validation of water system for pharmaceutical use
TRANSCRIPT
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VALIDATION OF WATER SYSTEM FOR PHARMACEUTICAL USE
o Introduction
o Water system requirements
o Water quality specifications
o Water purification methods
o Commissioning, qualification, operation and maintenance
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INTRODUCTION
o Information on Water for Pharmaceutical Use (WPU)
o Quality of water for APIs, finished products, etc.
o GMP for design, installation, operation of systems
o Supplementary to general GMP guidelines
o See also other guidelines, pharmacopoeia, etc.
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BACKGROUND TO WATER REQUIREMENTS AND USEo Water is the most widely used substance / raw materialo Used in production, processing, formulation, cleaning, quality
controlo Unique chemical properties
Able to dissolve, absorb, adsorb, suspend compounds and contaminants
o Different grades of water quality available
o Control quality of water Production Storage and distribution
o Contaminants, microbial and chemical qualityo Microbial contamination risk and concern
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WATER SYSTEM REQUIREMENTSo Design, installation, commissioning, qualification / validation, operation,
performance and maintenance to ensure reliable, consistent production of water of required quality
o Operate within design capacityo Prevent unacceptable microbial, chemical and physical contamination
during production, storage and distributiono Quality Assurance involved in approval of use after installation and
maintenance work
o Monitoring of water sources regularly Chemical and microbiological Endotoxin level where relevant
o Monitoring of system performance, storage and distribution systems
o Records of results, and action taken
o Validated sanitization procedure followed on a routine basis
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WATER QUALITY SPECIFICATIONSo Drinking water / potable watero Purified water (PW)o Highly Purified Water (HPW)o Water for Injection (WFI)
Drinking water / potable water
o Must comply with specification (WHO, ISO and national or regional agencies) – regular testing needed
o Supplied under continuous positive pressure
o Defect free plumbing system to prevent contamination
o Could be from public water supply system or natural sources
o Natural sources could include springs, wells, rivers and lakes
o Treatment includes softening, ion removal, particle reduction,
antimicrobial treatment
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Purified Water (PW)
o Prepared from potable water sourceo Meet pharmacopoeia specification for chemical and microbial purityo Protected from recontaminationo Protected from microbial proliferation
Highly Purified Water (HPW)
o Prepared from potable water sourceo Specification only in the European Pharmacopoeiao Same quality standard as WFI including limit for endotoxins, but
treatment method considered less reliable than distillationo Prepared by combination of methods including reverse osmosis (RO),
ultrafiltration (UF) and deionization (DI)
Water for Injections (WFI)o Prepared from potable water sourceo WFI is not sterileo WFI is not a final dosage form
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WATER PURIFICATION METHODSo Manufacturer to select appropriate method of purificationo Appropriate sequence of purification stepso Influenced by, e.g.
Water quality specification Yield (efficiency) of the system Feed water quality Reliability and robustness of treatment system Supplier support, maintenance and operation costs
Water purification system considerationso Leaching from contact materialso Adsorptiono Hygienic and sanitary designo Corrosion resistanceo Leakageo Proliferation of microbiological organisms
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PRODUCTION OF DRINKING WATERo Derived from raw water (e.g. well, river, reservoir)
o Processes may include: Filtration, softening Disinfection or sanitization Iron (ferrous) removal Precipitation Inorganic / organic reduction
o Storage tanks Closed, with protected vents Allows visual inspection, draining and sanitization
o Care to prevent and control microbiological contamination of sand filters, carbon beds, water softeners Back-flushing, chemical or thermal sanitization and frequent
regeneration, continuous waterflow
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PRODUCTION OF PURIFIED WATER (PW)o Use appropriate, qualified methods for production
o Methods use for production of PW Distillation Ion exchange Ultra filtration Reverse Osmosis
PRODUCTION OF HIGHLY PURIFIED WATER (HPW)o Use appropriate, qualified methods for productiono Appropriate sequence of techniqueso As for PWo Processes may include:
Ion exchange Ultra filtration Reverse Osmosis
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PRODUCTION OF WATER FOR INJECTIONS (WFI)
o Pharmacopoeia requires distillation as preferred technique for final purification step
o Factors to consider:
Feed water quality
Required water quality specification
Optimum generator sizing (prevent frequent start/stop)
Cool-down venting (avoid contamination ingress)
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COMMISSIONING, QUALIFICATION AND OPERATION CONSIDERATIONS
To discuss the operational considerations of water systems including
Start up, commissioning and qualification
Monitoring
Maintenance
System reviews
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START UP AND COMMISSIONINGo Should be planned, well defined, well documented
o Includes setting to work
o Includes system set-up
o Includes recording of system performance parameters
Qualificationo WPU,PW, HPW and WFI systems are "direct impact and quality critical systems“
o Therefore stages to be considered in qualification should include
DQ: Design review influenced by source water and required water quality
