water validation

A Seminar On VALIDATION OF WATER SYSTEMS FOR PHARMACEUTICAL USE: 

A Seminar On VALIDATION OF WATER SYSTEMS FOR PHARMACEUTICAL USE Prepared By : Vinay B. Patel Harshal Thakkar DEPARTMENT OF QUALITY ASSURANCE SHRI SARVAJANIK PHARMACY COLLEGE MEHSANA, GUJARAT 9/14/2011 1

Introduction: 

Introduction Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health . Different grades of water quality are required depending on the route of administration of the pharmaceutical products. 9/14/2011 2

Principles: 

Principles Like any starting material, water must conform to Good Manufacturing Practice norms It must be “potable” and comply with WHO Guidelines for drinking-water quality Potential for microbial growth Systems must be properly validated Water for parenteral use could not be contaminated with pyrogens or endotoxins Specifications and periodic testing is required 9/14/2011 3

Types of water : 

Types of water Purified water Water for Injection s – PFW & WFI Softened Water Water for Final Rinse Pure, or clean Steam Water for cooling Autoclaves 9/14/2011 4

Why purify raw water?: 

Why purify raw water ? Although reasonably pure, it is always variable Seasonal variations may occur in water Some regions have very poor quality water Must remove impurities to prevent product contamination. Control microbes to avoid contaminating products 9/14/2011 5

Contaminants of water: 

Contaminants of water There is n o pure water in nature , as it can contain up to 90 possible unacceptable contaminants Contaminant groups: I norganic compounds Or ga n ic compounds Solids Gases Micro-organisms 9/14/2011 6

Problem Minerals : 

Problem Minerals Calcium and magnesium Iron and manganese Silicates Carbon dioxide Hydrogen sulfide Phosphates Copper Aluminium Heavy metals ( Arsenic, lead, cadmium) Nitrates 9/14/2011 7

Micro Organisms – Biofilm: 

Micro Organisms – Biofilm Algae Protozoa Cryptosporidium Giardia Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms 9/14/2011 8

Turbidity : 

Turbidity Silt , clay , and suspended material cause turbidity S mall particles include "colloids" Removal of colloids is usually the first step in water treatment 9/14/2011 9 Water hardness Water hardness classification m g/L or ppm as CaCO 3 Soft 0-60 Moderate 61-120 Hard 121-180 Very Hard > 180

Source of raw water: 

Source of raw water R ain water Surface or ground w ater W ell or borehole Municipal or civil – “tap water” Purchased in bulk 9/14/2011 10

Raw water storage: 

Raw water storage May be required prior to pre-treatment according to local circumstances Check material of construction Concrete, steel are acceptable but check corrosion Plastics or plastic linings may leach Check cover To keep out insects, birds and animals Check disinfection practices 9/14/2011 11

WHO water treatment guidance: 

WHO water treatment guidance The following should be monitored Sources of water Treatment procedures Water treatment equipment Treated water tests Monitoring records required 9/14/2011 12

Pre-treatment steps: 

Pre-treatment steps Primary filtration and m ulti-media filter Coagulation or flocculation Desalination Softening 9/14/2011 13

Chlorine removal Activated-carbon (AC) filtration or bisulphite: 

Chlorine removal Activated-carbon (AC) filtration or bisulphite AC removes chlorine but bacteria can then grow AC filtration can remove organic impurities Bisulphite leaves sulphate residues but is anti-microbial 9/14/2011 14

Slide 15: 

raw water in « S” trap to sewer Water is kept circulating To water softener & DI plant cartridge filter 5 micrometers activated carbon filter spray ball break tank air break to drain centrifugal pump air filter float operated valve sand filter excess water recycled from deioniser 9/14/2011 15

Water Softener – schematic drawing: 

Water Softener – schematic drawing brine and salt tank brine "hard" water in zeolite water softener exchanges Ca and Mg for Na drain "soft" water to deioniser by pass valve 9/14/2011 16

Water purification: 

Water purification Remove particles, bacteria, pyrogen , organic, inorganic ions and silica Reverse Osmosis raw water High pressure Feed water under pressure Reject water Semi-permeable membrane Permeate water drain or recycle Low pressure Purified water 9/14/2011 17

Deionization Remove organic, inorganic ions, silica and carbon dioxide: 

Deionization Remove organic, inorganic ions, silica and carbon dioxide Cationic column Anionic column Hygienic pump Outlets or storage. Ozone generator UV light HCl NaOH Eluates to neutralization plant Air break to sewer Drain line from water softener Water must be kept circulating 1 2 3 4 5 6 1 2 3 4 5 6 Return to de-ioniser Cartridge filter 5 µm Cartridge filter 1 µm 9/14/2011 18

Water purification: 

