watersystemvalidation-Finaly.pptx

WATER FOR
PHARMACEUTICAL USE
Owais Ahmed.
Manager QA(Validation)
1

CONTENTS
1. Introduction.
2. Types of Water.
3. Specifications of Water for Pharmaceutical Use.
4. Different Equipment and Components for Water
System
5. Different Techniques used for Water Treatment.
6. Water Storage and distribution Requirements
7. Validation of Water System.
8. Routine Monitoring of Water System.
2

REFERENCES
World Health Organization WHO “Water for
Pharmaceutical Use” Annex 2
USP <1231> Water for Pharmaceutical Purposes.
EMA Guideline on the quality of water for
pharmaceutical use

OBJECTIVE
To understand:
4
1. Importance of Water in Pharmaceuticals.
2. Different types of water used in Pharmaceuticals.
3. Usage and Production requirements for different
type of water.
4. Different Purification techniques.
5. Specifications & Quality attributes.
6. Water System Design & Validation requirements.

INTRODUCTION
●High-quality water is essential for the manufacturing of
pharmaceuticals. Water is the most commonly used raw
material in pharmaceutical manufacturing.
●water is directly or indirectly used in the pharmaceutical
manufacturing such as a major component in injectable
products and in cleaning of manufacturing equipment.
●It is one of the raw material that is usually processed by the
pharmaceutical manufacturer prior to use because it cannot be
supplied by the vendor.
●Water is thus an important raw material in GMP and in
validating the manufacturing process.
5

INTRODUCTION
Why purification?
6
pure, it is
variations,
o Although tap water is reasonably
always variable due to seasonal
regional variation in quality.
o One must remove impurities and control microbes
to avoid contamination of products.
o Pretreatment depends on quality of feed water.

INTRODUCTION
6
Quality of water should be specific for product
quality.
Water contains,
●
●
●
●
Organic and inorganic impurities
Microbial contamination
Endotoxin
Particulate contamination
Low quality of water can lead to
▪
▪
▪
product degradation
product contamination
loss of product and profit

TYPES OF WATER
●Different grades of Water for Pharmaceutical
Purposes-
each type has its on characteristic for all parameters.
➢Potable water/Drinking-water
➢Purified water
➢Water for injection (WFI)
8

PURIFIED WATER
Purified Water (see the USP monograph) is used as an
excipient in the production of non-parenteral preparations
cleaning of non-parenteral product-contact components and
equipment.
Purified Water is also to be used as the minimum water quality
for all tests and assays in which “water” is indicated.

PURIFIED WATER PRODUCTION
The minimal quality of source water for the production of Purified Water is
Drinking Water.
This source water may be purified using unit operations that include deionization,
distillation, ion exchange, reverse osmosis, filtration, or other suitable purification
procedures
Purified Water must meet the requirements for ionic and organic chemical purity
and must be protected from microbial contamination
Purified Water systems that function under ambient conditions are particularly
susceptible to the establishment of biofilms of microorganisms, which can be the
source of undesirable levels of viable microorganisms or endotoxins in the water.
These ambient Purified Water systems require frequent sanitization and
microbiological monitoring to ensure that the water reaching the points of use has
appropriate microbiological quality

WATER FOR INJECTION
Water for Injection (see the USP monograph) is used as an
excipient in the production of parenteral and other preparations
where product endotoxin content must be controlled,
cleaning of certain equipment and parenteral product-contact
components.

WATER FOR INJECTION PRODUCTION
The minimal quality of source water for the production of Water for Injection is
Drinking Water
This source water may be treated to render it suitable for subsequent final
purification steps, such as distillation
The finished water must meet all of the chemical requirements specified in the
monograph, as well as an additional bacterial endotoxin specification.
The finished water must meet all of the chemical requirements specified in the
monograph, as well as an additional bacterial endotoxin specification. Because
endotoxins are produced by the kinds of microorganisms that are prone to inhabit
water systems, the equipment and procedures used by the system to purify, store,
and distribute Water for Injection should be designed to control microbial
contamination and must be designed to remove incoming endotoxins from the
source water. Water for Injection systems must be validated to reliably and
consistently produce and distribute this quality of water

DIFFERENT TECHNIQUES USED FOR
WATER TREATMENT
●De-chlorination (Sodium Bisulphite,
Carbon Filter)
●Filtration
●Ultra Filtration
●Softening
●Demineralization
●Reverse Osmosis
●UV Treatment
●Deionization
●Ozonization
15

METHODS OF WATER TREATMENT(REVERSE OSMOSIS):
 Osmosis is a special case of diffusion in which the molecules are water
and the concentration gradient occurs across a semipermeable
membrane. The semipermeable membrane allows the passage of water,
but not ions (e.g., Na+, Ca2+, Cl-) or larger molecules (e.g: glucose, urea,
bacteria).
 Reverse osmosis: it is a membrane based process technology to purify
water by separating the dissolved solids from feed stream resulting in
permeate and rejects stream for a wide range of applications in domestic
as well as industrial applications.
 It uses semipermeable spiral wound membranes to separate and remove
dissolved solids, organic pyrogens, submicron colloidal matter, bacteria
from water. Feed water is delivered under pressure through
semipermeable membrane, where water permeates through pores and is
delivered as purified water called permeate water and impurities are
rejected through reject stream.

