1) The document discusses validation of water systems for pharmaceutical use, including water quality specifications, purification methods, and commissioning, qualification, operation and maintenance of the systems. 2) It outlines various water grades including drinking water, purified water, highly purified water, and water for injections, and describes methods for producing each grade including distillation, ion exchange, ultrafiltration and reverse osmosis. 3) Validation of water systems aims to demonstrate the capability of the systems to consistently supply water meeting predetermined quality criteria through qualification testing over extended periods and under varying conditions.

1. 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
1

2. 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.
2

3. 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
3

4. 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
4

5. 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

6. 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
6

7. 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
7

8. 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
8

9. 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
9

10. 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)
10

11. COMMISSIONING, QUALIFICATION AND OPERATION
CONSIDERATIONS
To discuss the operational considerations of water
systems including
 Start up, commissioning and qualification
 Monitoring
 Maintenance
 System reviews
11

12. 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
12

13. 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
13

14. 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
14

15. 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

16. 16

17. 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
17

18. 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
18

19. 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
19

20. 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
20

21. 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
21

22. 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
22

23. 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
23

24. 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.
24

25. 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
25