1. Parametric Release: An Industry Perspective ABRASP Conference October 31, 2012
Mike Sadowski
Director Sterile Manufacture Support
Baxter Healthcare Corporation

2. Presentation Overview
Definitions of Parametric Release
History of Parametric Release of U.S. Moist Heat Sterilized Drug Products and Device Products
Limitations and Shortcomings of the Sterility Test
Moist Heat Parametric Release Standards and Guidance Documents
Essential Elements of a Parametric Release Program: PDA Technical Report 30 (201 Revision)
Other Sterilization Processes Suitable for Parametric Release

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)
The European definition of PR does not just focus on the elimination of the sterility test but applies this concept broadly across finished product quality attributes.

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 and US FDA CGP Sec , 2012)
This US definition applies only to Sterility Assurance programs but focuses on the sterilization process.

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. 30—2012 Revision)
The PDA definition includes the entire sterile product manufacturing process and ties critical operating parameters to release in lieu of the sterility test.

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—Enforcement Guide (August 2012)
This initial submission was submitted by my company, Baxter Healthcare. As you might expect, PR was a new and revolutionary concept back in We had to work with FDA to ensure proper understanding on both parts for the elements of the PR program. Finally after this was achieved, we obtained approval for PR in The compliance policy guide is a guide developed by the FDA enforcement branch to aid field investigators in inspections of companies that practice PR.

7. Baxter’s US Implementation History
All moist heat sterilized US products produced at the North Cove, NC, Jayuya, PR and Cleveland, MS facilities are released parametrically.
All new products in the United States, for the above facilities, are submitted for parametric release.
Baxter Confidential

8. History of Parametric Release -Moist Heat Sterilized Medical Devices
510K Device Submission (FDA CDRH) 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
We utilized a very scientifically strong development and validation approach. Since these products were not heat sensitive, we were able to develop a conservative overkill cycle approach. We followed that with a fractional validation approach where we developed a lethality curve for the gst indicator. Finally we performed a comprehensive qualification of each family of products and loading pattern.

9. Current Baxter Parametric Release Locations
Australia
Canada*
China
Colombia
Ireland
Spain
Singapore
United Kingdom (Thetford)
United States
*Manf. Locations: US and Canada

10. Sterility Test vs. Parametric Release

11. How Accurate is the Sterility Test Specified by Global Pharmacopoeias?

12. 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
Sterility Test
Test performed to determine if viable microorganisms are
present.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

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

14. 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

15. 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

16. Conclusion
Sterility assurance cannot be tested into the product, but rather is established through execution of a well designed and validated sterilization process.
Thus steam saturation, a highly critical factor for the
effectiveness of porous load autoclave cycles, is much less
important for closed container cycles and the only relevant
consideration for sterility assurance is the time/temperature
profile achieved in the containers located in the coldest part
of the load. In geometrically simple fixed loading patterns,
this load cold spot is readily reproducible.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

17. Moist Heat Sterilization Processes
The moist heat sterilization process is well-suited for the parametric release program
Well understood and dependable
Easily controlled & validated
Is universally recognized for its effectiveness
Delivers broad spectrum lethality (molds, yeasts, bacteria/spores, viruses)
There is an additional safety margin for overkill
cycles, each of these approaches will, if properly validated,
reliably achieve the required degree of sterility assurance.
Moist Heat is the most preferred sterilization process by global regulators.
Moist Heat: Steam, steam-air mixtures and superheated water (steam-water-air mixtures) used for sterilization. (PDA Technical Report No. 30—2012 Revision)
Slide taken from PDA TRI TR No. 30 Training Course 2012.

18. Global Parametric Release Standards and Guidance Documents
US Documents
FDA CPG Sec (2012) replaces CPG 7132a.13: Parametric Release – Terminally Heat Sterilized Drug Products (1987)
US Code of Federal Regulations 21 CFR /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
Guidance Documents and Standards for Parametric Release of Moist Heat Sterilized Products

19. Global Parametric Release Standards and Guidance Documents
EU and Global Documents
EU GMP Guidelines 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) (2012)
Guidance Documents and Standards for Parametric Release of Moist Heat Sterilized Products

20. PDA Technical Report No. 30 (2012 Revision)
Title: Parametric Release of Pharmaceutical and Medical Device Products 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
Addressed Comments in 2009/2010
Additional FDA Comments Received/Reconciled 2011
Published in May 2012

21. PDA TR-30 Task Force Members and 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
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 für Technik, University for Applied Sciences

