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 1 - 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)

Conductivity < 1.3 S/cm @ 25C < 1.3 S/cm @ 25C
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

Thai FDA Cleanroom Presentation 08.03.05 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 < 5 NTU (< 1 NTU)
Disinfectant Byproducts (Chorine, Bromite, Haloacetic
0.01, 1.0, 0.06, 0.10 mg/L
Acids, Trihalomethanes)
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 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)
Thai FDA Cleanroom Presentation 08.03.05 M+W Zander JENOPTIK Group.
Pharmaceutical Water System Design Specification
Key Design Parameters Key System Parameters
1. Construction Materials: PVC, SS304, 1. Water Quality Requirement
SS316 2. Feed Water Specification
2. Slope of Pipeworks 3. Purification System: Multimedia bed,
3. Water Recirculation Velocity and Softening, Akalinization, Double-pass
Temperature RO, EDI, Distillation
4. Sanitary Joints and Valves 4. Distribution Loop Temperature,
Conductivity, TOC
5. Draining/Flushing
5. User Points Requirement
6. Sampling Ports
6. Disinfection System: Ozone, UV, Heated
7. Dead Legs
and Chilled Water

Thai FDA Cleanroom Presentation 08.03.05 M+W Zander JENOPTIK Group.

Pharmaceutical Water System Design Specification
Quality Control Testing Qualification
1. Testing Program 1. Drawings with All Sampling Points
2. Sampling Plan and Schedule 2. Operation Parameters
3. Testing Parameters and Limits 3. Maintenance Program
1. Microbial 4. Cleaning Parameters
2. TOC and Endotoxin 5. Change Control
3. Chemical, pH, Conductivity
4. Water Temperature, Flow Velocity
5. UV Intensity
6. Ozone Levels
4. 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
Thai FDA Cleanroom Presentation 08.03.05
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
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
1. MultimediaFilter Activated
Filter Carbon
Removes removes
Heavy 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
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

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 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
Thai FDA Cleanroom Presentation 08.03.05 M+W Zander JENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
Key Components Storage, Maintenance, Distribution

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

Key Components User Storage, Maintenance, Distribution

(POC) WFI System
Raw
PW Water
Water Plant Source
POS POU

Multimedia Filter POE

Supply From PW System
POD Distillation Tank = 100 C
PW Boiling to Purified Steam
Condensation to generate WFI
1. Maintenance at > 80 C in
User
Return Distribution Loop and User Points
(POC)
WFI Distillation Plant POS POU

POE

POSPoint of supply POD

PODPoint of delivery
POC Point of connection Supply
POE Point of entry Storage tank
POUPoint of use Loop pump

.
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
Key Water
Tests Pre-Treatment
during Source Water Pre-Treatment Step
Multimedia
1. Filter
Raw Water Activated
Source: Total Carbon removes
Bioburden Level, Heavy
Heavy Metals, Organics, Turbidity, pH,
Metals andIons
Hardness Organic Compounds
to ensure that the Pre-Treatment Step will not be overloaded.
Multimedia
2. Filter
After Multimedia Filter / Water Softener / Anti-Scaling Turbidity, Hardness Ions
(Calcium,
Water Magnesium), Conductivity, pH, Total Bioburden Level
Softener/Anti-Scaling
3. After /Biosulfite
Bisulfite and Base Addition pH Level between 8.0 and 8.5 to ensure
Base Pre-Treatment
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:
System and 75 % Recovery
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
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 PW Water Storage, Maintenance,

Distribution
Raw Water Source
1. After PW Storage Tank Ozone Levels
Multimedia Filter
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
.
Thai FDA Cleanroom Presentation 08.03.05 M+W Zander JENOPTIK Group.
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 M+W Zander 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 M+W Zander 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 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
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.

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 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 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.