ULTRA FILTRATION
Ultrafiltration (UF) is a water purification process in
which water is forced through a semipermeable
membrane. Suspended solids and high-molecular-
weight solutes remain on one side of the membrane,
the retentate side, while water and low-molecular-
weight solutes filter through the membrane to the
permeate side.

DEMINERALIZATION
Demineralization is the process of removing mineral salts from water by
using the ion exchange process. It is completely free of dissolved
minerals as a result of one of the process.
 Distillation
 Deionization
 Membrane filtration
 Electro dialysis
 Or other technologies.
 Demineralized water also known as Deionized water.
 Deionization is a physical process which uses specially-manufactured
ion exchange resins which provides ion exchange site for the
replacement of the mineral salts in water with water forming H+ and
OH- ions. Because the majority of water impurities are dissolved salts,
deionization produces a high purity water that is generally similar to
distilled water, and this process is quick and without scale buildup.

 The following ions are widely found in raw waters
Cations
Calcium
Magnesium
Potassium
Sodium
anions
chloride
bicarbonate
nitrate
carbonate
ION EXCHANGE RESINS
 Cation exchange resins---will release hydrogen ions (H+)or other
positively charged ions in exchange for impurity cations present in water.
 Anion exchange resins---will release hydroxyl (OH-)ions or other
negatively charged ions in exchange for impurity anions present in
water.
The application of ion-exchange to water treatment and purification. There
are three ways in which ion-exchange technology can be used in water
treatment and purification

 First – cation exchange resins(soften water by base exchanger)
 Second—anion exchange resins(organic scavenging or nitrate removal)
 Third – both anionic and cationic resins.
Deionization types
For many laboratory and industrial applications ,high purity water which is
essentially free from ionic contaminants is required.
Water of this quality can be produced by deionization. The two most
common types of deionization are
 Two bed deionization
 Mixed bed deionization

 The two-bed deionizer consists of two vessels - one containing a cation-
exchange resin in the hydrogen (H+) form and the other containing an
anion resin in the hydroxyl (OH-) form. Water flows through the cation
column, whereupon all the cations are exchanged for hydrogen ions. To
keep the water electrically balanced, for every monovalent cation,
 e.g. Na+, one hydrogen ion is exchanged and for every divalent cation,
e.g. Ca2+, or Mg2+, two hydrogen ions are exchanged. The same
principle applies when considering anion-exchange. The decationised
water then flows through the anion column. This time, all the negatively
charged ions are exchanged for hydroxide ions which then combine with
the hydrogen ions to form water (H2O).

 In mixed-bed deionizers the cation-exchange and anion-exchange resins
are intimately mixed and contained in a single pressure vessel. The
thorough mixture of cation-exchangers and anion-exchangers in a single
column makes a mixed-bed deionizer equivalent to a lengthy series of
two-bed plants.

Mini DM Plant Specifications :
Model: eDM-5
Flow rate: 50 to 80 Lit/hr.
Space requirement: very compact- 1 m x 1m
Power: NIL, Min inlet pressure 0.5 kg/cm2
Output TDS: Less that 10 ppm
Output DM Qty.: 500 Lit at 100 ppm TDS
(Best suitable when feed water is corporation water TDS < 100 ppm)
 Applications :
Food Industry, Pharmaceutical industry, Automobile, laboratory

WATER FOR INJECTION(WFI)
water for injection or WFI is sterile, distilled, non-pyrogenic water
available in a single dose container for intravenous administration .WFI
is also available as a dispensing container for diluent use.
 WFI is purified by distillation and contains no added substances.
FACTORS AFFECTING WFI
 Quality of feed water.
e.g. Chlorine in water
 Size of the evaporator.
 Redissolving volatile impurities.
 Contamination of the vapour and distillate from metal part of the still.