22. 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

23. PDA Technical Report No. 1 (2007 Revision)
3.0 STERILIZATION SCIENCE AND TECHNOLOGY
3.1 Sterilization Models
3.1.1 Resistance Value (DT)
Direct Enumeration Method
Fraction-Negative Methods
Temperature Coefficient (z-value)
Lethal Rate (L) and Lethality (F)
Lethal Rate (L)
FPhysical Value (FPHY) F0
FBiological Value (FBIO)
3.3.2 Steam
Plant Steam
Process Steam
Pure Steam
3.3.3 Steam Quality Testing for Pure Steam
Non-Condensable Gases
Dryness Fraction and Dryness Value
Superheat
3.2 Process Indicators
3.2.1 Biological Indicators
3.2.2 Chemical Monitors
Chemical Indicators
Chemical Integrators
3.3 Thermal Science
3.3.1 Temperature and Heat
Conduction
Convection
Radiation
Heat Transfer Rate and a Comparison of Heat Capacities of
Heating Mediums

24. PDA Technical Report No. 1 (2007 Revision)
4.0 STERILIZATION PROCESS DEVELOPMENT
4.1 Design Approaches
4.1.1 Use of Survivor Curve in Cycle Design Approaches
Overkill Design Approach
Product-Specific Design Approach
4.3 Sterilization Processes
4.3.1 Saturated Steam Processes
Pre-vacuum Process
Gravity Displacement Process
4.3.2 Air Overpressure Processes
Steam-Air Mixture (SAM) Process
Superheated Water Process
4.4 Cycle Development
4.4.1 Porous/Hard Goods Cycle Development
Slowest-To-Heat Location on an Item
Item Preparation
Porous/Hard Goods Load Patterns
Porous/Hard Goods Operating Parameter Determination
Equilibration Time
Evaluating FPhysical & FBiological Agreement
4.4.2 Liquid Load Cycle Development
Container Cold Spot Mapping
Liquid Load Patterns
Liquid Loads Operating Parameter Determination

25. PDA Technical Report No. 1 (2007 Revision)
5.0 PROCESS PERFORMANCE QUALIFICATION
5.1 Physical Qualification
5.1.1 Temperature Distribution
5.1.2 Heat Penetration
5.2 Biological Qualification
5.2.1 Biological Indicator Challenge Systems
Determination of Population and Resistance of BI Challenge Systems
5.2.2 Use and Placement of Biological Indicators
Liquid Loads Cycle Qualification
Porous/Hard Goods Cycle Qualification
5.3 Process Performance Acceptance Criteria
5.4 Sterilizer Equivalence
5.5 Bracketing
5.5.1 Product Formulation Bracketing
5.5.2 Container Size/Fill Volume Bracketing
5.5.3 Item Bracketing
5.5.4 Load Bracketing
6.0 ONGOING PROCESS CONTROL
6.1 Routine Release
6.2 Sterilizer System Suitability
6.3 Change Control
6.4 Periodic Requalification

26. Manufacturing & Sterilization
TR No. 30 balances both microbiological and engineering perspectives on the development of a Parametric Release Program through employment of a Quality System over the entire manufacturing and sterilization process
Engineering
Microbiological
Manufacturing and Sterilization Process
Quality System
Slide taken from PDA TRI TR No. 30 Training Course.

27. 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

28. 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

29. 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

30. Product Design Control
Designed to Ensure Efficient Sterilization and to Maintain Sterile Barrier Properties Over the Product Shelf-Life
For Efficient Sterilization--Design promotes:
adequate removal of air (PHG)
moisture penetration
heat penetration
Sterilization Efficacy Validated

31. Container Closure System: Product & Packaging
Designed for efficient sterilization
Maintain sterility over the shelf life of the product
Validated after exposure to worst case sterilization processing
The product and its packaging should be designed for efficient sterilization and to maintain sterility over the shelf life of the product. The container closure system should be validated after exposure to worst-case sterilization processing (e.g., typically maximum time and temperature) to demonstrate microbial barrier integrity.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

32. Container Closure System
Microbial Barrier Properties are Validated
Elimination of the Sterility Test Could Reduce the Probability of Detection of a Catastrophic Microbial Barrier Failure
Concern
Sterility Cannot be Assured Without A Functional Microbial Barrier
Issue
Proper Design/Validation of Microbial Barrier Properties!
Resolution
The product and its packaging should be designed for efficient sterilization and to maintain sterility over the shelf life of the product. The container closure system should be validated after exposure to worst-case sterilization processing (e.g., typically maximum time and temperature) to demonstrate microbial barrier
integrity.
Microbiological based container closure integrity test methods include use of a challenge microorganism that is inoculated into a liquid aerosol, liquid immersion or powder test system. The microorganism challenge inoculation level is typically multiple orders of magnitude greater than the natural challenge level expected during shelf life of the product.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