IQ: Installation verification of the system
OQ: Operational qualification
PQ: Consistent and reliable performance of the system
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Three phase approach recommended over extended period – proves reliability and robustness
Phase 1 o A test period of 2-4 weeks – monitoring the system intensively
o System to operate continuously without failure or performance deviation
o The following should be included in the testing approachUndertake chemical and microbiological testing in accordance
with a defined plano Sample daily
incoming feed-waterafter each step in the purification processeach point of use and at other defined sample points
o Developappropriate operating ranges
and finalize operating, cleaning, sanitizing and maintenance procedures
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Phase 2o A further test period of 2-4 weeks – further intensive monitoring the system
o Deploying all the refined SOPs after the satisfactory completion of phase 1
o Sampling scheme generally the same as in phase 1
o Demonstrate Consistent operation within established ranges Consistent production and delivery of water of the required quantity and
quality when the system is operated in accordance with the SOPs
Phase 3
o Over 1 year after the satisfactory completion of phase 2
o Water can be used for manufacturing purposes during this phase
o Demonstrate extended reliable performance Ensure that seasonal variations are evaluated
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PURPOSE OF VALIDATIONo High quality of water – essential for manufacturing of pharmaceuticals
o Validation is defined as a documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria
o The purpose of validation is to demonstrate the capability of the water treatment to continuously supply the required quantity of water with the specified quality attributes
VALIDATION LIFE CYCLEo Prove the performance of processes or systems under all conditions
o Validation involves proving Engineering design Operating procedures Acceptable ranges for control parameters Maintenance procedures
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QUALIFICATION OF WATER SYSTEMS
o Quality of water and Selection of water for pharmaceutical use
o DQ of water systems
o Qualification of equipments and component for water systems
o Sanitization
Control of organic impurity
Control of inorganic impurity
Microbial quality of water Microbial counts Endotoxin counts
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QUALIFICATION OF EQUIPMENT AND COMPONENT FOR WATER SYSTEM
o Equipment and components used for the water system must maintain integrity and be anticorrosive and assured for technical integrity
o Piping – Stainless steel Cleaning for removing contaminants
o Material – Compatible with material use for sanitizing and cleaning purposeo Valveso Pumps – Cleanable pumps, centrifugal pumps, rotary lobe pumps, peristaltic
pumps and diaphragm pumps o Pressure gaugeso Heat exchangerso Distillation equipmento Filterso Deionizerso Ultraviolet light
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SANITIZATION
o Microbial control in water system is achieved primarily through sanitization practices
o Systems can be sanitized using Thermal or Chemical means
Thermal Approach
o Thermal approaches to system sanitization include periodic or continuously circulating hot water and the use of steam
o Limited to system compatible with higher temperature
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Chemical method
o Chemical methods, where compatible, can be used on a wider variety of construction materials
o Oxidizing agents
Hydrogen peroxide
Ozone
Per-acetic acid
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VALIDATION OF SANITIZATION STEPS
o Sanitization steps require validation to demonstrate the capability of reducing and holding microbial contamination at acceptable levels
o Validation of thermal methods should include a heat distribution study to demonstrate that sanitization temperatures are achieved throughout the system
o Validation of chemical methods requires a demonstration of adequate chemical concentrations throughout the system
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SYSTEM MONITORING
o After phase 3 – system review neededo Based on review including results, establish a routine monitoring plano Monitoring to include a combination of on-line monitoring and off-
line sample testingOnline monitoring includes
Flow Pressure Temperature Conductivity Total organic carbon
Offline sample testing includes Physical attributes Chemical attributes Microbial attributes
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MAINTENANCE OF WATER SYSTEMS
A controlled, documented maintenance programme 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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SYSTEM REVIEWSo WPU (PW, HPW and WFI) systems to be reviewed at appropriate
regular intervals
o Review team includes engineering, QA, operations and maintenance
o The review should consider matters such as: Changes made since the last review; System performance; Reliability; Quality trends; Failure events; Investigations; Out-of-specifications results from monitoring; Changes to the installation; Updated installation documentation; Log books; and The status of the current SOP list.
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INSPECTION OF WATER SYSTEMS
o WPU (PW, HPW and WFI) systems are likely to be the subject of regulatory inspection from time to time
o Users should consider conducting routine audit and self-inspection of established water systems
o WPU inspection and audit includes Sampling and monitoring plan Setting of monitoring and action level Monitoring results and evaluation of trends Review of any changes made to the system since the last audit Review of maintenance, failure and repair logs Checking calibration and standardization of critical instruments