Pharmaceutical Water CompendialTypes
1.Bulk forms
which are typically produced on site where they are used.
A-Purified Water (PW)
B-Water for Injection (WFI)
2.Packaged Forms
which are produced, packaged, and sterilized to preserve microbial quality
throughout their packaged shelf life.
A-Bacteriostatic WFI
B-Sterile Water for Inhalation
C-Sterile Water for Injection
D-Sterile Water for Irrigation
E-Sterile purified water

2.Packaged Forms
 A-Bacteriostatic Water (bacteriostatic water for injection) is sterile water
containing 0.9% benzyl alcohol that is used to dilute or dissolve
medications; the container can be reentered multiple times (usually by a
sterile needle) and the benzyl alcohol suppresses or stops the growth of
most potentially contaminating bacteria. The Bacteriostatic Water can be
used in diluting drugs that can subsequently be administered by
intravenous, intramuscular, or subcutaneous injection.

B-Sterile Water for Injection, USP is a sterile, non-pyrogenic preparation of
water for injection which contains no bacteriostatic, antimicrobial agent or
added buffer and is supplied only in single-dose containers to dilute or
dissolve drugs for injection. For I.V. injection, add sufficient solute to make
an approximately isotonic solution.PH 5.0 to 7.0
Precautions:
Do not use unless water is clear, seal is intact and container is undamaged.

 C-Sterile Water for Irrigation
Sterile Water for Irrigation is a sterile, distilled, non-pyrogenic water for
injection intended only for sterile irrigation, washing, rinsing and
dilution purposes. pH 5.5 (5.0 to 7.0).
Sterile Water for Irrigation contains no bacteriostat, antimicrobial agent
or added buffer and is intended for use only as a single-dose or short
procedure irrigation. When smaller volumes are required the unused
portion should be discarded.
Sterile Water for Irrigation may be classified as a sterile irrigant, wash,
rinse, diluent and pharmaceutical vehicle.
NOT FOR INJECTION BY USUAL PARENTERAL ROUTES
Do not heat container over 66°C (150°F).

 D-Sterile Water for Inhalation is Water for Injection that is packaged and
rendered sterile and is intended for use in inhalators and in the
preparation of inhalation solutions. It carries a less stringent
specification for bacterial endotoxins than Sterile Water for Injection,
and therefore, is not suitable for parenteral applications
 E-Sterile purified water: Is purified water that is packaged and rendered
sterile, contains no antimicrobial agent.

DISTILLATION
Distillation is a process of converting water from liquid to gaseous form.
TYPES OF DISTILLATION UNIT
two types of WFI distillation unit
Vapour compression still multiple still effect

1.Multiple effect still
A multiple effect still consists of a series of pressure columns
divided into two parts: a double tube sheet (DTS) heat exchanger
that acts as an evaporator, and an upper column used to separate
pyrogens; preventing drops carrying impurities from reaching the
end of the column.
2.Vapour compression still
In the VC process, evaporating the water produces vapor through
compression to increase the pressure saturation and temperature.
By transferring its excess heat to infeed water in a heat exchanger,
this compressed vapor condenses to produce WFI.

DIFFERENT EQUIPMENTS AND
COMPONENTS FOR WATER SYSTEM
11
●Piping
●Valves
●Pumps
●Pressure gauges
●Heat exchangers
●Distillation unit
●Filters
●Deionizers
●Sensors
●Auxiliary equipment

WATER STORAGE AND
DISTRIBUTION – CONSIDERATIONS
12
●Materials of Construction (Chemical and Heat
Compatibility)
●Stainless Steel (316L)
●Piping, fittings and components (e.g. valves, pumps
and connections must be of sanitary design
●Water distribution systems must be designed without
dead legs
●Smooth Surfaces (Mechanical Polish , Electropolish).
average surface roughness of not greater than 0.8
micrometre (Ra)
●Clean joints (e.g. 100% hand welds, 10% automatic
welds. )

Conti….
13
●Combination of on-line (TOC, Conductivity meter
etc.) and off-line monitoring (lab testing by proper
sampling) to ensure compliance with water
specification

Conti….
●Fixed pipework must be clearly labelled to
indicate contents and where applicable direction
of flow
●All piping for systems supplying purified water
or water of a higher standard must be
appropriately sloped to allow for self-drainage of
the entire distribution system
●The connections between water systems and the
drains must be fitted with air breaks to prevent
possible backflow from the drains into the
process

SANITIZATION OF WATER SYSTEMS
Sanitization of Purified Water (PW) systems can
be achieved through the generation of ozone
within the storage tank and a UV lamp before the
first point of use. This UV lamp is periodically
turned off to enable circulation of ozonized water
throughout the entire distribution loop.
Water systems that permanently circulate at a
temperature above 65°C (WHO guideline) or 70°C
(European guideline) are considered self-
sanitizing.

