Validation of Water

System
Prepared and presented by: Zubiya Shah and Sukanya Patil

Guided by: Dr Jaya Agnihotri

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CONTENTS:
1. INTRODUCTION
2. VALIDATION AND ITS APPROACHES
3. PURPOSE OF VALIDATION
4. GRADES OF WATER
5. SPECIFICATIONS OF WATER FOR PHARMACETICAL USE
6. SELECTION OF WATER FOR PHARMACETICAL USE
7. WATER PURIFICATION TECHNIQUES
8. VALIDATION LIFE CYCLE
9. STEPS OF VALIDATION
10. REFERENCE

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Introduction:
Water is a component of every pharmaceutical product, so water system must be
validated to ensure the consistent production of high quality water. The
pharmaceutical industry places a high priority on the quality of water used in
production of finished product, intermediate reagent preparation & analytical
processes & especially in case of parenteral products where quality of water must be
as per Pharmacopoeia. In present scenario the quality of pharmaceutical water is
maintained by setting a good pharmaceutical water system and this system
encompasses system design qualification, attention of the regulatory requirements
which are updated time to time. The continuous monitoring of water system is an
unequivocal regulatory requirements and a major cost strain on company personnel
and resources. Proper water system planning with personnel knowledge in all the
physical, chemical, engineering and microbiology issues associated with water is
essential. Proper pharmaceutical water system must 1. Achieve & maintain
compliance with pharmacopoeia requirements. 2. Have proper sampling system from
correct points with appropriate frequency. 3. Troubleshoot common contamination
problems. 4. Consistently produce water that meets industry standards for quality. 3
Validation and its approaches:
An eloquent but very serviceable definition was given in the FDA Guidelines on
Sterile Drug Products by Aseptic Processing (1987). It is a documented evidence
which provides a high degree of assurance that a specific process will consistently
produce a product meeting its predetermined specifications and quality attributes".
In essence, validation seeks experimentally obtained answers to: Does the process or
device do what it is intended to do? If so, for how long does it do it? For water
systems, defines validation as ensuring that the particular system will consistently
produce water of predictable quality when operated in the prescribed manner.
In common words validation involves proving,
• Engineering design
• Operating procedures and acceptable ranges for control parameters
• Maintenance procedures
To achieve this, the system must be sensibly designed, installed, and tested during
and after construction, and therefore for a prolonged period of time under all
conditions. There are two main basic approaches to validation:
i. Depending on evidence obtained through testing: Prospective and Concurrent
validation
ii. Depending on the analysis of accumulated data: Retrospective validation 4
Purpose of Validation:
 High quality water essential in the manufacturing of Pharmaceuticals.
 Most commonly used raw material.

Because it is used in:

1. Manufacturing of all dosage forms also for cleaning equpiments.
2. Major component for injectable products.
3. As a solvent in processing formulation and manufacture of pharmaceutical
product, API’s, analytical reagents.
 Therefore it plays a major role in manufacturing of pharmaceutical whether it
remains in the final prepared dosage form or is eliminated during the
manufacturing process.
THEREFORE IS AN IMPORTANT FACTOR IN GMP AND IN VALIDATING THE
MANUFACTURING PROCESS 5
Grades of water:
Major differences among grades of water consist following quality attributes:
Microbial counts, Endotoxin, which is due to the presence of microbes, Organic
and inorganic impurities.
Grades of water specified in the compendia (USP) are classified according to the
above quality attributes as:
1. Potable water
2. Purified water
3. Water for injection
4. Sterile water for injection
5. Sterile water for inhalation
6. Sterile water for irrigation
7. Sterile bacteriostatic water for injection. 6
Specifications of water for
pharmaceutical use:

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Selection of water for pharmaceutical use:

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Validation Life Cycle:-
1. Determination of Quality Attributes:
The quality attributes can be defined as gaining a clear understanding of the
required quality and intended use— most important issue-should be determined
before starting the validation. Without defining required quality attributes we
cannot establish validation protocols, which are the basis of all validation studies.

