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

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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

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Pharmaceutical Water System Guidelines and Regulations

Regulations and Guidelines
Thai FDA U.S. FDA Ministry of Public Health, 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 PIC/S Pharmaceutical Excipients, TRS 908-4 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) Conductivity pH Total Organic Carbon (TOC) Total Bioburden Endotoxin Coliform Level < 1.3 S/cm @ 25C 5.0 7.0 < 500 ppb < 10,000 CFU / 100 mL N/A 0 / 100 mL

Water For Injection (WFI) < 1.3 S/cm @ 25C 5.0 7.0 < 500 ppb < 10 CFU / 100 mL < 0.25 Endotoxin Units/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 Heterotropic Plate Count Turbidity Disinfectant Byproducts (Chorine, Bromite, Haloacetic Acids, Trihalomethanes) Disinfectants (Choramines, Chlorine, Chlorine Dioxide) 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 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)
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99 %, 99.9%, 99.99 % 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

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Pharmaceutical Water System Design Specification

Key Design Parameters
1. 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 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

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JENOPTIK Group.

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

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Pharmaceutical Water System: Plant Overview

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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
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Pharmaceutical Water System: Pre-Treatment of Raw Water

Key Components
Raw Water Source Multimedia Filter

Source Water Pre-Treatment

Multimedia Filter Activated Carbon removes Organic 1. Multimedia Filter Removes Heavy Metals,Heavy 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
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Pharmaceutical Water System: Key Components and Functions

Key Components
Raw Water Source Multimedia Filter

Ion Removal

Key Components

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 S/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 S/cm and TOC Levels should be < 100 ppb
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JENOPTIK Group.

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

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Pharmaceutical Water System: Key Components and Functions

Key Components
PW Water Plant Raw Water User (POC) POU POE POD

Storage, Maintenance, Distribution WFI System

Supply From PW System Distillation Tank = 100 C PW Boiling to Purified Steam Condensation to generate WFI

Source POS

Multimedia Filter

Return (POC) WFI Distillation Plant POS POE POD POSPoint of supply PODPoint of delivery Supply POC Point of connection POE Point of entry Storage tank Loop pump POUPoint of use

User

1. Maintenance at > 80 C in Distribution Loop and User Points

POU

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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 Bioburden Level, Heavy 1. Raw Water Source: Total Carbon removes Heavy Metals, Organics, Turbidity, pH, Metals and Organic Compounds Hardness Ions to ensure that the Pre-Treatment Step will not be overloaded. Multimedia Filter 2. After Multimedia Filter / Water Softener / Anti-Scaling Turbidity, Hardness Ions (Calcium, Magnesium), Conductivity, pH, Total Bioburden Level Water Softener/Anti-Scaling 3. After / Base Pre-Treatment Bisulfite 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 Pre-RO Treatment Filtration 4. After Pre-RO Treatment Filtration ( 5 Micron) Hardness to ensure no scaling of RO First Pass RO: 75 % Recovery Total Bioburden Level System and Conductivity and Second Pass RO: 75 % Recovery
Thai FDA Cleanroom Presentation 08.03.05

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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 1. After First Pass RO = DI Water Conductivity, Hardness, Chloride, pH, Multimedia Total Bioburden Level. Filter 2. 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

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
M+W Zander JENOPTIK Group.

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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

Thai FDA Cleanroom Presentation 08.03.05

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JENOPTIK Group.

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

Thai FDA Cleanroom Presentation 08.03.05

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JENOPTIK Group.

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.

Thai FDA Cleanroom Presentation 08.03.05

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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

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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 28Days) 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.

Thai FDA Cleanroom Presentation 08.03.05

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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 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
Thai FDA Cleanroom Presentation 08.03.05

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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.