VALIDATION OF
WATER SUPPLY SYSTEM
MALIBA PHARMACY COLLEGE.
1
CONTENTS
 Objectives
 Introduction
 Validation & System Qualification
 Monitoring
 Maintenance
 Revalidation & Change control
 Validation documentation
 Summary
2
OBJECTIVE
To understand:
1.
2.
3.
4.
5.
6.
3
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.
4
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.
5
INTRODUCTION
Quality of water should be specific for product
quality.
Water contains,

Organic and inorganic impurities

Microbial contamination

Endotoxin

Particulate contamination
6
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
7
8
9
DIFFERENT TECHNIQUES USED FOR
WATER TREATMENT
 De-chlorination (Sodium Bisulphite,
10
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
11
 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 Tri®Clamp, automatic orbital
12
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….
 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
13
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-
14
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.
15
WHY VALIDATION OF WATER SYSTEM?
 Most widely used and sometimes most expensive








16
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
17
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.
18
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-
19
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
20
Conti…
21
ALERT AND ACTION LEVELS:
 Alert and action levels are distinct from process




22
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.
23
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.
24
INSTALLATION QUALIFICATION
IQ is in the form of checklist and it should include-
25

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…
 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.
26
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.
27
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.
28
Conti…
Operation Qualification Checks-
29

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 ).
Conti…
30

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.
PERFORMANCE QUALIFICATION
31

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.
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.”
32
Conti…
33

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
 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
34
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
35
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
36
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
37
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.
38
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
39
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
40
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
maintenance
41
review of problems and faults during
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.
43
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.
44
VALIDATION REPORT
 STANDARD FORMAT
1.
2.
3.
4.



45
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.
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.
46
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.
47
REFERENCES
 “Validation in pharmaceutical industry” ; edited by P.P.
sharma ;first edition 2007 ; 193-220
Process Validation”; An international 3rd
edition; edited by R. A. Nash and A. H. Wachter; 401-442
 “Pharmaceutical
 “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.
48
THANK YOU
49