Parametric Release An Industry Perspective. October 22, Mike Sadowski Director Sterile Manufacture Support Baxter Healthcare Corporation

Transcription

1 Parametric Release An Industry Perspective October 22, 2010 Mike Sadowski Director Sterile Manufacture Support Baxter Healthcare Corporation

2 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) 3

4 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 21CFR (a) and (a). (US FDA Submission Guidance, 2010) 4

5 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 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?? 6

7 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

8 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 9

10 Limitations of Sterility Test Statistically Limited Detection Sensitivity (n = 20 samples) Microorganism Probability of One Sterility Concentration Test Positive 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! 10

11 Additional Sterility Test Shortcomings Limited Detection of Organisms Less than 1% of all microorganisms are culturable! Typically Employs SCD Broth at o C and FTM at o C 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 12

13 Moist Heat Sterilization Processes Key Strengths That Support Adoption of Parametric Release Non-toxic and Less Expensive Universally Recognized (Typical Temp of 110 o C to 121 o C) Broad Spectrum Lethality (Molds, Yeasts, Bacteria/Spores, Viruses) Oldest, Safest, Most Dependable Process Strong Relationship Between Physical/Biological Measurements (i.e., F PHY and F BIO ) Easily Controlled and Validated Preferred by Most Regulatory Bodies 13

14 Global Parametric Release Standards and Guidance Documents US Documents Guidance Documents and Standards for Parametric Release of Moist Heat Sterilized Products FDA CPG 7132a.13: Parametric Release Terminally Heat Sterilized Drug Products (1987) Revision in Progress (2010) US Code of Federal Regulations 21 CFR 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

15 Global Parametric Release Standards and Guidance Documents EU and Global Documents Guidance Documents and Standards for Parametric Release of Moist Heat EU Sterilized GMP Guidelines Products Annex 17 Parametric Release (2002) PIC/S PI 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

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 Q

17 PDA TR-30 Task Force Members and Contributors Task Force Members Contributors 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 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 für Technik, University for Applied Sciences

18 Introduction and Scope Updated to Present a Global and Sciencebased 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 18

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 19

20 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

21 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

22 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

23 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

24 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 (F BIO /F PHY 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 25

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 26

27 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

28 Sterilizer Design Equipment Configuration Under Change Control System Routine Maintenance IQ/OQ Validation Validated and controlled software programs. Geometric Temperature Distribution Studies -- Empty Chamber

29 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 F BIO, F PHY 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

30 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 31

32 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 33

34 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

35 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

36 Biological Indicator Selection Based on Cycle Design Approach Organism Name Overkill Geobacillus stearothermophilus Product Specific Bacillus subtilis 5230, Bacillus coagulans or Clostridium sporogenes Nominal D 121 value 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

37 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

38 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!!

39 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

40 Risk Assessment Summary Pharmaceutical Filter Products 0.45µm Manufacturing Flow Chart --Items Mix to Consider in Sterility Assurance Risk Assessment Water Ingredients Tank Integrity Testing Critical Parameters for Release Release/Packing Sterile Segregation Non-Sterile Manufacturing Environment Controls/Limits Filler Calibration Qualification Change Control Moist Heat Sterilizer 40 Bioburden Limits Cycle Development Sterilization Validation 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.

41 Other Sterilization Processes That Are Suitable for Parametric Release Ethylene Oxide Radiation? Aseptic Processing?!? Other Sterilization Processes are Suitable for Parametric Release 41

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 42

43 EO Parametric Release ISO :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 43

44 Radiation Sterilization Validation Includes Dose Mapping, Dose Setting and Dose Radiation Verification Sterilization rogram 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 44

45 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?? 46

47 Thank You for Your Interest in Parametric Release!! Additional Questions and Comments: 47