technical proplems in pharamceutical water tủ tài liệu bách khoa

Technical Challenges and Solutions to Pharmaceutical Water System Testing during Validation and Operation Presented by Mark Suparat Tang, Ph.D September 2005 Thai FDAj Presentation 08.04.05 JENOPTIK Group Topics of the Presentation Pharmaceutical Water System „ Guidelines and Regulations: USP Specification and PIC/S and WHO Monitoring, Testing, and Validation Requirements for the Water System „ Design, Construction, Commissioning, and Operation „ Operation as a Critical Utility in the framework of the Validation Master Plan „ Testing and Monitoring for Commissioning, Validation, and Operation Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Purpose of the Pharmaceutical Water System Thai Ministry of Public Health Food and Drug Administration: Pharmaceutical products should be manufactured under the requirements of good manufacturing practices by licensed manufacturers with the object of ensuring that users will receive efficacious, safe and good quality products Good Manufacturing Practice (GMP): The overriding principle which governs the quality of every aspect of making a medicine „ Every action will only be undertaken by following written instructions and documentation „ All facilities and machinery are correct for the purpose and that they, and the environment in which they are situated, is properly cleaned and appropriately treated „ Raw materials must be stored and handled correctly and that exactly the right materials must be used at all times „ That people, both production workers and support staff, must dress and behave as required, be properly supervised and above all, be trained correctly „ That Quality Control is undertaken at every stage of the storage, handling, manufacturing and packing cycle Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System Guidelines and Regulations Regulations and Guidelines „ Thai FDA Ministry of Public Health, FDA „ U.S FDA 21 CFR Part 210, 211, U.S Pharmacopoeia, U.S EPA NPDWRs U.S FDA Guide to Inspection of Highly Purified Water Systems; Annex - 35, Annex 15 - 9,10 „ WHO Pharmaceutical Excipients, TRS 908-4 „ PIC/S Guide 3.10, PI 009-1, Aide Memoire: Inspection of Utilities Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water Specification United States Pharmacopoeia 24-28 (USP 24-28) Purified Water (PW) Water For Injection (WFI) < 1.3 µS/cm @ 25°C < 1.3 µS/cm @ 25°C pH 5.0 – 7.0 5.0 – 7.0 Total Organic Carbon (TOC) < 500 ppb < 500 ppb < 10,000 CFU / 100 mL < 10 CFU / 100 mL N/A < 0.25 Endotoxin Units/mL / 100 mL / 100 mL Conductivity Total Bioburden Endotoxin Coliform Level Source Water Thai FDA Cleanroom Presentation 08.03.05 U.S EPA National Primary Drinking Water Regulations © M+W Zander JENOPTIK Group Pharmaceutical Water Specification Source Water: U.S Environmental Protection Agency (U.S EPA) National Primary Drinking Water Regulations (NPDWRs) Crypto, Giardia, Virus 99 %, 99.9%, 99.99 % Removal Heterotropic Plate Count < 500 CFU / mL Turbidity < NTU (< NTU) Disinfectant Byproducts (Chorine, Bromite, Haloacetic Acids, Trihalomethanes) 0.01, 1.0, 0.06, 0.10 mg/L Disinfectants (Choramines, Chlorine, Chlorine Dioxide) 4.0, 4.0, 0.80 mg/L Inorganic Metals: Limits Apply (Abbreviated List: Arsenic 0.01 mg/L, Cadium 0.005 mg/L, Chromium 0.10 mg/L, Copper 1.3 mg/L, Lead 0.015 mg/L, Mercury 0.002 mg/L Nitrate 10 mg/L, Nitrite mg/L, Selenium 0.05 mg/L, Thalium 0.002 mg/L) Organic Compounds : Limits Apply (Abbreviated List: Benzene 0.005 mg/L, Benzo(a)pyrene (PAHs) 0.0002 mg/L, Carbon Tetrachloride 0.005 mg/L, Chlorobenzene 0.1 mg/L, DBCP 0.0002 mg/L, o-Chlorobenzene 0.6 mg/L, Dichloromethane 0.005 mg/L, Toluene mg/L) Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System Design Specification Key Design Parameters Key System Parameters Construction Materials: PVC, SS304, SS316 Water Quality Requirement Slope of Pipeworks Purification System: Multimedia bed, Softening, Akalinization, Double-pass RO, EDI, Distillation Water Recirculation Velocity and Temperature Sanitary Joints and Valves Draining/Flushing Sampling Ports Dead Legs Thai FDA Cleanroom Presentation 08.03.05 Feed Water Specification Distribution Loop – Temperature, Conductivity, TOC User Points Requirement Disinfection System: Ozone, UV, Heated and Chilled Water © M+W Zander JENOPTIK Group Pharmaceutical Water System Design Specification Quality Control Testing Qualification Testing Program Drawings with All Sampling Points Sampling Plan and Schedule Operation Parameters Testing Parameters and Limits Maintenance Program Microbial Cleaning Parameters TOC and Endotoxin Change Control Chemical, pH, Conductivity Water Temperature, Flow Velocity UV Intensity Ozone Levels Out-Of-Specification (OOS) Trend Analysis Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Plant