Post on 22-Feb-2019
Parametric Release—An Industry Perspective
October 22, 2010
Mike Sadowski
Director Sterile Manufacture Support
Baxter Healthcare Corporation
Presentation Overview
1. Definitions of Parametric Release
2. History of Parametric Release of U.S. Moist Heat
Sterilized Drug Products and Device Products
3. Limitations and Shortcomings of the Sterility Test
4. Moist Heat Parametric Release Standards and
Guidance Documents
5. Essential Elements of a Parametric Release
Program: PDA Technical Report 30 (2010 Draft)
6. Other Sterilization Processes Suitable for Parametric
Release
2
3
Parametric Release – Europe Definition
− A system of release that gives the assurance that
product is of the intended quality based on information
collected during the manufacturing process and on the
compliance with specific GMP requirements related to
Parametric Release.
•(EU Annex 17, 2001)
US Parametric Release Definition
− A sterility assurance release program where
demonstrated control of the sterilization process
enables a firm to use defined critical process
controls, in lieu of the sterility test, to fulfill the
intent of 21CFR211.165(a) and 211.167(a).
•(US FDA Submission Guidance, 2010)
4
Global Parametric Release Definition
-A sterility release program that is founded upon effective
control, monitoring and documentation of a validated
sterile-product manufacturing process where sterility
release is based on demonstrated achievement of
critical operational parameters in lieu of end-product
sterility testing.
(PDA Technical Report No. 30—2010 Draft)
5
6
History of Parametric Release
-Moist Heat Sterilized Drug Products
• First Drug Parametric Release Submission in the United States in 1981
• Approval Granted in January, 1985, Prior to Issuance of Formal Guidance to the Industry
• The Initial Submission Served as the Model for Future Requirements
• FDA Compliance Policy Guide 7132a.13 issued in 1987
• No Further Parametric Release Approvals Until the mid-90’s
• FDA Submission Guidance (February, 2010)
• Updated FDA CPG—Expected in Q4, 2010??
History of Parametric Release
-Moist Heat Sterilized Medical Devices
510K Device Submission Approved in 1992
Reusable Product Line – ―Green‖ Initiative Sold to
Hospitals
Linens -- Including Gowns and Towels
Surgical Instruments in Steam-Permeable Metal Box
No Specific Guidance Available for Parametric Release
for Medical Devices at That Time
Strong Sterilization Science Approach Utilized
Parametric Release Was Essential to Support Business
Model
7
Current Baxter Parametric Release Locations
•Australia
•Canada*
•China
•Columbia
•Germany
•Ireland
•Spain
•Singapore
•United Kingdom
(Thetford)
•United States
*Manf. Locations: US and Canada
9
Sterility Test vs.
Parametric Release
10
Limitations of Sterility Test•Statistically Limited
– Detection Sensitivity (n = 20 samples)
Microorganism
Concentration
Probability of One Sterility
Test Positive
1.0 1.0
0.1 0.88
0.01 0.18
0.001 0.02
10-6 1.9 X 10-5
Note: The 20 Sample Sterility Test is only capable of detecting a
contamination rate of 0.01 (Equals SAL of 10-2 While 10-6 Required for Sterility)
only 18% of the time!
Additional Sterility Test Shortcomings
Limited Detection of Organisms
•Less than 1% of all microorganisms are culturable!
