Parametric Release of Products Terminally Sterilized with Moist Heat

February 24, 2021

Q&A – Visit www.pigeonhole.at/PDAMW

PDA Midwest: Agenda

1. Limitations and Shortcomings of the Sterility Test

2. Definitions of Parametric Release

3. History of Parametric Release of U.S. Moist Heat Sterilized Drug Products

4. Moist Heat Parametric Release Standards and Guidance Documents

5. Essential Elements of a Parametric Release Program: PDA Technical Report 30 (2012)

6. Risk Assessment

How Accurate is the Sterility Test Specified by Global Pharmacopoeias?

Sterility Test

Despite its extensive use as the primary criterion for release of sterile product, ‘the sterility test is limited in its sensitivity and is statistically ill-suited for the evaluation of sterility for terminally sterilized products given the exceedingly low probability of detection of contaminated units.’

<1222> Terminally Sterilized Pharmaceutical Products—Parametric Release, USP 33 / NF 28. The United States Pharmacopeial Convention: Rockville, MD, 2010, p. 768

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!

And if Statistical Limitations Weren’t Enough…

Additional Shortcomings of the Sterility Test

•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

What is the Best Scientific Approach for Ensuring Sterility??

Parametric Release

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)

Parametric Release - US 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).

−FDA approval of the parametric release program will be based on how well the firm has addressed the risks to product sterility.

(US FDA Submission Guidance, 2010 and US FDA CGP Sec. 490.200, 2012)

Parametric Release – PDA TR30 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—2012 Revision)

35+ Years

How long has Parametric Release been used to support the sterility of products terminally sterilized with moist heat?

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—Enforcement Guide (August 2012)

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 the business model

Promotion of Parametric Release

Support for Parametric Release

Primary Support:

Best Demonstrated Scientific Practice

Secondary Support--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

1) Parametric Release is not recognized by regulatory authorities in all countries

What are some of the reasons why Parametric Release is not more broadly used for products terminally sterilized with moist heat?

2) Approval of Parametric Release requires costly submissions

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

US Documents

• FDA CPG Sec. 490.200 (2012) replaces CPG 7132a.13: Parametric Release – Terminally Heat Sterilized Drug Products (1987)

• US Code of Federal Regulations 21 CFR 211.165/167

• 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 40 <1222> Terminally Sterilized Pharmaceutical Products—Parametric Release

Global Parametric Release Standards and Guidance Documents

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) (2012)

Global Parametric Release Standards and Guidance Documents

PDA Technical Report No. 30 (Revised 2012)

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

• Published in May 2012

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

PDA TR-30 – 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

Parametric Release Program

• Built on the Foundation of a Comprehensive and Mature Quality System

• Risk Assessment Conducted to Demonstrate Mitigation of all Risks to Sterility

• Personnel Training

• Product Design Control

• Equipment and Facility Design and Qualification

• Process Development and Validation

• Manufacturing Control

• Quality Risk Management System

• Change Control System

Survivor Curve Model Log NF = -F/DT + Log N0SC

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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 Barriero 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

Raw Material, In-Process and Pre-Sterilization Product Bioburden

Pre-sterilization 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

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” *•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

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 Monitors

Product Segregation Example

Product Tracking and Control

TR No. 30 (Section 3.4.2): A validated, automated product tracking and control system (that is based on evidence of thermal exposure and capable of distinguishing processed from non-processed product) may be used to segregate sterilized from non-sterilized product.

Note: Manufacturing tracking and control system to monitor and control product movement based on achievement of critical parameters

PR Program Enhancement Opportunities / Advanced Risk Mitigation Measures

Risk Mitigation• Identifies items (raw materials,

intermediates, end-products, equipment, and personnel) via bar-codes and batch

• Associates items by bar-code to, recipes, bill of materials, process flow

Automated Product Tracking and Control System –Barcode on Sterilizer Truck

Risk Mitigation

• Modulates and controls flow through the manufacturing value chain by enforcing rules per manufacturing schedule

• Automatically prevents and flags all production and quality exceptions

• Ensures item segregation and expedites product disposition

Automated Tracking and Control System Bar Code Readers

PR Program Enhancement Opportunities / Advanced Risk Mitigation Measures

Manufacturing Process Control

Sterile Product Release

• 2X Manual Review to Ensure All Critical Sterilization Parameters Met

• Mix to Sterilize Time

• Sterilizer Validation/Calibration

• Sterilizer System Suitability Tests

• Validated Load Pattern

• Achievement of Key and Critical Sterilization Cycle Parameters

• Bioburden Population/Resistance Results (Not Overkill)

• Particulate/Bioburden Control Filter Integrity Results-Filter Must be Integral

• 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 smithii 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

FDA approval of the parametric release program will be based on how well the firm has addressed the risks to product sterility. A risk assessment statement consistent with the principles of ICH Q9 (ICH 2006) should be provided that describes the following: • Current strategies for control of the terminal sterilization program;

• Risk that these strategies might fail to ensure sterility; and

• How prior manufacturing experience and knowledge were incorporated into the risk assessment

(US FDA Submission Guidance, 2010 and US FDA CGP Sec. 490.200, 2012)

Parametric Release – Risk Assessment

Parametric Release – Risk Assessment

Raw Materials

Processing

Sterilization

Steps (Mixing Details)

Steps (Filling Details)

Step 1: Process Flow Diagram

Step 2: ID Risks to Non-Sterility

Step 3: ID Risk Mitigations/Controls

Can your product be approved for Parametric Release?Approval of the parametric release program will be based on how well the firm has

addressed the risks to product sterility.

End

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