J ENOPTIK 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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.
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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, Cadium0.005 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,
Thalium0.002 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
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 J oints 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Plant Overview
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Pre-Treatment of Raw Water
Source Water Pre-Treatment
Multimedia 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 Components
Raw Water Source
Multimedia Filter
Source Water Pre-Treatment
1. 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
Key Components
Raw Water Source
Multimedia Filter
Key Components
Raw Water Source
Multimedia Filter
Ion Removal
1. 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 S/cmand Hardness should be < 20 ppmas 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/cmand TOC Levels should be <100
ppb
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
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
Key Components
Raw Water Source
Multimedia Filter
.
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Key Components and Functions
Key Components
Raw Water Source
Multimedia Filter
.
PW Water Plant
WFI Distillation Plant
POD
POU
(POC)
POE
User
POSPoint of supply
PODPoint of delivery
POC Point of connection
POE Point of entry
POUPoint of use
Storage tank
Loop pump
POS
POS
POD
POU
(POC)
User
POE
Supply
Return
Storage, Maintenance, Distribution
WFI System
Supply 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Key Test Points
Source Water Pre-Treatment
Multimedia 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 Components
Raw Water Source
Multimedia Filter
Key Tests during Source Water Pre-Treatment Step
1. 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
Pharmaceutical Water System: Key Test Points
Key Components
Raw Water Source
Multimedia Filter
Key Components
Raw Water Source
Multimedia Filter
Key Tests during Ion Removal Process
1. 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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 Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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 Biofilmand 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 Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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.
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK Group.
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
Pharmaceutical Water System: Data Monitoring and Tracking
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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.
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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
M+W Zander Thai FDA Cleanroom Presentation 08.03.05 J ENOPTIK 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