•Typically Employs SCD Broth at 20-25oC and FTM at 30-35oC for 14 Days
•All Organisms do not Grow at These Conditions
•Incubation Conditions (Temperature, Aerobic/Anaerobic, Gasses)
•Time Required for Visual Indication of Growth
•Test Medium (pH, Salt Content, Nutrients)
•State of the Organisms (i.e., Spores, Injured)
•Potential for False Positives
12
Secondary Support for Parametric Release
Primary Support: Best Demonstrated Scientific Practice
Sterility Test is Costly
• Multiple Product Samples from each Load
• Clean Room Validation Maintenance
• Specially Trained and Experienced Personnel
• Labor or Outsourcing Costs
• Media and Equipment Preparation
• High Product Inventories Required
• 14 Day Sterility Test ―Hold‖
• Product Cost
13
Moist Heat Sterilization Processes
Key Strengths That Support Adoption of Parametric Release
• Non-toxic and Less Expensive
• Universally Recognized (Typical Temp of 110oC to 121oC)
• Broad Spectrum Lethality (Molds, Yeasts, Bacteria/Spores,
Viruses)
• Oldest, Safest, Most Dependable Process
• Strong Relationship Between Physical/Biological
Measurements (i.e., FPHY and FBIO)
• Easily Controlled and Validated
• Preferred by Most Regulatory Bodies
Guidance Documents and Standards for Parametric Release of
Moist Heat Sterilized Products
US Documents
• FDA CPG 7132a.13: Parametric Release – Terminally
Heat Sterilized Drug Products (1987) –Revision in
Progress (2010)
• US Code of Federal Regulations 21 CFR 211.167
• FDA Guidance for Industry – Submission of
Documentation in Applications for Parametric Release of
Human and Veterinary Drug Products Terminally
Sterilized by Moist Heat Processes (2010)
• USP 33 <1222> Terminally Sterilized Pharmaceutical
Products—Parametric Release
14
Global Parametric Release Standards
and Guidance Documents
Guidance Documents and Standards for Parametric Release of Moist
Heat Sterilized Products
EU and Global Documents
• EU GMP Guidelines Annex 17—Parametric Release
(2002)
• PIC/S PI 005-3 Recommendation on Guidance on
Parametric Release (2007)
• European Medicines Agency – Guideline on Real Time
Release Testing (formerly Guideline on Parametric
Release) (Issued for comment in 2010)
15
Global Parametric Release Standards
and Guidance Documents
16
PDA Technical Report No. 30 (2010 Revision)
Title: Parametric Release of Pharmaceutical Products and Medical Devices Terminally Sterilized by Moist Heat
• Replaces TR No. 30; Issued in 1999
• Task Force/Reviewer Consists of Moist Heat Sterilization Experts
• Scientists and Engineers
• Industry, Pharmacopoeia Members, Regulators and Private Consultants
• China, Europe and United States
• Initiated in March 2007
• Addressing Comments in 2009/2010
• Expected Issuance in Q4 2010
PDA TR-30 Task Force Members and
Contributors
Task Force Members
Mike Sadowski, Baxter Healthcare(Task Force Chair)
Marion Andersen, BS SM, Fresenius Medical Care
Tom Berger, Ph.D., Hospira, Inc.
Steve Douglas, Hospira, Inc.
Julian Kay, GSK UK
Terry Munson, Parexel Consulting
Ronald J. Nekula, Sr., Bayer HealthCare
Dr. Radhakrishna Tirumalai, USP
Bob Tomaselli, Johnson & Johnson
Contributors
James P. Agalloco, Agalloco & Associates
Thomas Genova, Johnson & Johnson
Christopher Smalley, Wyeth
Russell Madsen, The Williamsburg Group
Brenda Uratani, FDA
John Metcalfe, CDER, FDA
Andrew Hopkins, MHRA
Marla Stevens-Riley, CDER, FDA
Dr. Steffen Prowe, Beuth-Hochschule fürTechnik, University for Applied Sciences
18
Introduction and Scope
• Updated to Present a Global and Science-based Perspective
• Many New Guidances and Standards Issued Since 1999 Across the Globe
• Content Strongly Influenced by FDA, USP, EP, PIC/S, and Annex 17
• Covers Pharmaceuticals, Biopharmaceuticals and Medical Devices that are Terminally Sterilized with Moist Heat
• Builds on the PDA TR No. 1 (General Moist Heat) Foundation—Companion Document
19
Elements of a Parametric Release Sterilization Program
Developed to Reduce the Risk of Manufacture
and Release of Non-Sterile Product
• Mature Quality System
• Successful History of Strong Compliance with
cGMP’s
Parametric Release Prerequisites
Sterility Assurance Program Built on the Foundation of a
Comprehensive and Mature Quality System
• Personnel Training
• Product Design Control
• Equipment and Facility Design and Qualification
• Process Development and Validation
• Manufacturing Control
• Quality Risk Management System
• Change Control System
Personnel
Education Background Includes Engineering and
Microbiology
Professional Experience in Sterilization Engineering and
Microbiology
Specific Documented Training in Moist Heat
Sterilization and Sterility Assurance
Sufficient Authority to Provide Oversight to Development,
Validation and Ongoing Control/Monitoring of the Sterility
Assurance Program
Validation Plans and Scientific Approach
Disposition of Product
Could be Two Individuals or One Individual Qualified in
Engineering and Microbiology Disciplines
Product Design Control
Designed to Ensure Efficient Sterilization and to Maintain
Sterile Barrier Properties Over the Product Shelf-Life
• Sterilization Efficacy Validated
• Microbial Barrier Properties—Sterility Cannot be
