorption capacity.
Inability to be regenerated in
situ.
Shedding of bacteria, endotoxins,
organic chemicals and fine
 Unit Operations
 Concerns
Activated Carbon Filter
 Control Measures
Monitor water flow rates and
differential pressures.
Sanitize with hot water.
Backwashing.
Replacement of carbon bed.
 Unit Operations
 Concerns
Activated Carbon Filter
 Activated carbon filters remove
organic contaminants from
water, but bisulfite does not.
 The advantage of using bisulfite
to remove chlorine is that
bisulfite does not facilitate
microbial growth as occurs with
the activated carbon filter.
 Unit Operations
 Concerns
De-ionization (DI) or Electrode-
ionization (EDI)
 DI system of charged resins that
require periodic regeneration with an
acid and base.
 DI System consists of
Cationic resins-capture + ions
Anionic resins-capture - ions
Mixed resins-capture both + & - ions
 Unit Operations
Concerns
 De-ionization (DI) or Electrode-
ionization (EDI)
 Cationic resins
 regenerated with HCl or H2SO4
 replaces captured positive ions with
hydrogen ions
 Anionic resins
 regenerated with NaOH or KOH
 replaces captured negative ions with
hydroxide ions.
 Unit Operations
 Concerns
Free endotoxin is negatively charged
so some of it is also removed by
anionic resin.
 Both regenerant chemicals are
biocidal.
 Electrode-ionization (EDI)
 EDI System consists of
Mixed resin
Selectively permeable membranes
Electric charge
 Unit Operations
 Concerns
Electrode-ionization (EDI)
 Electric charge provides a continuous
flow (product and waste concentrate)
and continuous regeneration.
 Process
1. As the water passes through the resin
it is de-ionized.
2. Resin acts as a conductor which allows
the electric charge to drive the
captured ions through the resin,
membrane and removal in waste water
stream.
 Unit Operations
 Concerns
Electrode-ionization (EDI)
 Process
3. The electric charge also
separates the water in the resin
section into hydrogen and
hydrogen ions.
4. This permits continuous
regeneration.
 EDI starts with partially PUW
because it can’t start with
heavier ion load of source water.
 Unit Operations

Concerns
De-ionization (DI) or Electrode-
ionization (EDI)
 Concern
Microbial and endotoxin
control.
Chemical additive impact on
resins and loss.
Degradation and fouling of
resin.
 Unit Operations

Concerns
De-ionization (DI) or Electrode-
ionization (EDI)
 Concern
Channelling due to biofilm
agglomeration of resin particles.
Organic leaching from new
resins.
 Unit Operations
 De-ionizationConcerns
(DI) or Electrode-
ionization (EDI)
 Control Measures
Recirculation loops.
Effluent microbial control by UV
light.
Conductivity monitoring.
Microbial monitoring.
Frequent regeneration.
 Unit Operations
 Concerns
Reverse Osmosis (RO)
 RO units employ semi-permeable
membranes.
 The PORES of RO membranes are
intersegmental spaces among
the polymer molecules.
 They allow permeation of water
molecules, but do not permit
passage of hydrated chemical
ions.
 Unit Operations

Concerns
Reverse Osmosis (RO)
Reverse osmosis (RO) theory
High pressure Low pressure

Semi-permeable
membrane
Feed
water

under Purified water

pressure raw water

Permeate
Reject
water

drain or recycle water

 Unit Operations
 Reverse Osmosis (RO)
Concerns
Typical 2-stage RO schematic
Water from softener or de-ioniser

Second stage reject water goes back to first stage buffer tank
1st stage buffer tank
Branch First stage RO cartridge
1st stage reject concentrate

Branch

First stage filtrate feeds second stage RO

. excess back to 1st stage buffer tank
with
Air break
to sewer 2nd stage buffer tank
Second stage RO cartridge

High pressure
pump
Cartridge
filter 1 µm Hygienic pump
Second stage RO water
meets Pharmacopoeia Water returns to 1st stage buffer tank
standards Outlets or storage
 Unit Operations
 Concerns
Reverse Osmosis (RO)
 Process stream
Supply water Product water Waste
water
 First pass is often not enough to meet
PUW conductivity specifications.
 A second pass of the permeate water
is required through another RO stage
to achieve permeate purity.
 Unit Operations

Concerns
Reverse Osmosis (RO)
 Concern

pH, temperature and

differential pressure affects
membrane permeability.

Permeate recovery rate.

Membrane material.

Membrane and seal integrity.

 Unit Operations
 Concerns
Reverse Osmosis (RO)
 Control Measures
Suitable pre-treatment of
influent water stream.
Appropriate membrane material
selection.
Integrity challenges.
Membrane heat tolerance.
Periodic sanitization.
Monitoring differential pressures,
conductivity, microbial levels &
TOC.
 Unit Operations

Concerns
Ultra-filtration

 Ultra-filtration is often employed

to remove endotoxins.

 It uses semi-permeable
polysulfone membranes.
 Unit Operations
 Concerns
Ultra-filtration

 Ultra-filtration works by a molecular

sieving principle.