2. The Validation Protocol:

A written plan stating how validation will be conducted and defining acceptance
criteria.

The validation protocol is a detailed plan for conducting a validation study. It is

drafted by the individual or task group responsible for the project, reviewed for
content and completeness following the firm’s protocol review procedure, and
approved by designated individuals. It describes the responsibilities of each
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individual or unit involved in the project.
3. Steps of Validation:
A sequence of steps is involved in the validation of the pharmaceutical water
system. Traditionally these steps are identified as,

• Design Qualification ( DQ )
• Installation Qualification ( IQ )
• Operational Qualification ( OQ )
• Performance Qualification ( PQ )
The final validated condition is a sum total of the proceeding qualification. It
is necessary that the efficacy and proof of the tests trials and experiments be
performed successfully at least three consecutive times to constitute positive
conformation satisfactory to the FDA validation requirement.

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1) Design Qualification ( DQ )
It involves equipment validation. It is derived from the requirements of the
water purification process. With a water system, this generally means that the
quality of the water will minimally meet either US pharmacopeia (USP) Purified
Water or Water- for injection specification, depending on its usage. It is the
design documents that set the standards and goals of the hardware. The Design
Qualification will list the activities necessary to the consistent production of
the stipulated grade of water. It will contain a full description of the system
specifying its acceptable operating ranges and limits. It will supply full
schematics of the electrical, mechanical, and water flows for subsequent
verification of their proper installation. It will identify the specific purification
units, the various control devices, and the safety and alarm systems, which will
specify sampling plans and ports for chemical and microbial testing, stipulate
sanitizing methods, and define procedures for the analysis and plotting of data.
DQ is prepared according to the URS (Users Requirement Specifications) and
pharmacopeial standards.

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The various components of water generation systems that need to be validated
include the following:
COMPONENT DESIRED FEATURES/FUNCTIONS

Selected material: stainless steel; should be designed for reliability, pressure control,
Piping
nullifying presence of extractable contaminants.

Optimal size/capacity: 2000-4000 gallons, Hydrophobic air filters- restrict entrance of

Holding Tanks
microbes in tanks.
Valves Generally used types: Gate, Ball, Butterfly and Diaphragm.
Removes undissolved solids and bacterial contaminants
Filters Control measures: Pressure and flow monitoring, backwashing, sanitizing and
replacing the filter media etc.

Deionizers and
Removes dissolved solids, resins must be periodically regenerated.
Reverse Osmosis

Removes organic chlorine compounds and low molecular weight carbon compounds,
Carbon Beds required design features:
selection of proper particle size, avoidance of hydraulic channeling etc.
Biocidal wavelength: 254 nm; UV dose variables: lamp intensity, residence time
UV Lights
distribution and water transmittance should be properly measured.
Deactivates bacterial endotoxins and removes dissolved solids not otherwise removed
Distillation Still
by RO units and deionizers.
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Ozone and Heat Sterilant Strong oxidizing agent, effective at low concentration. Both are used as biocidal.
2) Installation Qualification ( IQ )
The IQ protocol will consist of a system description followed by a standard operation
procedure section. Before the operational characteristics of the system can be
investigated, the proper installation and assembly of the various components of
equipment require verification. This follows a careful check that each piece of
equipment ordered and received is identical with that stipulated in the system
design. The installation qualification confirms the "as- built” drawings, and ensures
the suitability of the complete system.
 
As stated in the FDA guidelines –“This phase of validation includes examination of
equipment design; determination of calibrations, maintenance, and adjustment
requirements; and identifying critical features that could affect the process and
product. Information obtained from these studies should be used to establish written
procedures covering equipment calibration, maintenance, monitoring, and control."
 