Water purification Distillation Remove particles, bacteria, pyrogen , organic, non-volatile, inorganic ions and silica for WFI Ultrafiltration Kill bacteria and breakdown TOC Can be used for WFI or for Water For Final Rinsing for parenteral manufacturing (if permitted) Removes organic contaminants , such as endotoxins Operation at 80°C , and sterilization at 121 °C 9/14/2011 19

Slide 20: 

Auto DI RO/Auto DI 2 stages RO Purified water 9/14/2011 20

Sampling: 

Sampling There must be a sampling procedure. Sample integrity must be assured. Sampler training Sample point Sample size Sample container Sample label Sample storage and transport Arrival at the laboratory Start of test 9/14/2011 21

Sampling Point: 

Sampling Point 9/14/2011 22

Testing - setting specifications for purified water: 

Testing - setting specifications for purified water 9/14/2011 23

Testing: 

Testing Method verification Chemical testing Microbiological testing test method types of media used incubation time and temperature objectionable and indicator organisms manufacturer must set specifications 9/14/2011 24

Water for Injections: 

Water for Injections International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens Usually prepared by distillation Storage t ime should be less than 24 hours Microbial limits must be specified 9/14/2011 25

Pyrogens and endotoxins: 

Pyrogens and endotoxins Any compound injected into mammals which gives rise to fever is a “ Pyrogen ” Endotoxins are pyrogenic , come from Gram negative b acterial cell wall fragments D etect endotoxins using a test for lipopolysaccharides (LPS) rabbit test detects pyrogens LAL test detects endotoxins U ltrafiltration , distillation, & RO may remove pyrogens 9/14/2011 26

Suggested bacterial limits (CFU /mL): 

Suggested bacterial limits (CFU / mL ) Sampling location Target Alert Action Raw water 200 300 500 Post multimedia filter 100 300 500 Post softener 100 300 500 Post activated carbon filter 50 300 500 Feed to RO 20 200 500 RO permeate 10 50 100 Points of Use 1 10 100 9/14/2011 27

WHO water treatment guidance : 

WHO water treatment guidance All water-treatment systems should be subject to: planned maintenance validation monitoring Maintenance work should be documented For reliable production, water treatment plants should be: Designed Constructed Maintained Operated within design limits Controlled to prevent microbial growth 9/14/2011 28

Prepare a checklist or an aide memoire and review: 

Prepare a checklist or an aide memoire and review Water Quality Manual Water system drawing Validation Sampling procedures, locations and plan Records of testing Sanitation and maintenance Schedules of maintenance 9/14/2011 29

Review water quality manual: 

Review water quality manual A water quality manual is advisable A brief description of water systems is required Include drawings of the purification, storage distribution system (P&ID) The water quality manual should show: 9/14/2011 30 pipelines non-return (or check) valves breather points couplings pipe slopes Velocities valves sampling points drain points Instrumentation flow rates

Validation plan for a water system : 

Validation plan for a water system Establishing standards for quality attributes and operating parameters. Defining systems and subsystems suitable to produce the desired quality attributes from the available source water. Selecting equipment, controls, and monitoring technologies. Developing an IQ stage consisting of instrument calibration, inspection to verify that the drawings accurately depict the as built configuration of the water system, and, where necessary, special tests to verify that the installation meets the design requirements . 9/14/2011 31

Slide 32: 

Developing an OQ stage consisting tests and inspection to verify that the equipment, system alerts, and controls are operating reliably and that appropriate alert and action levels are established. This phase of qualification may overlap with aspects of the next step. Developing a prospective PQ stage to confirm the appropriateness of critical parameter operating ranges. A concurrent or retrospective PQ is performed to demonstrate system reproducibility over an appropriate time period. During this phase of validation, Alert and action levels for key quality attributes and operating parameters are verified . 9/14/2011 32

Slide 33: 

Supplementing a validation maintenance program (also called continuous validation life cycle) that includes a mechanism to control changes to the water system and establishes and carries out scheduled preventive maintenance, including recalibration of instruments. In addition, validation maintenance includes a monitoring program for critical process parameters and a corrective action program. 9/14/2011 33

WATER SYSTEM VALIDATION LIFE CYCLE: 

WATER SYSTEM VALIDATION LIFE CYCLE 9/14/2011 34

WATER SYSTEM VALIDATION: 

WATER SYSTEM VALIDATION The operational considerations of water systems including: Start up, commissioning and qualification Monitoring Maintenance System reviews 9/14/2011 35

Start up and commissioning: 

Start up and commissioning Precursor to qualification and validation Should be planned, well defined, well documented Includes setting to work Includes system set-up Includes recording of system performance parameters Controls loop tuning 9/14/2011 36

Qualification: 

Qualification WPU, PW, HPW and WFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). DQ: Design review influenced by source water and required water quality IQ: Installation verification of the system OQ: operational qualification 9/14/2011 37

Performance Qualification (PQ): 