VALIDATION CONCEPT
14
●To prove the performance of processes or systems under
all conditions expected to be encountered during future
operations.
(document)
●To prove the performance, one must
that the processes or systems
demonstrate
consistently
produce the specified quantity and quality of water when
operated and maintained according to specific written
operating and maintenance procedures.
●validation involves proving-
1. Engineering design
2.Operating procedures and acceptable ranges for control
parameters
3. Maintenance procedures to accomplish it

Conti..
●the system must be carefully,
-designed
-installed
-tested during processing, after construction, and
under all operating conditions.
●Variations in daily, weekly and annual system
usage patterns must be validated.
39

VALIDATION CYCLE:
It includes four major steps-
●Determination of Quality Attributes
●The Validation Protocol
●Steps of Validation
●Control during routine operation
40

DETERMINATION OF QUALITY ATTRIBUTES
●The quality attributes, is gaining a clear
understanding of the required quality of water and
its intended use
●Should be determined before starting the
validation.
●Without defining required quality attributes, we
cannot establish validation protocols.
41

THE VALIDATION PROTOCOL
19
●A written plan stating how validation will be
for
conducted and defining acceptance criteria
quality.
●For example, the protocol for a manufacturing
process-
it identifies -process equipment
-critical process parameters
-product characteristics,
-sampling,
-test data to be collected,
-number of validation runs
-acceptable test results

STEPS OF VALIDATION
●Establishing standards for quality attributes
●Defining system and subsystem
●Designing equipment, control, & monitoring
technologies
●Establishing standards for operating parameters
●Developing an IQ stage & OQ stage
●Establishing alert and action levels
●Developing a prospective PQ stage
●Completing protocols and documenting each
steps
43

ALERT AND ACTION LEVELS:
22
●Alert and action levels are distinct from process
parameters and product specifications.
●They are used for monitoring and control rather than
accept or reject decisions.
●The levels should be determined based on the statistical
analysis of the data obtained by monitoring at the PQ
step.
●Alert levels are levels or ranges that when exceeded
indicate that a process may have drifted from its normal
operation condition.
●Alert levels indicate a warning and do not necessarily
require a corrective action. Exceeding an action level
indicates that corrective action should be taken to bring
the process back into its normal operating range.

SYSTEM QUALIFICATION
23
Validation Master Plan
User Requirement Specification
Design Qualification
Installation Qualification
Operation Qualification
Performance Qualification
Re- Qualification.

DESIGN QUALIFICATION OF WATER SYSTEM
Based on the URS, supplier designs the equipment.
● This is 1st step in the qualification of new water supply
systems.
● Define process schematically by use of PFD and P&IDs.
● It is documented the design of the system & will include :
-Functional Specification.(Storage, purification, etc)
-Technical/Performance specification for equipment.
(requirements of water volume and flow, define pumps and
pipe sizes )
-Detailed layout of the system.
Design must be in compliance with GMPs and other regulatory
requirements.
47

INSTALLATION QUALIFICATION
IQ is in the form of checklist and it should include-
● Instrumentation checked against current engineering
drawings and specifications
● Review of P&ID
● Verification of materials of construction
● Installation of equipment with piping
● Calibration of measuring instruments
● Collection and collation of supplier operating and
working instructions and maintenance requirements
48

Conti…
●Installation of system as per Design requirements.
●Installation Verification-
Systematic range of adjustments, measurements
and tests should be carried out to ensure proper
installation.
●Documentation include details of completed
installation.
49

Conti…
50
• IQ Document should contain,
➢Instrument name, model, I.D. No., Personnel
responsible for activities and Date.
➢A fully verified installation that complies with the
documented design. (all deviations will have been
recorded and assessed.)
➢ All equipment documentation and maintenance
requirements would be documented.
➢ Completed calibration of measuring
instruments.
➢ Verification of Materials of construction.

OPERATION QUALIFICATION
Definition : The purpose of OQ is to establish, through
documented testing, that all critical components are
capable of operating within established limits and
tolerances.
●it is the functional testing of system components
mainly the critical components.
●The purpose of OQ is also to verify and document that
the water supply system provides acceptable operational
control under “at-rest” conditions.
51

Conti…
52
Operation Qualification Checks-
● Ability to provide water of sufficient quality and
quantity to ensure achievement of specifications.
●Ability to maintain general parameters like
temperature, pressure, flow at set points.
●Ability to maintain any critical parameters(pH,
TOC, endotoxin, microbial level, conductivity etc ).

Conti…
53
●Includes the tests that have been developed from
knowledge of processes, systems and equipment.
●Tests include a condition or a set of conditions with
upper and lower operating limits, sometimes referred
to as ‘worst case’ conditions.