For an IQ of water generation system, the following would typical key elements.
Utilities requiring verifications includes, compressed air, steam, feed water and
electricity. Each elements should be checked at the time of installation of
equipment for water generation systems. 13
3) Operational Qualification ( OQ )
When installation of the equipment assemblage has been verified as being correct,
it becomes possible to undertake the OQ documentation of the system. The
purpose of OQ is to establish, a documented evidence through system 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
generation system provides acceptable operational control under "at-rest"
conditions.
 
Operation Qualification checks the ability of water purification system to provide
water of sufficient quantity along with high degree of quality to ensure the
achievement of specifications, to maintain general parameters like pressure,
temperature, flow at set points, to maintain any critical parameters (pH, TOC,
endotoxin, microbial level, conductivity etc.) ,includes the tests that have been
developed from knowledge of processes, equipment system, and tests include a
condition or a set of conditions with lower operating limits, sometimes referred to
as `worst case' conditions.
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4) Performance Qualification ( PQ )
The purpose of the PQ protocol is to provide a rigorous testing to demonstrate the
reproducibility and effectiveness of the total integrated system. The system's set
points, control sequences, and operating parameters are probed. The process is
challenged repeatedly to prove its consistent performance. All the acceptance
criteria are to be met under "worst-case" process conditions. When failures occur
they should be identified and corrected. Tests should be re-run to vouch for the
elimination of the causes of failure. Consistency of acceptable product water quality
is sought.
 
The purpose of PQ is to verify, prove and document that water generation system
provides acceptable control under
`Full Operational' conditions. PQ should follow successful completion of IQ and OQ.
 
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.” 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
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another.
 QUALIFICATION PHASES: Three phase approach recommended according to
WHO Technical Report Series 929 to prove heftiness and reliability.
 
(i) Phase I: This requires a testing period of 2 - 4 weeks for monitoring enactment
deviation. Periodic sampling along with testing at predetermined assay tests are
performed on the samples as per the defined plan. This phase also involves the
development of appropriate operating ranges along with the completion of
cleaning, sanitizing and maintenance procedures. At the end of this phase, systems
are simulated to perform under stress conditions such as start-up after power
failure or emergency halts. The system is also tested under standard maintenance
restorations, filter changes, etc.

(ii) Phase II: This phase involves the same sampling scheme as in phase I. It should
include further monitoring of the system for a test period of 2 - 4 weeks. After the
completion of the phase I, all the refined SOPs are deployed. During this phase water
is utilized for manufacturing purpose. This step establishes that the system is under
control, within predetermined specifications. Testing at this phase also ensures
consistent production and delivery of water of required quantity with high degree of
quality when the system is operated in accordance with SOPs. 16
(iii) Phase III: This is a confirmatory step in which frequency and number of
sampling locations are less than the previous phases and proves that the
system exhibits prolonged reliable performance and is under control over an
extended period of time. It requires a duration of around one year after the
satisfactory end of phase II. During this phase, water can be used for
manufacturing purpose. Periodic deviations of the feed water are also
examined in this phase. This final phase should be commenced only after
satisfying the requirements mentioned in the protocols for phase I and II test.
In this phase, a complete microbiological and chemical analysis must be done
and results should be presented graphically using various computer
applications. A written, reviewed and approved complete validation report
should be prepared according to the firm procedures. Validation project is
considered only after the approval of final reports by appropriate authorities.

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4) Preventive Maintenance

This element is frequently considered to be the responsibility of the Site

Maintenance and Operations department and often is given a low priority
within an engineering design team. There is a clear requirement to keep a
facility in a state of qualification. A preventative maintenance program is an
essential component of a schedule of work to achieve this objective. The
Validation Master Plan must identify the need for this program and, hence to
flag its importance to the designers. The role of vendors and suppliers is very
important in this area. Operation and maintenance manuals should be
considered as a key part of the specification program. This activity should be
conducted during the design phase, and the documentation required should be
included in the requisition. The execution of a preventive maintenance
program can take on greater relevance within the pre commissioning and
commissioning phases demonstrating that, once qualified, a unit has been
maintained both in a proper manner and in accordance with the supplier's
instructions.

