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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)

< 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

< 10,000 CFU / 100 mL

< 10 CFU / 100 mL

N/A

< 0.25 Endotoxin Units/mL

0 / 100 mL

0 / 100 mL

Conductivity

Total Bioburden
Endotoxin
Coliform Level

Source Water

Thai FDA Cleanroom Presentation 08.03.05

U.S. EPA National Primary Drinking Water Regulations

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


Acids, Trihalomethanes)

0.01, 1.0, 0.06, 0.10 mg/L

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

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JENOPTIK Group.

Pharmaceutical Water System Design Specification


Key Design Parameters

Key System Parameters

1. Construction Materials: PVC, SS304,


SS316

1. Water Quality Requirement

2. Slope of Pipeworks

3. Purification System: Multimedia bed,


Softening, Akalinization, Double-pass
RO, EDI, Distillation

3. Water Recirculation Velocity and


Temperature
4. Sanitary Joints and Valves
5. Draining/Flushing
6. Sampling Ports
7. Dead Legs

Thai FDA Cleanroom Presentation 08.03.05

2. Feed Water Specification

4. Distribution Loop Temperature,


Conductivity, TOC
5. User Points Requirement
6. Disinfection System: Ozone, UV, Heated
and Chilled Water

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


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
Thai FDA Cleanroom Presentation 08.03.05

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
Filter
Activated
Carbon
removes
1.
Multimedia
Filter
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

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
Thai FDA Cleanroom Presentation 08.03.05

M+W Zander

JENOPTIK Group.

Pharmaceutical Water System: Key Components and Functions


Storage, Maintenance, Distribution

Key Components
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


User

Key Components
PW
Water
Plant
Raw
Water

(POC)

Source
POS

POU

Multimedia Filter

Storage, Maintenance, Distribution


WFI System
Supply From PW System

POE

Distillation Tank = 100 C

POD

PW Boiling to Purified Steam


Condensation to generate WFI
User

Return

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

(POC)
WFI Distillation Plant

POU

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

.
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
Water
Pre-Treatment
Key
Tests
during
Source Water Pre-Treatment Step
Multimedia
Filter
Activated
removes
1.
Raw Water
Source:
Total Carbon
Bioburden
Level, Heavy
Heavy Metals, Organics, Turbidity, pH,
Metals andIons
Organic
Compounds
Hardness
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 /Biosulfite
and Base Addition pH Level between 8.0 and 8.5 to ensure
Bisulfite
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:
% Recovery
System
and 75
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
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.

.
Thai FDA Cleanroom Presentation 08.03.05

3. From All User Points - Conductivity, pH,


Total Bioburden, TOC, Endotoxin Levels
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 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

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.

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