Parametric Release Regulatory Requirements. Terry E. Munson Technical Vice President PAREXEL International, LLC

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1 Parametric Release Regulatory Requirements Terry E. Munson Technical Vice President

2 History First application approved for parametric release in 1985 Formed the basis for the FDA Compliance Policy Guide 7132a.13 issued in 1987 No further requests for parametric release until mid 90s FDA Submission Guideline issued February, 2010 October 22,

3 CPG 7132a.13 Defined Parametric Release as a sterility release procedure based upon effective control, monitoring, and documentation of a validated sterilization process cycle in lieu of release based upon end-product sterility testing Only applies to terminal moist heat sterilization of drug products October 22,

4 CPG 7132a.13 - Requirements Cycle has been validated to achieve microbial bioburden reduction to 10 0 with a minimum safety factor of an additional 6 log reduction. Cycle Validation Chamber Heat Distribution Load Configuration Heat Distribution Heat Penetration of Product Bioburden Studies Lethality Study referencing a test organism of known resistance Identify cycle parameters as Critical or non-critical Critical Time, Pressure, Temperature Non-Critical Heat-up Time, Cooling Time, etc. October 22,

5 CPG 7132a.13 - Requirements Failure of more than one critical parameter must result in automatic rejection of the sterilizer load Integrity of the container closure system has been validated Bioburden Testing Total Aerobic Count Total Spore Count For each batch October 22,

6 CPG 7132a.13 - Requirements Chemical or biological Indicators are included in each truck, tray or pallet of each sterilizer load. Chemical Indicators Cannot be used to evaluate cycle lethality Should have a time/temperature response Should be stable For each cycle - minimum degradation values established Biological Indicators Document biological indicator characteristics Can be used to evaluate cycle lethality Can be used in place of one critical parameter October 22,

7 CPG 7132a.13 - Requirements Reason for having indicators in each load GMP regulation 21 CFR (a) requires that for each batch of drug product purporting to be sterile and/or pyrogen free, there shall be appropriate laboratory testing to determine conformance to such requirements. October 22,

8 Submission Guideline Submission of Documentation in Applications for Parametric Release of Human and veterinary Drug Products Terminally Sterilized by Moist Heat Processes, February 2010 Applicable to Human and Animal Drugs and Biological products. Parametric Release is defined as 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 21 CFR (a) and (a). October 22,

9 Submission Guideline Validation of the Sterilization Cycle Should be conducted in accordance with Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, November 1994 Defines the criteria to be submitted in the application October 22,

10 Submission Guideline A sterilization load monitor, either in the form of a physical chemical or biological indicator, is included with each load to satisfy the requirement for a laboratory test. Required by (a) Must be placed in appropriate positions to indicate that the load was exposed to the sterilization process October 22,

11 Submission Guideline Content of the Submission Control Strategy for Terminal Sterilization Program Rationale for method used to monitor and control terminal sterilization process Rationale for selection of critical parameters Description of the acceptance criteria for parametric release Description of the proposed production loading pattern Description of microbiological monitoring plan for product and components October 22,

12 Submission Guideline Content of the Submission (cont.) Risk Assessment, process Understanding and Prior Knowledge Consistency of performance of the terminal sterilization cycle within validated limits Risk to sterility of product The terminal sterilization cycle Production loading pattern Container closure system Potential contamination risks from the environment Experience with the proposed or similar product or similar sterilization cycle Discussion of your overall prior knowledge and production and testing experience October 22,

13 Submission Guideline Content of the Submission (cont.) Documentation for Parametric Release Process Detailed description of the current terminal sterilization cycle Identification of the critical parameters minimum and maximum limits for each Certify that meeting critical parameters will be used as the primary release criterion for product release. Sterility test cannot be used to overrule failed cycles. Acknowledgement that any sample tested by the reference test method for sterility will pass October 22,

14 Submission Guideline Content of the Submission (cont.) Documentation for Parametric Release Process (cont) Description of the sterilization load monitors Type of monitor that will be used How the load monitor will be used and analyzed What functions are being measured by the monitor Rationale for the location of the monitor Recommends that Class 5 indirect monitors (ISO 15882, 2008) be used. Justification for the classification of the indirect monitors used Documentation of the control system to verify exposure of the load to the sterilization process Show the link between batch release criteria and the commitments in the application October 22,

15 Filing Must submit an application for new drug products Must submit a prior approval supplement for already approve drug products October 22,

16 FDA Approval Process Starts when application or supplement is accepted Reviewers will start review of the submitted documents At the same time a GMP status request is sent to the Office of Compliance in the respective Centers. Center for Drug Evaluation and Research Center for Veterinary Medicine Center for Biologics Evaluation and Research October 22,

17 FDA Approval Process (cont) The Office of Compliance will query their database for the sites listed in the application/supplement. If last inspection over two year will send a request for inspection to the appropriate District Office. If GMP status questionable - will send a request for inspection to the appropriate District Office. If inspection and GMP status is acceptable will inform reviewers that GMP status is acceptable Application/Supplement will be approved if GMP status is acceptable and the documentation in the application/supplement meets October 22,

18 EU Requirments In addition to the basic validation data the EU also Requires: Need sterility test history for acceptance A qualified sterility assurance engineer should be on site Need two independent systems to check for compliance to specifications October 22,

19 Future Manufacturers are still going to be slow to implement parametric release because of the addition requirements put on the sterilization process. October 22,

20 Contact Information Terry E. Munson Technical Vice President PAREXEL Consulting Phone: October 22,

Sterility Assurance and Risk Management: A CDER Microbiologist s Perspective

Sterility Assurance and Risk Management: A CDER Microbiologist s Perspective John W. Metcalfe, Ph.D. Senior Review Microbiologist FDA/CDER/OPQ/OPF/Division of Microbiology Assessment Center for Drug Evaluation