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5) Control during routine operation:-
 CHANGE CONTROL: A smoothly operating water system may undergo departures
for reasons other than alterations in its water supply. These are to be explained,
defined, and documented appropriately. Given water purification units such as
ion- exchange beds may become exhausted, RO membranes will require cleaning,
tanks and pipes may need re- sanitization, and so on. In general, the devices and
accoutrements constituting the system will periodically require such maintenance-
related activities as replenishment, refurbishing, cleaning, sanitization,
replacement, and renewal of different kinds. Furthermore, the various items will
require attention on different time schedules. The necessary system
documentation will, therefore, also include a body of information relating to the
proper maintenance of each piece of equipment. The relevant documentation
composes the standard maintenance procedures necessary to the system’s correct
handling.
 REVALIDATION: Revalidation and evaluation should be executed depending upon
the impact of the change on the water generation system. Routine monitoring and
examination will continue under the same condition as those that existed during
the original validation. Routine maintenance or replacement of parts should
provide a specific written procedure, which must be validated at the time of
initial validation. 19
 ALERT AND ACTION LEVEL: Alert and Action Levels. Validated and established
systems should be periodically monitored to confirm that they continue to
operate within their design specifications and consistently produce water or
air of acceptable quality. Monitored data may be compared to established
process parameters or product specifications. A refinement to the use of
process parameters and product specifications is the establishment of alert
and action levels, which signal a shift in process performance. Alert and
action levels are distinct from process parameters and product specifications
in that 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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Water Purification Techniques:
(1) DISTILLATION: Distillation is probably the oldest method of water purification.
Water is the first heated to the boiling point. The water vapor rises to a condenser
where cooling water lowers temperature, so the vapor is condensed, collected and
stored. Many contaminants remain behind in the boiling vessel. However, the
process has several.
(2) ION EXCHANGE: The ion exchange process percolates water through spherical,
porous bead resin materials (ion exchange resins). Ions in the water are exchanged
for other ions fixed to the beads. The two most common ion exchange methods are
softening and deionization. Softening is used primarily as a pretreatment method to
reduce water hardness before reverse osmosis (RO) processing. Deionization (DI)
beads exchange either hydrogen ions for cations or hydroxyl ions for anions.
(3) ACTIVATED CARBON: Activated carbon is made of organic material porous
particulates containing a maze of small pores, which account for the substance’s
highly developed surface. 1 g of activated carbon has a surface of up to 1000 m2 .
Activated carbon used in water purification is available in two forms, natural
activated carbon and synthetic activated carbon. 21
(4) ULTRAFILTRATION: A microporous membrane filter removes particles according to pore size.
By contrast, an UF membrane functions as a molecular sieve. It separates dissolved molecules on
the basis of their size – often reported as the “molecular weight” (both parameters are related,
but not always directly) – by passing a solution through an infinitesimally fine filter.
(5) REVERSE OSMOSIS: RO is the most economical method of removing 95-99% of all
contaminants. The pore structure of RO membranes is much tighter than that of UF membranes.
RO membranes are capable of rejecting practically all particles, bacteria and organics >200 Da
molecular weight (including pyrogens) at a rate close to 99%.
(6) ELIX ION EXCHANGE TECHNIQUE: This technology is a combination of electrodialysis and ion
exchange, resulting in a process which effectively deionizes water, while the ion exchange
resins are continuously regenerated by the electric current in the unit. This electrochemical
regeneration replaces the chemical regeneration of conventional ion exchange systems.
(7) ULTRAVIOLET RADIATION: UV radiation has been widely used as a germicidal treatment for
water. Mercury low-pressure UV lamps generate light at different wavelengths, including 185
and 254 nm. UV lamps with a regular quartz sleeve allow passage of 254 nm light. These lamps
are an effective means of sanitizing water. The adsorption of UV light by the DNA in the
microbial cells results in the inactivation of the microorganism
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REFERENCE:
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