VALIDATION OF WATER SUPPLY SYSTEM

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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
• 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

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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.

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INTRODUCTION

• Why purification?
• Although tap water is reasonably pure, it is
  always variable due to seasonal variations,
  regional variation in quality.
• One must remove impurities and control microbes
  to avoid contamination of products.
• 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

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DIFFERENT TECHNIQUES USED FOR WATER TREATMENT

• De-chlorination (Sodium Bisulphite, Carbon
  Filter)
• Filtration
• Ultra Filtration
• Softening
• Demineralization
• Reverse Osmosis
• UV Treatment
• Deionization
• Ozonization

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DIFFERENT EQUIPMENTS AND COMPONENTS FOR WATER
SYSTEM

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

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WATER STORAGE AND DISTRIBUTION CONSIDERATIONS

• Materials of Construction (Chemical and Heat
  Compatibility)
• Stainless Steel (316 or 316L)
• Teflon, Silicone, Viton (gaskets, diaphragms)
• Minimize Dead Legs (lt 2 pipe diameters)
• Smooth Surfaces (Mechanical Polish ,
  Electropolish)
• Clean joints (sanitary TriClamp, 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.)

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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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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-
• 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 steps-
• Determination 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 determined before starting the
  validation.
• Without defining required quality attributes, we
  cannot establish validation protocols.

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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-
• it identifies -process equipment
• -critical
  process parameters
• -product
  characteristics,
• -sampling,
• -test data
  to be collected,
• -number of
  validation runs
• -acceptable
  test results

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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 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 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
  PIDs.
• 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 PID
• 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

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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 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.

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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.

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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 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

• 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.

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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

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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
• 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.

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

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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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