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

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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)

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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)

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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

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Current Baxter Parametric Release Locations

•Australia

•Canada*

•China

•Columbia

•Germany

•Ireland

•Spain

•Singapore

•United Kingdom

(Thetford)

•United States

*Manf. Locations: US and Canada

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Sterility Test vs.

Parametric Release

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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

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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

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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

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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)

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Global Parametric Release Standards

and Guidance Documents

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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

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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

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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

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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

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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

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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

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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

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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?!?

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Other Sterilization Processes That Are

Suitable for Parametric Release

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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

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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

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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

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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

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