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.

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
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TYPES OF WATER
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

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

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DIFFERENT EQUIPMENTS
AND COMPONENTS FOR
Piping
WATER SYSTEM
Valves

Pumps
Pressure gauges
Heat exchangers
Distillation unit
Filters
Deionizers
Sensors
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Auxiliary equipment

WATER STORAGE AND

Materials of Construction (Chemical and Heat Compatibility)
DISTRIBUTION
Stainless Steel (316 or 316L)
Teflon, Silicone, Viton (gaskets, diaphragms)
CONSIDERATIONS
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 160F for 30 minutes followed by

1% Phosphoric Acid or Nitric Acid at 150F to 180 F for 10
minutes.)

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Conti.
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

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 To prove the performance

of processes or systems under all
VALIDATION
CONCEPT

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-

1. Engineering design
2.Operating procedures and acceptable ranges for control
parameters
3. Maintenance procedures to accomplish it
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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

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
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VALIDATION CYCLE:
It includes four major stepsDetermination 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
A written plan stating how validation will
PROTOCOL
conducted and defining acceptance criteria
quality.

be
for

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
ACTION
Alert and AND
action levels
are distinct
parameters and product specifications.
LEVELS:

from process

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.
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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
Calibration of measuring instruments
Collection and collation of supplier operating and
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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

installation.
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include details of completed

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
Definition : The purpose of OQ is to establish, through
QUALIFICATION

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 ChecksAbility

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
performance systems. Monitoring parameters include:

Monitoring and feed back data are important in maintaining the

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.
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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. 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.

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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

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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.

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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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