JENOPTIK Group.Thai FDAj Presentation 08.04.05
Technical Challenges and Solutions to Pharmaceutical Water System Testing during
Validation and Operation
Technical Challenges and Solutions to Pharmaceutical Water System Testing during
Validation and Operation
September 2005
Presented by Mark Suparat Tang, Ph.D.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Purpose of the Pharmaceutical Water SystemThai 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.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System Guidelines and Regulations
Regulations and GuidelinesThai FDA Ministry of Public Health, FDAU.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 908-4PIC/S Guide 3.10, PI 009-1, Aide Memoire: Inspection
of Utilities
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Pharmaceutical Water Specification
United States Pharmacopoeia 24-28 (USP 24-28)
Purified Water (PW) Water For Injection (WFI)
Conductivity < 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
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
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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 % RemovalHeterotropic Plate Count < 500 CFU / mLTurbidity < 5 NTU (< 1 NTU)Disinfectant Byproducts (Chorine, Bromite, HaloaceticAcids, Trihalomethanes) 0.01, 1.0, 0.06, 0.10 mg/L
Disinfectants (Choramines, Chlorine, Chlorine Dioxide) 4.0, 4.0, 0.80 mg/LInorganic 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 1 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 1 mg/L)
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System Design Specification
Key Design Parameters1. Construction Materials: PVC, SS304,
SS316
2. 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 Parameters1. 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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System Design Specification
Quality Control Testing1. 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
Qualification1. Drawings with All Sampling Points
2. Operation Parameters
3. Maintenance Program
4. Cleaning Parameters
5. Change Control
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Pharmaceutical Water System: Plant Overview
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Pharmaceutical Water System: Key Components and Functions
Typical Components1. 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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Pre-Treatment of Raw Water
Source Water Pre-TreatmentMultimedia Filter – Activated Carbon removes Heavy
Metals and Organic Compounds
Multimedia Filter
Water Softener/Anti-Scaling
Bisulfite / Base Pre-Treatment
Pre-RO Treatment Filtration
First Pass RO: 75 % Recovery
Second Pass RO: 75 % Recovery
Key ComponentsRaw Water Source
Multimedia Filter
Source Water Pre-Treatment1. Multimedia Filter – Removes Heavy Metals, Organic Compounds, General Turbidity
2. Water Softener / Anti-Scaling – Removes Hardness Ions (Calcium, Magnesium)
3. Biosulfite - Facilitates removal of Sulfate and Chlorine
4. Base Addition – Converts Carbon Dioxide to Carbonate
5. Pre-RO Treatment Filtration ( 5 Micron) – Gross particles/precipitate removal
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
Key ComponentsRaw Water Source
Multimedia Filter
Key ComponentsRaw Water Source
Multimedia Filter
Ion Removal1. First Pass Reverse Osmosis
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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Components and FunctionsStorage, Maintenance, Distribution
PW SystemPW 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
Key ComponentsRaw Water Source
Multimedia Filter
.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
Key ComponentsRaw Water Source
Multimedia Filter
.
PW Water Plant
WFI Distillation Plant
POD
POU(POC)
POE
User
POS…Point of supplyPOD…Point of deliveryPOC Point of connectionPOE Point of entryPOU…Point of use
Storage tankLoop pump
POS
POS
POD
POU(POC)
User
POE
Supply
Return
Storage, Maintenance, Distribution
WFI SystemSupply From PW System
Distillation Tank = 100 °C
PW Boiling to Purified Steam
Condensation to generate WFI
1. Maintenance at > 80 °C in Distribution Loop and User Points
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Test Points
Source Water Pre-TreatmentMultimedia Filter – Activated Carbon removes Heavy
Metals and Organic Compounds
Multimedia Filter
Water Softener/Anti-Scaling
Bisulfite / Base Pre-Treatment
Pre-RO Treatment Filtration
First Pass RO: 75 % Recovery
Second Pass RO: 75 % Recovery
Key ComponentsRaw Water Source
Multimedia Filter
Key Tests during Source Water Pre-Treatment Step1. Raw Water Source: Total Bioburden Level, Heavy Metals, Organics, Turbidity, pH,
Hardness Ions to ensure that the Pre-Treatment Step will not be overloaded.
2. After Multimedia Filter / Water Softener / Anti-Scaling – Turbidity, Hardness Ions (Calcium, Magnesium), Conductivity, pH, Total Bioburden Level
3. After Biosulfite 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
4. After Pre-RO Treatment Filtration ( 5 Micron) – Hardness to ensure no scaling of RO System and Conductivity and Total Bioburden Level
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Test Points
Key ComponentsRaw Water Source
Multimedia Filter
Key ComponentsRaw Water Source
Multimedia Filter
Key Tests during Ion Removal Process1. After First Pass RO = DI Water – Conductivity, Hardness, Chloride, pH,
Total Bioburden Level.
2. After Second Pass RO and/or EDI = PW Water – Conductivity, Hardness, Chloride, Ammonia, Sulfate, Heavy Metal, pH, Total Bioburden Level, TOC.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Test Points
Key ComponentsRaw 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 System1. From Distillation Tank – Hardness,
Conductivity, TOC
2. Distribution Loop – Flow Velocity, Temp.
3. From All User Points - Conductivity, pH, Total Bioburden, TOC, Endotoxin Levels
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Tests for USP
Conductivity Test1. 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 ImmediateConductivity Measurement
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Tests for USP
Total Organic Carbon (TOC) Test2. 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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Key Tests for USP
pH, Total Bioburden, and Endotoxin Levels3. 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.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Keys Tests and Quality Relevant Parameters ConductivityTOCTemperaturepHOzone concentration
Should be monitored by In-Line Detectors andRecorded by data loggers on to paper or electronic
Pharmaceutical Water System: Data Monitoring and Tracking
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Qualification
Qualification: Commissioning and Validation1. 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.
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 JENOPTIK Group.
Pharmaceutical Water System: Summary
User Requirement Specification Definition is the KeyImportant 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
© M+W ZanderThai FDA Cleanroom Presentation 08.03.05 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 DevelopmentQuality Control Laboratory ManagerQuality Assurance Product Release AuditorQuality Assurance Vendor Auditor
Educational BackgroundPh.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