Overview Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Components and Functions Typical Components Raw Water Source Multimedia Filter Water Softener/Anti-Scaling Bisulfite / Base Pre-Treatment Pre-RO Treatment Filtration First Pass RO: ~75 % Recovery Second Pass RO: ~75 % Recovery Electro De-Ionization (EDI) PUW Storage Tank 10 Ozone / UV Ozone Destruct 11 Distillation for WFI 12 Distribution Loop / User Points Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Pre-Treatment of Raw Water Key Components Raw Water Source Multimedia Filter Source Water Pre-Treatment Multimedia Filter – Activated Carbon removes Multimedia Filter – Removes Heavy Metals,Heavy Organic Compounds, General Turbidity Metals and Organic Compounds Water Softener / Anti-Scaling – Removes Hardness Ions (Calcium, Magnesium) Multimedia Filter Biosulfite - Facilitates removal of Sulfate and Chlorine Water Softener/Anti-Scaling Base Addition – Converts Carbon Dioxide to Carbonate Bisulfite / Base Pre-Treatment Pre-RO Treatment Filtration ( Micron) – Gross particles/precipitate removal Pre-RO Treatment Filtration First Pass RO: 75 % Recovery Second Pass RO: 75 % Recovery Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Components and Functions Key Components Raw Water Source Multimedia Filter Ion Removal Key Components Raw Water Source First Pass Reverse Osmosis Multimedia Filter Permeate from First Pass RO is “DI Water” With Optimal Recovery Settings, First Pass RO DI Water Conductivity should be < 50 µS/cm and Hardness should be < 20 ppm as Carbonate DI Water = Feed Water for Second Pass RO System Second Pass RO Water could be further treated with Electro De-Ionization (EDI) to generate USP PW Water PW Water Conductivity should be < 1.3 µS/cm and TOC Levels should be < 100 ppb Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Components and Functions Storage, Maintenance, Distribution Key Components Raw Water Source PW System Multimedia Filter „ PW PVDF/316L Storage Tank „ Ozone Generator – Microbial Destruct and TOC Destruct „ UV Ozone Destruct – Ozone conversion to Oxygen „ Distribution Loop and User Points „ Supply to WFI System Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Components and Functions User Key Components PW Water Plant Raw Water (POC) Source POS POU Multimedia Filter Storage, Maintenance, Distribution WFI System „ Supply From PW System POE „ Distillation Tank = 100 °C POD „ PW Boiling to Purified Steam „ Condensation to generate WFI User Return Maintenance at > 80 °C in Distribution Loop and User Points (POC) WFI Distillation Plant POU POS POE POD POS…Point of supply POD…Point of delivery Supply POC Point of connection POE Point of entry Storage tank Loop pump POU…Point of use Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter Source Water Pre-Treatment Key Tests during Source Water Pre-Treatment Step Multimedia Filter – Activated removes Raw Water Source: Total Carbon Bioburden Level, Heavy Heavy Metals, Organics, Turbidity, pH, Metals andIons Organic Compounds Hardness to ensure that the Pre-Treatment Step will not be overloaded Multimedia Filter After Multimedia Filter / Water Softener / Anti-Scaling – Turbidity, Hardness Ions (Calcium, Magnesium), Conductivity, pH, Total Bioburden Level Water Softener/Anti-Scaling After /Biosulfite and Base Addition – pH Level between 8.0 and 8.5 to ensure Bisulfite Base Pre-Treatment complete conversion of Carbon Dioxide to Carbonate for removal by First Pass RO Pre-RO Treatment Filtration After Pre-RO Treatment Filtration ( Micron) – Hardness to ensure no scaling of RO First Pass RO: % Recovery System and 75 Conductivity and Total Bioburden Level Second Pass RO: 75 % Recovery Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter Key Components Key Tests during Ion Removal Process Raw Water Source After First Pass RO = DI Water – Conductivity, Hardness, Chloride, pH, Multimedia Total Bioburden Level Filter After Second Pass RO and/or EDI = PW Water – Conductivity, Hardness, Chloride, Ammonia, Sulfate, Heavy Metal, pH, Total Bioburden Level, TOC Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter PW Water Storage, Maintenance, Distribution After PW Storage Tank – Ozone Levels UV Destruct – UV Levels After UV Ozone Destruct – Ozone Levels Distribution Loop – Flow Velocity From All User Points - Conductivity, pH, Total Bioburden, TOC WFI System From Distillation Tank – Hardness, Conductivity, TOC Distribution Loop – Flow Velocity, Temp Thai FDA Cleanroom Presentation 08.03.05 From All User Points - Conductivity, pH, Total Bioburden, TOC, Endotoxin Levels © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Tests for USP Conductivity Test Purpose: To measure residual ions in the PW/WFI Water that would be toxic for human ingestion or IM/IV injection or that could encourage