 Ultra-filters with molecular weight

cutoff rating in the range of 10,000 to
20,000 Da are typically used for
removing endotoxins.
 Unit Operations
 Concerns
Ultra-filtration

 Ceramic ultra-filters are another

molecular sieving technology.

 Ultra-filters are durable, back

washable, chemically cleanable and
steam sterilizable, but may require
higher operating pressures.
 Unit Operations
 Concerns
Ultra-filtration
 Concern

Compatibility of membrane material

with heat and sanitizing agents.
Membrane integrity.
Fouling by particles and micro
organisms.
Seal integrity.
 Unit Operations
 Ultra-filtration Concerns
 Control Measures
Filtration medium selection.
Sanitization.
Flow design.
Integrity challenge.
Regular cartridge changes.
Monitoring TOC and differential
pressure.
 Unit Operations
 Distillation Concerns
 Distillation is a method for
purification of water for
pharmaceutical use by heating.
 The unit provides purification via

thermal vaporization

mist elimination and

water vapour condensation

 Unit Operations

Concerns
Distillation

 Distillation design includes-

Single effect distillation

Multi effect distillation and

Vapor compression
 Unit Operations Concerns
 Distillation
 Concern

Presence of hardness and

silica impurities that may
corrode the heat transfer
surfaces.
Presence of those impurities
that could volatize and
condense with water vapour.
 Unit Operations
Concerns
 Distillation
 Concern

Faulty mist elimination.

Evaporator flooding.
Stagnant water in condensers
and evaporators.
Pinhole evaporator and
condenser leak.
 Unit Operations
 Concerns
Distillation
 Corrective Measures

Prior effective removal of

hardness & silica.

Prior removal of volatile

impurities.

Reliable mist elimination.

 Unit Operations
 Concerns
Distillation
 Corrective Measures
Use of sanitary pumps and
compressors.
Proper drainage during
inactive period.
On-line conductivity
monitoring with automated
diversion to waste if unacceptable.
Integrity testing for leaks.
Flow Diagram of BOSCH
Water System
Flow Diagram of Pharma Plan
Water System
Sampling and Testing
 Sampling and Testing
 Sampling
 The sampling ports themselves
should be designed to prevent
microbial contamination of the
water system during sampling
and also to prevent
contamination of the sample
itself.
 The water system design should
allow for sampling ports at each
 Sampling and Testing
 Sampling
 The sampler should be trained to
work on aseptic handling practices
to avoid contaminating the sample
during sampling.
 Samples for microbiological
analysis should be tested in the
shortest time available (Within 2
h). In case they are not tested
within a few hours, the sample
should be chilled to less than 8°C
 Sampling and Testing
 Testing
 Testing of chemical and
microbiological contamination
should be consistent.
 Trained, skilled technicians and
laboratory personnel should use
properly maintained, calibrated
laboratory equipment when
performing analyses.
 Sampling and Testing
 Limits
 Alert levels should be based on the initial qualification data
and thereafter periodically reassessed on data obtained
during subsequent re-qualifications, routine monitoring,
and investigations.

 Alert, Alert level excursions

should be documented and
reviewed, and include an
investigation to determine
whether the excursion is a single
(isolated) event or if results are
indicative of an adverse trend or
system deterioration.
 Sampling and Testing
 Testing
 Action limits, Each action limit
excursion should be investigated
to determine the probable root
causes and any potential impact
on the quality of products and
manufacturing processes as a
result of the use of the water
 Testing Specifications of
PUW / WFI
Purified Water
Water For Injection (WFI)
(PW)
Conductivity < 1.3 µS/cm @ 25°C < 1.3 µS/cm @ 25°C
pH 5.0 – 7.0 5.0 – 7.0
Total Organic
< 500 ppb < 500 ppb
Carbon (TOC)
Total Bioburden < 100 CFU / mL < 10 CFU / 100 mL
Endotoxin N/A < 0.25 Endotoxin Units/mL
Coliform Level
Absent / 100 mL Absent / 100 mL
E. coli
P. aeruginosa Absent / 100 mL Absent / 100 mL
U.S. EPA, WHO National Primary Drinking Water
Source Water
Regulations
 Testing Specifications of
SuggestedPUW
bacterial
/ WFIlimits (CFU / mL)

Sampling location Alert Action

Raw water 300 500

Post multimedia 300 500
filter softener
Post 300 500
Post activated carbon 300 500
Feed to RO
filter 200 500
RO permeate 50 100
PUW 10 100
WFI - 10/100 ml
 EU Annex 1 Water System
• Measures taken to minimize the risk of presence of particulates, microbial
contamination/proliferation and endotoxin/pyrogen (e.g. sloping of piping to
provide complete drainage and the avoidance of dead legs).
• Water produced should comply with the current monograph of the relevant
Pharmacopeia.
• Water systems should be qualified and validated to maintain the appropriate levels
of physical, chemical and microbial control, taking the effect of seasonal variation
into account.
• Water flow should remain turbulent through the pipes in water distribution systems
to minimize the risk of microbial adhesion, and subsequent biofilm formation.

• Water for injections (WFI) should be constant circulation at a temperature above

70°C).
• Hydrophobic bacteria retentive vent filters , prevent condensation formation on the
filter (e.g. by heating), filter interity tested before installation and after use.