1. The need for water quality manual
2. reason for usage of pharmaceutical water
3. The technical requirements for water supply
4. Different types of water supply systems.
5. Validation requirements.
6. Qualification & inspection requirement
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.
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.
Quality of water should be specific for product
Organic and inorganic impurities
Low quality of water can lead to
loss of product and profit
TYPES OF WATER
Different grades of Water for Pharmaceutical
type has its on characteristic for all parameters.
Water for injection(WFI)
Sterile water for injection, inhalation, irrigation
Sterile bacteriostatic water for injection
DIFFERENT TECHNIQUES USED FOR
De-chlorination (Sodium Bisulphite,
DIFFERENT EQUIPMENTS AND
COMPONENTS FOR WATER SYSTEM
WATER STORAGE AND
DISTRIBUTION – CONSIDERATIONS
Materials of Construction (Chemical and Heat
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
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.)
Design of the following should be appropriate to
prevent recontamination after treatment-
Tank UV light
Combination of on-line (TOC, Conductivity meter etc.)
and off-line monitoring (lab testing by proper sampling)
to ensure compliance with water specification
To prove the performance of processes or systems under
all conditions expected to be encountered during future
To prove the performance, one must demonstrate
(document) that the processes or systems consistently
produce the specified qquuaannttiittyy aanndd qquuaalliittyy 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
3. Maintenance procedures to accomplish it
the system must be carefully,
-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
Most widely used and sometimes most expensive
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
To operate system within design capacity
To prevent unacceptable microbial, chemical and
physical contamination during production, storage
To monitor system performance, storage and
It includes four major steps-
Determination of Quality Attributes
The Validation Protocol
Steps of Validation
Control during routine operation
DETERMINATION OF QUALITY ATTRIBUTES
The quality attributes, is gaining a clear
understanding of the required quality of water and
its intended use
Should be determined before starting the
Without defining required quality attributes, we
cannot establish validation protocols.
THE VALIDATION PROTOCOL
A written plan stating how validation will be
ccoonndduucctteedd and defining aacccceeppttaannccee ccrriitteerriiaa for
For example, the protocol for a manufacturing
identifies -process equipment
-critical process parameters
-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
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
ALERT AND ACTION LEVELS:
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
Alert levels are levels or ranges that when exceeded
indicate that a process may have drifted from its normal
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.
Validation Master Plan
User Requirement Specification
DESIGN QUALIFICATION OF WATER SYSTEM
Based on the URS, supplier designs the equipment.
This is 1st step in the qualification of new water supply
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
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
Installation of system as per Design requirements.
Systematic range of adjustments, measurements
and tests should be carried out to ensure proper
Documentation include details of completed
• 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
Verification of Materials of construction.
Definition : The purpose of OQ is to establish, through
documented testing, that all critical components are
capable of operating within established limits and
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.
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 ).
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.
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
PQ verifies that over time, the critical
parameters, as defined in the DQ are being
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
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.
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
Chemical and microbiological testing should
include in accordance with a defined plan
Sample daily from-
after each step in the purification process
each point of use and at other defined sample
appropriate operating ranges
and finalize operating, cleaning, sanitizing
and maintenance procedures
Demonstrate production and delivery of water of
the required quality and quantity
Use and define the standard operating procedures
(SOPs) for operation, maintenance, sanitization
Verify provisional alert and action levels
Develop and define test-failure procedure
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
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.
Over 1 year after the satisfactory completion of
Water can be used for manufacturing purposes
during this phase
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 and feed back data are important in maintaining
the performance systems. Monitoring parameters include:
Flow, pressure, temperature, conductivity, TOC
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
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
A controlled, documented maintenance covering :
Defined frequency with plan and instructions
SOPs for tasks
Control of approved spares
Record and review of problems and faults during
System sanitization and bioburden control
Systems in place to control proliferation of microbes
Techniques for sanitizing or sterilization
Consideration already during design stage – then
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
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.
Written at the conclusion of the equipment IQ, OQ
and at completion of process validation.
Will serve as primary documentation for FDA
Will serve as reference document when changes to
the system are occurred and revalidation is needed.
1. Executive summary
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.
Verification of design documentation, including
◦ Description of installation and functions
◦ Specification of the requirements
Instructions for performance control
Training of personnel (program and records)
Inspection of plant
Finally certification (Sign Off) by Engineering,
User (Production) and QA Heads.
Water supply systems,
Play a major role in the quality of
Must be designed properly by professionals.
Must be validated as a critical system.
“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.