Technical Challenges and Solutions to Pharmaceutical Water System Testing during Validation and Operation

Transcription

1 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

2 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

3 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.

4 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 1-35, Annex 15-9,10 WHO Pharmaceutical Excipients, TRS PIC/S Guide 3.10, PI 009-1, Aide Memoire: Inspection of Utilities

5 Pharmaceutical Water Specification United States Pharmacopoeia (USP 24-28) Purified Water (PW) Water For Injection (WFI) Conductivity < C < C ph Total Organic Carbon (TOC) < 500 ppb < 500 ppb Total Bioburden < 10,000 CFU / 100 ml < 10 CFU / 100 ml Endotoxin N/A < 0.25 Endotoxin Units/mL Coliform Level 0 / 100 ml 0 / 100 ml Source Water U.S. EPA National Primary Drinking Water Regulations

6 Pharmaceutical Water Specification Source Water: U.S. Environmental Protection Agency (U.S. EPA) National Primary Drinking Water Regulations (NPDWRs) Crypto, Giardia, Virus Heterotropic Plate Count Turbidity Disinfectant Byproducts (Chorine, Bromite, Haloacetic Acids, Trihalomethanes) Disinfectants (Choramines, Chlorine, Chlorine Dioxide) Inorganic Metals: Limits Apply 99 %, 99.9%, % Removal < 500 CFU / ml < 5 NTU (< 1 NTU) 0.01, 1.0, 0.06, 0.10 mg/l 4.0, 4.0, 0.80 mg/l (Abbreviated List: Arsenic 0.01 mg/l, Cadium mg/l, Chromium 0.10 mg/l, Copper 1.3 mg/l, Lead mg/l, Mercury mg/l Nitrate 10 mg/l, Nitrite 1 mg/l, Selenium 0.05 mg/l, Thalium mg/l) Organic Compounds : Limits Apply (Abbreviated List: Benzene mg/l, Benzo(a)pyrene (PAHs) mg/l, Carbon Tetrachloride mg/l, Chlorobenzene 0.1 mg/l, DBCP mg/l, o-chlorobenzene 0.6 mg/l, Dichloromethane mg/l, Toluene 1 mg/l)

7 Pharmaceutical Water System Design Specification Key Design Parameters 1. Construction Materials: PVC, SS304, SS Slope of Pipeworks 3. Water Recirculation Velocity and Temperature 4. Sanitary Joints and Valves 5. Draining/Flushing 6. Sampling Ports 7. Dead Legs Key System Parameters 1. Water Quality Requirement 2. Feed Water Specification 3. Purification System: Multimedia bed, Softening, Akalinization, Double-pass RO, EDI, Distillation 4. Distribution Loop Temperature, Conductivity, TOC 5. User Points Requirement 6. Disinfection System: Ozone, UV, Heated and Chilled Water

8 Pharmaceutical Water System Design Specification Quality Control Testing 1. Testing Program 2. Sampling Plan and Schedule 3. Testing Parameters and Limits 1. Microbial 2. TOC and Endotoxin 3. Chemical, ph, Conductivity 4. Water Temperature, Flow Velocity 5. UV Intensity 6. Ozone Levels 4. Out-Of-Specification (OOS) Trend Analysis Qualification 1. Drawings with All Sampling Points 2. Operation Parameters 3. Maintenance Program 4. Cleaning Parameters 5. Change Control

9 Pharmaceutical Water System: Plant Overview

10 Pharmaceutical Water System: Key Components and Functions Typical Components 1. Raw Water Source 2. Multimedia Filter 3. Water Softener/Anti-Scaling 4. Bisulfite / Base Pre-Treatment 5. Pre-RO Treatment Filtration 6. First Pass RO: ~75 % Recovery 7. Second Pass RO: ~75 % Recovery 8. Electro De-Ionization (EDI) 9. PUW Storage Tank 10.Ozone / UV Ozone Destruct 11.Distillation for WFI 12.Distribution Loop / User Points

11 Pharmaceutical Water System: Pre-Treatment of Raw Water Key Components Raw Water Source Multimedia Filter Source Water Pre-Treatment 1. Multimedia Filter Filter Activated Removes Carbon Heavy removes Metals, Heavy Organic Compounds, General Turbidity Metals and Organic Compounds 2. Water Softener / Anti-Scaling Removes Hardness Ions (Calcium, Magnesium) Multimedia Filter 3. Biosulfite - Facilitates removal of Sulfate and Chlorine Water Softener/Anti-Scaling 4. Base Addition Converts Carbon Dioxide to Carbonate Bisulfite / Base Pre-Treatment 5. Pre-RO Treatment Filtration ( 5 Micron) Gross particles/precipitate removal Pre-RO Treatment Filtration First Pass RO: 75 % Recovery Second Pass RO: 75 % Recovery

12 Pharmaceutical Water System: Key Components and Functions Key Components Raw Water Source Multimedia Filter Key Components Ion Removal Raw Water Source 1. First Pass Reverse Osmosis Multimedia Filter 2. Permeate from First Pass RO is DI Water. 3. With Optimal Recovery Settings, First Pass RO DI Water Conductivity should be < 50 µs/cm and Hardness should be < 20 ppm as Carbonate 4. DI Water = Feed Water for Second Pass RO System 5. Second Pass RO Water could be further treated with Electro De-Ionization (EDI) to generate USP PW Water. 6. PW Water Conductivity should be < 1.3 µs/cm and TOC Levels should be < 100 ppb

13 Pharmaceutical Water System: Key Components and Functions Key Components Raw Water Source Multimedia Filter Storage, Maintenance, Distribution PW System 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.