Performance Qualification (PQ) Presentation focusing on PQ PQ demonstrates consistent and reliable performance of the system Validation of water systems should consist of at least three phases: Phase 1: investigational phase; Phase 2: short-term control; and Phase 3: long-term control. 9/14/2011 38

Phase 1: 

Phase 1 A test period of 2–4 weeks - monitoring the system intensively System to operate continuously without failure or performance deviation The following should be included in the testing approach: Undertake chemical and microbiological testing in accordance with a defined plan Sample daily: incoming feed-water after each step in the purification process each point of use and at other defined sample points 9/14/2011 39

Phase 1: 

Phase 1 Develop: appropriate operating ranges and finalize operating, cleaning, sanitizing and maintenance procedures Demonstrate production and delivery of product water of the required quality and quantity Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting Verify provisional alert and action levels Develop and refine test-failure procedure 9/14/2011 40

Phase 2: 

Phase 2 A further test period of 2–4 weeks – further intensive monitoring the system Deploying all the refined 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 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 9/14/2011 41

Phase 3: 

Phase 3 Over one 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 9/14/2011 42

Ongoing system monitoring: 

Ongoing system monitoring After Phase 3 – system review needed Based on review including results, establish a routine monitoring plan Monitoring to include a combination of on-line monitoring and off- line sample testing Data analysed for trends Monitoring parameters to 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 9/14/2011 43

Maintenance: 

Maintenance 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 9/14/2011 44

System review: 

System review WPU (PW, HPW and WFI) systems to be reviewed at appropriate regular intervals Review team includes engineering, QA, operations and maintenance The review to cover, e.g. changes made since the last review; system performance; r eliability ; 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 s 45

Preventative Maintenance Program: 

Preventative Maintenance Program Pretreatment Component Example – Activated Carbon Unit Item Suggested Frequency Consequences Media Replacement 6 Months TOC and/or Chloramine Breakthrough Sanitize Column Internals 6 Months Microbial Excursion Replace Gaskets 2 Years Leak/Shutdown Access Gaskets 6 Months Leak/Shutdown Clean/Replace Distributors 1 Year Failure – Media in Product Water Instrument Calibration 1 Year Improper System Operation Replace Valve Diaphragms 2 Years Bypass/Cross Contamination 9/14/2011 46

Ion Removal Component Example – RO Unit: 

Ion Removal Component Example – RO Unit Item Suggested Frequency Consequences “Rotate RO Membranes” 6 Months Loss in Product Water Flow Rate and Quality (Chemical and TVB) Contract Clean Rotated Membranes 6 Months Loss in Product Water Flow Rate and Quality (Chemical and TVB) Chemical Sanitization 6 Months TVB Excursions Interconnector O-Rings 6 Months Waste-to-Product Leak End Fitting O-Rings 6 Months Waste-to-Product Leak Instrument Calibration 1 Year Loss of System Control Replace Interconnectors 1 Year Waste-to-Product Leak 9/14/2011 47

Slide 48: 

Item Suggested Frequency Consequences Replace Feed Water Pump Seals 2 Years Pump Leak – Introduction of Air/Water – TVB Increase Vale Seals/Diaphragms 2 Years Bypass Sanitize Pressure Vessels 6 Months TVB Excursions Change Prefilters 1 Week Foulant Increase Resulting in TVB Increase Hot Water Sanitize (if equipped) 2 Weeks TVB Excursions Replace “Rotated Membranes” 3 Years Loss in Product Water Flow Rate and Quality (Chemical and TVB) Repassivate 1-2 Years Rouging – Biofilm – TVB Increase Derouge & Repassivate 1-3 Years Rouging – Biofilm – TVB Increase Hot Water Sanitization 1 Week 1 Month TVB Excursions Chemical Sanitization 6 Months Biofilm – TVB Excursion 9/14/2011 48

Storage & Distribution Loop Example – USP Purified Water Storage Tank (No Ozone): 

Storage & Distribution Loop Example – USP Purified Water Storage Tank (No Ozone) Item Suggested Frequency Consequences Instrument Calibration 1 Year Loss of Level Control Inspect Rupture Disc 6 Months TVB Excursion Replace Rupture Disc 1 Year TVB Excursions Replace Hydrophobic Vent Filter Cartridge 6 Months TVB Excursion Inspect Tank Interior 6 Months Rouging/Biofilm Replace Manway Gasket 1 Year TVB Excursion/Leak 9/14/2011 49

REFERENCE : 

REFERENCE WHO good manufacturing practices: water for pharmaceutical use. Geneva, World Health Organization 2005 (WHO Technical Report Series, No. 929), Annex 3. WHO Expert Committee on Specifications for Pharmaceutical Preparations . Geneva, World Health Organization 2006 (WHO Technical Report Series, No. 937), Annex 4. 9/14/2011 50

Slide 51: 

9/14/2011 51 Thank You