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VALIDATION OF WATER SUPPLY

SYSTEM

MALIBA PHARMACY COLLEGE.

CONTENTS

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Objectives Introduction Validation & System Qualification Monitoring Maintenance Revalidation & Change control Validation documentation Summary

OBJECTIVE

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To understand:

1. The need for water quality manual 2. reason for usage of pharmaceutical water

supply systems.3. The technical requirements for water supply

systems.4. Different types of water supply systems.5. Validation requirements.6. Qualification & inspection requirement

INTRODUCTION

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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.

INTRODUCTION

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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.

INTRODUCTION

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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

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Different grades of Water for Pharmaceutical Purposes-

each 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

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DIFFERENT TECHNIQUES USED FOR WATER TREATMENT

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De-chlorination (Sodium Bisulphite, Carbon Filter)

FiltrationUltra FiltrationSofteningDemineralizationReverse OsmosisUV TreatmentDeionizationOzonization

DIFFERENT EQUIPMENTS AND COMPONENTS FOR WATER SYSTEM

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PipingValvesPumpsPressure gaugesHeat exchangersDistillation unitFiltersDeionizersSensorsAuxiliary equipment

WATER STORAGE AND DISTRIBUTION – CONSIDERATIONS

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

Minimize Dead Legs (<= 2 pipe diameters)

Smooth Surfaces (Mechanical Polish , Electropolish)

Clean joints (sanitary Tri®Clamp, automatic orbital welding) Passivate interior surfaces to form barrier between water and

free iron (0.5 to 1% alkali at 160ºF for 30 minutes followed by 1% Phosphoric Acid or Nitric Acid at 150ºF to 180º F for 10 minutes.)

Conti….

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Design of the following should be appropriate to prevent recontamination after treatment-

Vent 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

VALIDATION CONCEPT

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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 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..

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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.

WHY VALIDATION OF WATER SYSTEM?

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Most widely used and sometimes most expensive ingredient

Drug component even if not in productGenerally reviewed in depth by RegulatorsMany recalls water relatedAlways considered direct impact systemTo ensure reliable, consistent production of water of

required qualityTo operate system within design capacityTo prevent unacceptable microbial, chemical and

physical contamination during production, storage and distribution

To monitor system performance, storage and distribution systems

VALIDATION CYCLE:

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It includes four major steps-Determination of Quality Attributes

The Validation Protocol

Steps of Validation

Control during routine operation

DETERMINATION OF QUALITY ATTRIBUTES

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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.

THE VALIDATION PROTOCOL

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A written plan stating how validation will be conductedconducted and defining acceptance criteria acceptance criteria for 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

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Establishing standards for quality attributesDefining system and subsystemDesigning equipment, control, & monitoring

technologies Establishing standards for operating parametersDeveloping an IQ stage & OQ stageEstablishing alert and action levelsDeveloping a prospective PQ stageCompleting protocols and documenting each

steps

Conti…

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ALERT AND ACTION LEVELS:

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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

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Validation Master Plan

User Requirement Specification

Design Qualification

Installation Qualification

Operation Qualification

Performance Qualification

Re- Qualification.

DESIGN QUALIFICATION OF WATER SYSTEM

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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.

INSTALLATION QUALIFICATION

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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

Conti…

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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.

OPERATION QUALIFICATION

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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 FDA’s 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.

QUALIFICATION PHASES

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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 deviationChemical and microbiological testing should

include in accordance with a defined plan

Conti…

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Sample daily from-incoming feed-waterafter each step in the purification processeach point of use and at other defined sample

points

Develop:appropriate operating rangesand finalize operating, cleaning, sanitizing

and maintenance procedures

Conti…

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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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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 3Over 1 year after the satisfactory completion of phase 2Water can be used for manufacturing purposes during

this phaseDemonstrate:

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

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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 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

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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

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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.

VALIDATION REPORT

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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.

VALIDATION REPORT

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STANDARD FORMAT1. Executive summary2. Discussion3. Conclusions & recommendation4. 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 DocumentationVerification of design documentation, including

◦ Description of installation and functions◦ Specification of the requirements

Instructions for performance controlOperating proceduresMaintenance instructionsMaintenance recordsTraining of personnel (program and records)Environmental records Inspection of plant

Finally certification (Sign Off) by Engineering, User (Production) and QA Heads.

SUMMARY

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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.

REFERENCES

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“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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