VALIDATION OF WATER SYSTEM FOR

PHARMACEUTICAL USE
o Introduction

o Water system requirements

o Water quality specifications

o Water purification methods

o Commissioning, qualification, operation and

maintenance

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 INTRODUCTION
o Information on Water for Pharmaceutical Use (WPU)

o Quality of water for APIs, finished products, etc.

o GMP for design, installation, operation of systems

o Supplementary to general GMP guidelines

o See also other guidelines, pharmacopoeia, etc.

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BACKGROUND TO WATER REQUIREMENTS AND USE
o Water is the most widely used substance / raw material
o Used in production, processing, formulation, cleaning, quality
control
o Unique chemical properties
 Able to dissolve, absorb, adsorb, suspend compounds and contaminants
o Different grades of water quality available
o Control quality of water
 Production
 Storage and distribution

o Contaminants, microbial and chemical quality

o Microbial contamination risk and concern

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 WATER SYSTEM REQUIREMENTS
o Design, installation, commissioning, qualification / validation, operation,
performance and maintenance to ensure reliable, consistent production
of water of required quality
o Operate within design capacity
o Prevent unacceptable microbial, chemical and physical contamination
during production, storage and distribution
o Quality Assurance involved in approval of use after installation and
maintenance work
o Monitoring of water sources regularly
 Chemical and microbiological
 Endotoxin level where relevant
o Monitoring of system performance, storage and distribution systems
o Records of results, and action taken
o Validated sanitization procedure followed on a routine basis

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 WATER QUALITY SPECIFICATIONS
o Drinking water / potable water
o Purified water (PW)
o Highly Purified Water (HPW)
o Water for Injection (WFI)

Drinking water / potable water

o Must comply with specification (WHO, ISO and national or regional
agencies) – regular testing needed
o Supplied under continuous positive pressure
o Defect free plumbing system to prevent contamination

o Could be from public water supply system or natural sources

o Natural sources could include springs, wells, rivers and lakes
o Treatment includes softening, ion removal, particle reduction,
antimicrobial treatment 5
Purified Water (PW)
o Prepared from potable water source
o Meet pharmacopoeia specification for chemical and microbial purity
o Protected from recontamination
o Protected from microbial proliferation

Highly Purified Water (HPW)

o Prepared from potable water source
o Specification only in the European Pharmacopoeia
o Same quality standard as WFI including limit for endotoxins, but
treatment method considered less reliable than distillation
o Prepared by combination of methods including reverse osmosis (RO),
ultrafiltration (UF) and deionization (DI)

Water for Injections (WFI)

o Prepared from potable water source
o WFI is not sterile
o WFI is not a final dosage form
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 WATER PURIFICATION METHODS
o Manufacturer to select appropriate method of purification
o Appropriate sequence of purification steps
o Influenced by, e.g.
 Water quality specification
 Yield (efficiency) of the system
 Feed water quality
 Reliability and robustness of treatment system
 Supplier support, maintenance and operation costs

Water purification system considerations

o Leaching from contact materials
o Adsorption
o Hygienic and sanitary design
o Corrosion resistance
o Leakage
o Proliferation of microbiological organisms
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 PRODUCTION OF DRINKING WATER
o Derived from raw water (e.g. well, river, reservoir)
o Processes may include:
 Filtration, softening
 Disinfection or sanitization
 Iron (ferrous) removal
 Precipitation
 Inorganic / organic reduction

o Storage tanks
 Closed, with protected vents
 Allows visual inspection, draining and sanitization

o Care to prevent and control microbiological contamination of sand

filters, carbon beds, water softeners
 Back-flushing, chemical or thermal sanitization and frequent
regeneration, continuous waterflow

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 PRODUCTION OF PURIFIED WATER (PW)
o Use appropriate, qualified methods for production

o Methods use for production of PW

 Distillation
 Ion exchange
 Ultra filtration
 Reverse Osmosis

PRODUCTION OF HIGHLY PURIFIED WATER (HPW)

o Use appropriate, qualified methods for production
o Appropriate sequence of techniques
o As for PW
o Processes may include:
 Ion exchange
 Ultra filtration
 Reverse Osmosis
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PRODUCTION OF WATER FOR INJECTIONS (WFI)
o Pharmacopoeia requires distillation as preferred technique for final
purification step

o Factors to consider:

 Feed water quality

 Required water quality specification

 Optimum generator sizing (prevent frequent start/stop)

 Cool-down venting (avoid contamination ingress)

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COMMISSIONING, QUALIFICATION AND OPERATION
CONSIDERATIONS

To discuss the operational considerations of water

systems including

 Start up, commissioning and qualification

 Monitoring

 Maintenance

 System reviews

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 START UP AND COMMISSIONING
o Should be planned, well defined, well documented
o Includes setting to work
o Includes system set-up
o Includes recording of system performance parameters

