5.M&W

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


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.


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


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


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)


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


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


Pharmaceutical Water System: Plant Overview


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


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




Multimedia Filter


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


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


Multimedia Filter

.




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


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


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




Multimedia Filter


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.




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


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



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



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.


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


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.


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


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

5.M&W

Documents

water temperature

water quality requirement

mgl nitrate

feed water specification

raw water source

water recirculation

water softenerantisca

w zander jenoptik group