VALIDATION OF WATER SUPPLY SYSTEM

MALIBA PHARMACY COLLEGE.

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CONTENTS
Objectives

Introduction
Validation & System Qualification

Monitoring
Maintenance Revalidation & Change control Validation documentation Summary
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OBJECTIVE
To understand:
1. 2. 3. 4. 5. 6.
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The need for water quality manual reason for usage of pharmaceutical water supply systems. The technical requirements for water supply systems. Different types of water supply systems. Validation requirements. Qualification & inspection requirement

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.

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INTRODUCTION
Why purification?
o Although tap water is reasonably pure, it is

always variable due to seasonal variations, 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.
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INTRODUCTION
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

Purposeseach type has its on characteristic for all parameters.

Potable water Purified water Water for injection(WFI) Sterile water for injection, inhalation, irrigation Sterile bacteriostatic water for injection

DIFFERENT TECHNIQUES USED FOR WATER TREATMENT

De-chlorination (Sodium Bisulphite,

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Carbon Filter) Filtration Ultra Filtration Softening Demineralization Reverse Osmosis UV Treatment Deionization Ozonization

DIFFERENT EQUIPMENTS AND COMPONENTS FOR WATER SYSTEM

Piping

Valves
Pumps Pressure gauges

Heat exchangers
Distillation unit Filters

Deionizers
Sensors
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Auxiliary equipment

WATER STORAGE AND DISTRIBUTION CONSIDERATIONS

Materials

of Construction (Chemical and Compatibility) Stainless Steel (316 or 316L) Teflon, Silicone, Viton (gaskets, diaphragms)

Heat

Minimize Dead Legs (<= 2 pipe diameters) Smooth Surfaces (Mechanical Polish , Electropolish) Clean joints (sanitary TriClamp, automatic orbital

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welding) Passivate interior surfaces to form barrier between water and free iron (0.5 to 1% alkali at 160F for 30 minutes followed by 1% Phosphoric Acid or Nitric Acid at 150F to 180 F for 10 minutes.)

Conti.
Design of the following should be appropriate to

prevent recontamination after treatmentVent filter Sanitary overflow Tank UV light Conical Bottom Steam sterilization

Combination of on-line (TOC, Conductivity meter etc.)

and off-line monitoring (lab testing by proper sampling) to ensure compliance with water specification
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VALIDATION CONCEPT
To prove the performance of processes or systems under

all conditions expected to be encountered during future operations. To prove the performance, one must demonstrate (document) that the processes or systems consistently produce the specified quantity and quality of water when operated and maintained according to specific written operating and maintenance procedures.
validation involves proving-

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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.

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WHY VALIDATION OF WATER SYSTEM?

Most widely used and sometimes most expensive

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ingredient Drug component even if not in product Generally reviewed in depth by Regulators Many recalls water related Always considered direct impact system To ensure reliable, consistent production of water of required quality To operate system within design capacity To prevent unacceptable microbial, chemical and physical contamination during production, storage and distribution To monitor system performance, storage and distribution systems

VALIDATION CYCLE:
It includes four major steps Determination of Quality Attributes
The Validation Protocol Steps of Validation

Control during routine operation

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DETERMINATION OF QUALITY ATTRIBUTES

The

quality attributes, is gaining a clear understanding of the required quality of water and its intended use

Should

be validation.

determined

before

starting

the

Without defining required quality attributes, we

cannot establish validation protocols.

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THE VALIDATION PROTOCOL

A written plan stating how validation will be

conducted and defining acceptance criteria for quality.

For example, the protocol for a manufacturing

process-

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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
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Conti

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ALERT AND ACTION LEVELS:

Alert and action levels are distinct from process

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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
Validation Master Plan User Requirement Specification Design Qualification Installation Qualification Operation Qualification Performance Qualification

Re- Qualification.

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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.

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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

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Calibration of measuring instruments

Collection and collation of supplier operating and working instructions and maintenance requirements

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.
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Conti
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.
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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.
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Conti
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 ).

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Conti

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.

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PERFORMANCE QUALIFICATION

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.

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Conti
According to the FDAs advice: The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent PQ studies of the process.

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Conti

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.

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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 2-4 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
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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

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Conti
Demonstrate production and delivery of water 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
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Phase 2(verification step)

A further test period of 2-4 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
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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.
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Phase 3
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
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MONITORING
Monitoring and feed back data are important in maintaining

the performance systems. Monitoring parameters include: Flow, pressure, temperature, conductivity, TOC
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 microbial

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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 determined.

MAINTENANCE
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

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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.

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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.

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VALIDATION REPORT
STANDARD FORMAT 1. 2. 3. 4.

Executive summary Discussion Conclusions & recommendation 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.

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Complete Documentation

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.

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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.

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REFERENCES
Validation in pharmaceutical industry ; edited by P.P.

sharma ;first edition 2007 ; 193-220

Pharmaceutical

Process Validation; An international 3rd edition; edited by R. A. Nash and A. H. Wachter; 401-442

Validation of Pharmaceutical Processes; by Agalloco

James, Carleton J.Fredrick; 3rd edition; 59-92.

"Pharmaceutical Process Validation", Drugs and Pharm

Sci. Series, Vol. 129, 3rd Ed., edited by B. T. Loftus & R. A. Nash, Marcel Dekker Inc., N.Y. Pg. No. 440-460.
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THANK YOU
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