Assured Without Integral Barrier
o Validated for Integrity After Exposure to ―Worst Case‖
Parameters—e.g., Maximum Time and Temperature
for Sterilization Process
• Microbial Ingress or Correlated Physical Method
• Covered by Change Control System at Onset of Validation
Equipment and Facility Design
Control of Environmental Bioburden -- Driving Factor in
Design
•Allows for Effective Cleaning and Sanitization
•Schedule, Procedure and Agents Specified
•Air Handling Systems Provide Air from Controlled (i.e.,
Filtered) Source
•Hierarchy of Air Flow From Most Critical Areas to Less
Critical Areas
•Product Movement is Controlled to Provide for
Segregation
•Use/Presence of Water is Strictly Controlled
Equipment and Facility Design
Environmental Control and Monitoring
•Environment, Water and Gasses
•Air Sampling and Testing
•Surface Sampling and Testing
•Material Sampling and Testing
•Trending Analysis
•Alert and Action Levels
•Corrective/Preventive Actions
25
Raw Material, In-Process and Pre-
Sterilization Product Bioburden
•Presterilization Product Bioburden
• Overkill Design Approach--Less Frequent
–(FBIO/FPHY≥ 12 Minutes)
• Product Specific Design—Each Batch Until Adequate History
• Validated Method
• Population and Heat Resistance for Spores
–Comparison to BI Used for Validation
• Control of Growth in Product Prior to Sterilization
26
Raw Material, In-Process and Pre-
Sterilization Product Bioburden
• Pharmaceutical Grade Raw Materials from
Qualified Suppliers
• In-Process Microbiological Monitoring
• Microbial Retentive Filters Prior to Filling
• Presterilization Product Bioburden
Sterilizer Design
•Use of Current Technology Wherever Possible
•Precise Control/Accurate Monitoring
•Calibration Program
•Redundant Measurement of Temperature
•Independent Measurement Loop
•Comparison to Check for ―Drift‖
•Each Sterilization Cycle
•Cooling Water – Low Micro Content
•―Closed Loop‖ Preferred
•Double Door* vs. Single Door for Segregation
•Covered by Change Control System
*Preferred
Sterilizer Design
•Equipment Configuration Under Change Control System•Routine Maintenance•IQ/OQ Validation
•Validated and controlled software programs.
•Geometric Temperature Distribution Studies
-- Empty Chamber
Sterilization Process
Development and Validation is Overseen by
Sterilization Engineer/Microbiologist•Typically Uses a ―Worst Case‖ Strategy
• Master Solution Approach
• Hardest to Sterilize Locations
• Maximum and Minimum Loading Patterns
• BI = Greater Challenge Than Product Bioburden
•Ensures that Required FBIO, FPHY and SAL/PNSU Requirements
are Met
•Combination Studies
•Temperature Distribution Probes
• Heat Penetration Probes Inside Product
• Biological Indicators Inside Product
• Suspensions Used to Inoculate Solutions
• Inoculated Discs/Strips for Dry Sites
Manufacturing Process Control
Segregation of Product
•Double Door Autoclaves
•Unload Door Only Opens if All Critical
Sterilization Cycle Parameters Met (Software
Control)
•Single Door Autoclaves
•Comprehensive Procedure to Control Loading
and Unloading of Product
•Movable Barriers and Status Labeling
•Robust Procedures
•Load Monitor
31
Manufacturing Process Control
Segregation of Product
• Load Monitors
–Used to Provide Segregation Between Processed and Unprocessed Product in Concert with Physical Barriers and Control Procedures
–Chemical Indicators or Integrators
–Cannot be Used in Place of a BI for Development and Validation
• A Properly Designed and Validated Product Tracking System Can be Used Instead of Load
Product Segregation Example
33
Manufacturing Process Control
Sterile Product Release
• 2X Manual Review to Ensure All Critical Sterilization Parameters Met
– Mix to Sterilize Time
– Sterilizer Validation/Calibration Status
– Sterilizer System Suitability Tests
– Validated Load Pattern
– Achievement of Key and Critical Sterilization Cycle Parameters
– Bioburden Population/Resistance Results*
– Filter Integrity Results
– Load Monitor Results
– Reconciliation of Product
Manufacturing Process Control
Sterile Product Release•Validated Automated Review/Disposition•Sterility Test Cannot be Used to Support Sterile
Release if a Critical Parameter is Not Met•Leverage Successful History of Critical
Parameter Achievement in Risk Assessment•Deviations for Critical and Key Parameters
Disposition--Input from Sterilization Microbiologist/Engineer
Change Control System
•Designed to Continually Ensure Validated State
• Equipment
• Product
• Process
•Must be ―Active‖ Prior to Onset of Initial Validation
•Owned and Administered by the Quality Unit
•Requires Input from Sterilization
Microbiologist/Engineer
Biological Indicator
•Selection Based on Cycle Design Approach
•Organism Name
•Overkill—Geobacillus stearothermophilus
•Product Specific—Bacillus subtilis 5230, Bacillus
coagulans or Clostridium sporogenes
•Nominal D121value of 0.5 minutes or greater
preferred
•Qualified Supplier (Audit)
•Confirmation of Purity
•Spore Population in Suspension or on Carrier
•Resistance Analysis (D-value, z-value and Survival/Kill Time)
•Expiration Date
•Validated Storage Conditions
Risk Assessment
•Absolutely Essential!!!