PERFORMANCE QUALIFICATION
54
●The purpose of PQ is to verify and document that
water supply system provides acceptable control
under ‘ Full Operational ‘ conditions.
●PQ should follow successful completion of IQ
and OQ.
●PQ verifies that over time, the critical
parameters, as defined in the DQ are being
achieved.

Conti…
55
●PQ is used to demonstrate consistent achievement of
critical parameters over time.
(such as pH, TOC, conductivity)
●PQ and OQ tests are sometimes performed in
conjunction with one another.

QUALIFICATION PHASES
●Three phase approach recommended according to
WHO Technical Report Series 929 to prove
reliability and robustness.
Phase 1 (investigational phase):
●A test period of 2 weeks – monitor the system
●System to operate continuously without failure or
performance deviation
●Chemical and microbiological testing should
include in accordance with a defined plan
56

Conti…
● Sample daily from-
●incoming feed-water
●after each step in the purification process
●each point of use and at other defined sample
points
● Develop:
●appropriate operating ranges
●and finalize operating, cleaning, sanitizing
and maintenance procedures
57

Conti…
water of
58
●Demonstrate production and delivery of
the required quality and quantity
●Use and define the standard operating procedures
(SOPs) for operation, maintenance, sanitization
and troubleshooting
●Verify provisional alert and action levels
●Develop and define test-failure procedure

Phase 2(verification step)
59
●A further test period of 2 weeks – further intensive
monitoring of the system
●Utilization of all the SOPs after the satisfactory
completion of phase 1
●Sampling scheme generally the same as in phase 1
●Water can be used for manufacturing purposes during
this phase

Conti..
Phase-2 demonstrates:
●Consistent operation within established ranges. so
it demostrate that the system is in control.
●Consistent production and delivery of water of the
required quantity and quality when the system is
operated in accordance with the SOPs.
60

Phase 3
61
●Over 1 year after the satisfactory completion of
phase 2
●Water can be used for manufacturing purposes
during this phase
Demonstrate:
●extended reliable performance
●that seasonal variations are evaluated
●Sample locations, sampling frequencies and tests
should be reduced to the normal routine pattern
based on established procedures proven during
phases 1 and 2

MONITORING
40
● Monitoring and feed back data are important in maintaining
the performance systems. Monitoring parameters include:
● Flow, pressure, temperature, conductivity, TOC
microbial
● Samples taken:
● From points of use, and specific sample points
● In a similar way how water is used in service
● Tests should include physical, chemical and
attributes
➢ For example, stable state can be achieved by applying
automatic continuous monitoring of TOC and conductivity of
the water system. They are the major quality attributes of
water by which organic and inorganic impurities can be

MAINTENANCE
41
A controlled, documented maintenance covering :
● Defined frequency with plan and instructions
● Calibration programme
● SOPs for tasks
● Control of approved spares
● Record and review of problems and faults during
maintenance

MAINTENANCE
System sanitization and bioburden control
●Systems in place to control proliferation of microbes
●Techniques for sanitizing or sterilization
●Consideration already during design stage – then
validated
●Special precautions if water not kept in the range of
70 to 80 degrees Celsius

REVALIDATION & CHANGE CONTROL
●Once the validation is completed, the standard operating
procedures (SOPs) are formalized.
●Routine operation should be performed according to the
established SOP.
●If any deviation from SOP observed, determine the change
and their impact on whole system
●Revalidation and evaluation should be performed
depending upon the impact of the change on system.
65

VALIDATION REPORT
●Written at the conclusion of the equipment IQ, OQ
and at completion of process validation.
●Will serve as primary documentation for FDA
regulatory inspection
●Will serve as reference document when changes to
the system are occurred and revalidation is needed.
66

VALIDATION REPORT
●STANDARD FORMAT
1. Executive summary
2. Discussion
3. Conclusions & recommendation
4. List of attachment
➢ Topic should be presented in the order in which they
appear in the protocol.
➢Protocol deviation are fully explained & justified.
➢The report is signed & dated by designated representatives
of each unit involved in water system validation.
67

Complete Documentation
68
●Verification of design documentation, including
◦ Description of installation and functions
◦ Specification of the requirements
●Instructions for performance control
●Operating procedures
●Maintenance instructions
●Maintenance records
●Training of personnel (program and records)
●Environmental records
●Inspection of plant
Finally certification (Sign Off) by Engineering,
User (Production) and QA Heads.

SUMMARY
Water supply systems,
● Play a major role in the quality of
pharmaceuticals.
● Must be designed properly by professionals.
● Must be validated as a critical system.
69

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