Qualification
o WPU,PW, HPW and WFI systems are "direct impact and quality critical systems“

o Therefore stages to be considered in qualification should include

 DQ: Design review influenced by source water and required water quality

 IQ: Installation verification of the system

 OQ: Operational qualification

 PQ: Consistent and reliable performance of the system

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Three phase approach recommended over extended period – proves
reliability and robustness

Phase 1
o A test period of 2-4 weeks – monitoring the system intensively

o System to operate continuously without failure or performance

deviation

o The following should be included in the testing approach

 Undertake chemical and microbiological testing in accordance
with a defined plan
o Sample daily
 incoming feed-water
 after each step in the purification process
 each point of use and at other defined sample points
o Develop
 appropriate operating ranges
 and finalize operating, cleaning, sanitizing and maintenance
procedures
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Phase 2
o A further test period of 2-4 weeks – further intensive monitoring the system

o Deploying all the refined SOPs after the satisfactory completion of phase 1

o Sampling scheme generally the same as in phase 1

o Demonstrate
 Consistent operation within established ranges
 Consistent production and delivery of water of the required quantity and
quality when the system is operated in accordance with the SOPs

Phase 3

o Over 1 year after the satisfactory completion of phase 2

o Water can be used for manufacturing purposes during this phase

o Demonstrate
 extended reliable performance
 Ensure that seasonal variations are evaluated
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 PURPOSE OF VALIDATION
o High quality of water – essential for manufacturing of pharmaceuticals

o Validation is defined as a documented program that provides a high degree of

assurance that a specific process, method, or system will consistently produce
a result meeting pre-determined acceptance criteria

o The purpose of validation is to demonstrate the capability of the water

treatment to continuously supply the required quantity of water with the
specified quality attributes

VALIDATION LIFE CYCLE

o Prove the performance of processes or systems under all conditions

o Validation involves proving

 Engineering design
 Operating procedures
 Acceptable ranges for control parameters
 Maintenance procedures 15
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 QUALIFICATION OF WATER SYSTEMS
o Quality of water and Selection of water for pharmaceutical use

o DQ of water systems

o Qualification of equipments and component for water systems

o Sanitization

Control of organic impurity

Control of inorganic impurity

Microbial quality of water

 Microbial counts
 Endotoxin counts

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 QUALIFICATION OF EQUIPMENT AND COMPONENT
FOR WATER SYSTEM
o Equipment and components used for the water system must maintain integrity
and be anticorrosive and assured for technical integrity
o Piping – Stainless steel
Cleaning for removing contaminants
o Material – Compatible with material use for sanitizing and cleaning purpose
o Valves
o Pumps – Cleanable pumps, centrifugal pumps, rotary lobe pumps, peristaltic
pumps and diaphragm pumps
o Pressure gauges
o Heat exchangers
o Distillation equipment
o Filters
o Deionizers
o Ultraviolet light

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 SANITIZATION

o Microbial control in water system is achieved primarily through

sanitization practices

o Systems can be sanitized using

 Thermal or
 Chemical means

Thermal Approach

o Thermal approaches to system sanitization include periodic or

continuously circulating hot water and the use of steam

o Limited to system compatible with higher temperature

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Chemical method

o Chemical methods, where compatible, can be used on a wider variety

of construction materials

o Oxidizing agents

 Hydrogen peroxide

 Ozone

 Per-acetic acid

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 VALIDATION OF SANITIZATION STEPS
o Sanitization steps require validation to demonstrate the capability of
reducing and holding microbial contamination at acceptable levels

o Validation of thermal methods should include a heat distribution

study to demonstrate that sanitization temperatures are achieved
throughout the system

o Validation of chemical methods requires a demonstration of

adequate chemical concentrations throughout the system

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 SYSTEM MONITORING
o After phase 3 – system review needed
o Based on review including results, establish a routine monitoring plan
o Monitoring to include a combination of on-line monitoring and off-
line sample testing
Online monitoring includes
 Flow
 Pressure
 Temperature
 Conductivity
 Total organic carbon
Offline sample testing includes
 Physical attributes
 Chemical attributes
 Microbial attributes

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 MAINTENANCE OF WATER SYSTEMS

A controlled, documented maintenance programme 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

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 SYSTEM REVIEWS
o WPU (PW, HPW and WFI) systems to be reviewed at appropriate
regular intervals
o Review team includes engineering, QA, operations and maintenance

o The review should consider matters such as:

 Changes made since the last review;
 System performance;
 Reliability;
 Quality trends;
 Failure events;
 Investigations;
 Out-of-specifications results from monitoring;
 Changes to the installation;
 Updated installation documentation;
 Log books; and
 The status of the current SOP list.

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 INSPECTION OF WATER SYSTEMS
o WPU (PW, HPW and WFI) systems are likely to be the subject of
regulatory inspection from time to time

o Users should consider conducting routine audit and self-inspection of

established water systems

o WPU inspection and audit includes

 Sampling and monitoring plan
 Setting of monitoring and action level
 Monitoring results and evaluation of trends
 Review of any changes made to the system since the last audit
 Review of maintenance, failure and repair logs
 Checking calibration and standardization of critical instruments

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