•Leverage Foundation of a Robust Quality System
•Conducted to Assess the Risk of Producing and Releasing
Non-Sterile Product (Terminally Sterilized Products (PNSU
< 10-6)
•FMEA Approach from PDA TR No. 44 Endorsed
•Example Included in the Appendix
•Uses Highlighted Program Elements to Evaluate and
Mitigate Risk
•Suitable for Use With More Detailed Inputs
Risk Assessment
Successful History Leveraged to Evaluate Risk of
Manufacture and Release of Non-Sterile Product
•Bioburden Results
•Key and Critical Sterilization Process Deviation
Rate
•Qualification and Requalification Results
•Sterility Test Results?—No!!
Risk Assessment
Content
•Personnel
•Product Design
•Manufacturing Process
•Product Bioburden Monitoring and Control
•Product Segregation
•Sterilization System
•Ongoing Monitor and Control of the Sterilization
Process
•Biological Indicator Certification
Pharmaceutical Products Manufacturing Flow Chart
--Items to Consider in Sterility Assurance Risk Assessment
40
Calibration
Qualification
Change Control
Filter 0.45µm
Filler
Moist Heat
Sterilizer
Non-SterileSterile
Release/Packing
Bioburden
LimitsIntegrity Testing
Cycle Development
Sterilization Validation
Manufacturing Environment Controls/Limits
Note: Typically, the development and qualification
approaches and manufacturing limits for all items
in red are the same and are not dependent
upon the drug molecule processed.
Mix
Tank
Segre
gatio
n
Water
Ingredients
Critical
Parameters for
Release
Risk Assessment Summary
Other Sterilization Processes are Suitable for
Parametric Release
• Ethylene Oxide
• Radiation ?
• Aseptic Processing?!?
41
Other Sterilization Processes That Are
Suitable for Parametric Release
42
EO Sterilization
Typically Uses ―Conventional BI Release‖
• Achievement of Physical Sterilization Parameters
• Time, Temperature, Pressure, Humidity (delta P), EO Gas Utilization (delta P and weight)
• BI Inactivation
• 10+ BI’s per Load
• 7 Day Incubation Period—All BI’s Must be Negative
– Shorter Based on RIT Study
• Additional Time May be Needed for Off-gassing of EO Residuals
43
EO Parametric Release
ISO11135-1:2007, Sterilization of healthcare products—Ethylene Oxide--Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices--Supports Adoption of Parametric Release
AAMI TIR 20: 2001, ―Parametric Release of EO Sterilization‖
Requirements:
• Generation of BI Survivor Curves w/Process Challenge Device (PCD)/Full Load
• Specific Validated Load Configurations
• Half Cycle Overkill Approach (Common)
• Sufficient Bioburden Control
• State of the Art Control/Monitoring
– Humidity %
– EO Gas Concentration
44
Radiation Sterilization rogramValidation Includes Dose Mapping, Dose Setting and Dose
Verification
True Bioburden-Based Validation Approach
Caution Use of Biological Indicator Approach
• BI = Product Specific Approach
• Bacillus pumilus is Not the Most Resistant Organism for Radiation
• Some Vegetatives are More Resistant Than Some Spores
• Biological Indicators Should Not be Used Unless Bioburden Resistance Testing is Performed on Each Batch
Current Approach is a Combination of Parametric/Dosimetric Release (Hours After Processing) ≠ ―True Parametric Release‖
Radiation Sterilization
Radiation Parametric Release
Application of Parametric Release Concepts to Radiation Sterilization
• Development of a Dose Predicting Model
• Eliminate Dosimeters
• Development of Standardized Approach
• Minimal Cost-Savings Compared to Other Sterilization Technologies
45
46
Future PR Opportunities
Aseptic Processing?!!!
• Development and Implementation of Advanced Aseptic
Processing Approaches
– Isolators, Robotics
• Development and Implementation of Continuous and Real
Time/Rapid Microbiological Monitoring
• Development of a Model for Product Contamination
• Comprehensive Application of Risk Assessment Tools
– Absolute Understanding of All Contamination Vectors
• Increased Process Knowledge
• Value of Sterility Test??
Thank You for Your Interest in Parametric Release!!
Additional Questions and Comments:
mike_sadowski@baxter.com
47