Microbial growth „ Challenges: Exposure to Atmospheric Carbon Dioxide that dissolves in water to form Carbonic Acid that increase Conductivity necessitates In-line or Immediate Conductivity Measurement Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Tests for USP Total Organic Carbon (TOC) Test Total Organic Carbon: To measure any Microbial Growth in the PW/WFI Water System – Biofilm and to measure any resulting Carcinogenic Compounds (e.g Phenols) that would be toxic for human ingestion or IM/IV injection and to detect any potential Endotoxin build-up „ Potential Solutions: Pooling of Test Samples depending on the LOD and LOQ of the test, Alternate-Day or Weekly Testing during 28-Day Testing „ Potential Solutions: More frequent Ozone treatment to eliminate TOC with validated reduce testing schedule and plan Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Key Tests for USP pH, Total Bioburden, and Endotoxin Levels pH: To measure residual ions in the PW/WFI Water that could encourage Microbial growth Total Bioburden:To measure Microbial Growth in the PW/WFI Water System that will lead to increase TOC and Endotoxin levels Endotoxin Level Testing with LAL: To measure toxins resulting from cellular break down during and after Microbial Growth in the PW/WFI Water System that will lead to toxic shock if injected Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Data Monitoring and Tracking Keys Tests and Quality Relevant Parameters „ Conductivity „ TOC „ Temperature „ pH „ Ozone concentration Should be monitored by In-Line Detectors and Recorded by data loggers on to paper or electronic Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Qualification Qualification: Commissioning and Validation Validation Master Plan and Site Master Plan User Requirement Specification and Process and Instrumentation Diagram Direct Impact System Designation for Critical Utility System: Purified Water System GMP Review and Component Criticality Review = Design Qualification (DQ) System Construction Completion, Pre-Commissioning, Commissioning Dossier Installation Qualification (IQ) = After Pre-Commissioning, Vendor Validation Documentation Review, Installation Confirmation with P&ID Yellow-line Markup and System Walkdown Operation Qualification (OQ) = After IQ and Commissioning with PW Water Testing, Critical Operation and Functional Testing with PW Water Testing (Optional for 28Days) Performance Qualification (PQ) = After OQ, PW Water Testing for 28-Days from All Key Testing Points and User Points for All USP PW/WFI Tests Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group Pharmaceutical Water System: Summary User Requirement Specification Definition is the Key Important information about how to plan a new PW/WFI generation, storage and distribution system: „ Which quality and quantity I need at the points of use? „ At which temperatures I need the water? „ What kind of materials I want to use? „ Where can the system be installed? „ Define a piping and instrument standard for the project based on cGMP issues „ Foresee some kind of sanitization procedure „ What kind of automation I require? „ What kind of documentation is needed? „ Preventive Maintenance and spare parts „ Quality Partner and Contractor Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group About the Speaker – Mark Suparat Tang, Ph.D Professional Experience M+W Zander (Thailand) (10/2003 – Present) „ cGMP Quality Systems Specialist Alpha Therapeutic / Baxter (1/1998 – 10/2003) „ Senior Principal Scientist and Project Manager for Alpha-1 Anti-trypsin • • • „ „ „ „ FDA Technical Issues for Drug Approval and Licensing Yield and Quality Improvement Cleaning Validation and Process Validation Senior Principal Scientist – Research and Development Quality Control Laboratory Manager Quality Assurance Product Release Auditor Quality Assurance Vendor Auditor Educational Background Ph.D in Biochemistry and Pharmacology (1997) „ University of Pennsylvania School of Medicine Department of Pharmacology Post-doctoral Research Fellow (1/1997- 12/1997) „ California Institute of Technology Department of Chemical Engineering Thai FDA Cleanroom Presentation 08.03.05 © M+W Zander JENOPTIK Group  ... Microbial Growth in the PW/WFI Water System that will lead to increase TOC and Endotoxin levels Endotoxin Level Testing with LAL: To measure toxins resulting from cellular break down during and after... Pharmaceutical Water System Design Specification Quality Control Testing Qualification Testing Program Drawings with All Sampling Points Sampling Plan and Schedule Operation Parameters Testing Parameters... Multimedia bed, Softening, Akalinization, Double-pass RO, EDI, Distillation Water Recirculation Velocity and Temperature Sanitary Joints and Valves Draining/Flushing Sampling Ports Dead Legs Thai