14 Pharmaceutical Water System: Key Components and Functions Key Components PW Raw Water Water Plant Source Multimedia Filter POS POD User (POC) POU POE Storage, Maintenance, Distribution WFI System Supply From PW System Distillation Tank = 100 C PW Boiling to Purified Steam Condensation to generate WFI Return User 1. Maintenance at > 80 C in Distribution Loop and User Points WFI Distillation Plant POS (POC) POU POE POS Point of supply POD POD Point of delivery POC Point of connection POE Point of entry POU Point of use Storage tank Loop pump Supply.

15 Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter Key Source Tests Water during Pre-Treatment Source Water Pre-Treatment Step 1. Multimedia Raw Water Filter Source: Activated Total Carbon Bioburden removes Level, Heavy Metals, Organics, Turbidity, ph, Hardness Metals and Ions Organic to ensure Compounds that the Pre-Treatment Step will not be overloaded. 2. Multimedia After Multimedia Filter Filter / Water Softener / Anti-Scaling Turbidity, Hardness Ions Water (Calcium, Softener/Anti-Scaling Magnesium), Conductivity, ph, Total Bioburden Level 3. Bisulfite After / Biosulfite Base Pre-Treatment and Base Addition ph Level between 8.0 and 8.5 to ensure complete conversion of Carbon Dioxide to Carbonate for removal by First Pass RO Pre-RO Treatment Filtration 4. After Pre-RO Treatment Filtration ( 5 Micron) Hardness to ensure no scaling of RO First System Pass RO: and 75 Conductivity % Recovery and Total Bioburden Level Second Pass RO: 75 % Recovery

16 Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter Key Components Key Tests during Ion Removal Process Raw Water Source 1. After First Pass RO = DI Water Conductivity, Hardness, Chloride, ph, Total Bioburden Multimedia Level. Filter 2. After Second Pass RO and/or EDI = PW Water Conductivity, Hardness, Chloride, Ammonia, Sulfate, Heavy Metal, ph, Total Bioburden Level, TOC.

17 Pharmaceutical Water System: Key Test Points Key Components Raw Water Source Multimedia Filter. PW Water Storage, Maintenance, Distribution 1. After PW Storage Tank Ozone Levels 2. UV Destruct UV Levels 3. After UV Ozone Destruct Ozone Levels 4. Distribution Loop Flow Velocity 5. From All User Points - Conductivity, ph, Total Bioburden, TOC WFI System 1. From Distillation Tank Hardness, Conductivity, TOC 2. Distribution Loop Flow Velocity, Temp. 3. From All User Points - Conductivity, ph, Total Bioburden, TOC, Endotoxin Levels

18 Pharmaceutical Water System: Key Tests for USP Conductivity Test 1. 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

19 Pharmaceutical Water System: Key Tests for USP Total Organic Carbon (TOC) Test 2. 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

20 Pharmaceutical Water System: Key Tests for USP ph, Total Bioburden, and Endotoxin Levels 3. ph: To measure residual ions in the PW/WFI Water that could encourage Microbial growth 4. Total Bioburden:To measure Microbial Growth in the PW/WFI Water System that will lead to increase TOC and Endotoxin levels. 5. 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.

21 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

22 Pharmaceutical Water System: Qualification Qualification: Commissioning and Validation 1. Validation Master Plan and Site Master Plan 2. User Requirement Specification and Process and Instrumentation Diagram 3. Direct Impact System Designation for Critical Utility System: Purified Water System 4. GMP Review and Component Criticality Review = Design Qualification (DQ) 5. System Construction Completion, Pre-Commissioning, Commissioning Dossier 6. Installation Qualification (IQ) = After Pre-Commissioning, Vendor Validation Documentation Review, Installation Confirmation with P&ID Yellow-line Markup and System Walkdown 7. Operation Qualification (OQ) = After IQ and Commissioning with PW Water Testing, Critical Operation and Functional Testing with PW Water Testing (Optional for 28- Days) 8. 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.

23 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 do I need at the points of use? At which temperatures do I need the water? What kind of materials do 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 do I require? What kind of documentation is needed? Preventive Maintenance and spare parts Quality Partner and Contractor

24 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/ /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) California Institute of Technology Department of Chemical Engineering