33. Challenge Microorganism
The challenge microorganism inoculation level is typically multiple orders of magnitude greater than the natural challenge level expected during shelf life of the product
Microbiological based container closure integrity test methods include use of a challenge microorganism that is inoculated into a liquid aerosol, liquid immersion or powder test system. The microorganism challenge inoculation level is typically multiple orders of magnitude greater than the natural challenge level expected during shelf life of the product.
Microbial barrier integrity should be validated against worst case sterilization processing (e.g., time/temperature)
Microorganism challenge inoculation level is typically multiple orders of magnitude greater than the natural challenge level expected during shelf life of the product
Slide taken from PDA TRI TR No. 30 Training Course 2012.

34. Microbiological Challenge Test Methods
Liquid Aerosol Liquid Immersion Powder Test System
Microbial Test Methods
Microbiological based container closure integrity test methods include use of a challenge microorganism that is inoculated into a liquid aerosol, liquid immersion or powder test system.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

35. Physical Challenge
Physical test methods may also be used for validation of microbial barrier properties of container closure systems provided that the sensitivity of these methods has been favorably correlated to the sensitivity of a microbiological method.
Technical Report No. 27, Pharmaceutical Package Integrity; Parenteral Drug Association, Bethesda, MD, 1998
Physical integrity test methods may also be used for validation of microbial barrier properties of container closure systems provided that the sensitivity of these methods has been favorably correlated to the sensitivity of a microbiological method. Physical test methods may include dye/chemical penetration tests, Helium leak tests as well as pressure and vacuum leak tests.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

36. Physical Test Methods
Dye/chemical penetration tests Helium leak tests Pressure and vacuum leak tests
Physical Test Methods
Physical integrity test methods may also be used for validation of microbial barrier properties of container closure systems provided that the sensitivity of these methods has been favorably correlated to the sensitivity of a microbiological method. Physical test methods may include dye/chemical penetration tests, Helium leak tests as well as pressure and vacuum leak tests.
Technical Report No. 27, Pharmaceutical Package Integrity; Parenteral Drug Association, Bethesda, MD, 1998
Slide taken from PDA TRI TR No. 30 Training Course 2012.

37. Container Closure Integrity
Container closure integrity of fusion type containers (including ampoules and blow-fill-seal) should be one hundred percent verified.
FDA. Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practices, Pharmaceutical cGMPs, September 2004
Container closure integrity of fusion type containers (including ampoules and blow-fill-seal) should be one hundred percent verified.

38. 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

39. Manufacturing Process Design
Controlling Bioburden by Design
Effective Control of Product Bioburden
Manufacturing
Process
Manufacturing Environment
The manufacturing process includes manufacturing and sterilizing medical device and pharmaceutical products. Design of the manufacturing environment and process should ensure that product bioburden is effectively controlled.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

40. Controlling & Monitoring of Product Bioburden
Equipment and facilities designed for effective cleaning & disinfection
Air handling systems with adequate pressure and velocity (controlled source).
Personnel hygiene, operating practices, and controlled garment requirements
Defined process and hold time limits for both bulk fluids and filled containers
Microbial retentive filters
Adequate control of pre-sterilization bioburden is achieved through proper design of the manufacturing facility and processes. The following should be incorporated into the design and operating procedures of the manufacturing facility to ensure bioburden control:
Equipment and facilities should be designed to allow effective cleaning and disinfection. The schedule, procedure and chemical agents for cleaning and disinfection should be specified.
Air handling systems should provide air from a controlled (i.e., filtered) source with adequate pressure and velocity.
Microbial retentive filters along with control procedures should be used where possible on solution fill lines.
Defined process and hold time limits for both bulk fluids and filled containers should be adhered to prior to sterilization.
Personnel hygiene, operating practices, and controlled garment requirements should be specified.
A comprehensive environmental microbial monitoring program should be established. This program should use alert and action levels to prompt corrective action to minimize the effect of environmental contamination in or on the product. A similar program to monitor and control the microbiological condition of starting materials and process aids (including water, containers, closure systems, gases and lubricants) should be developed to minimize the contribution of bioburden from these sources where possible.
Environmental Microbial Monitoring Program : Monitor condition of starting materials and process aids (including water, containers, closure systems, gases and lubricants)
Slide taken from PDA TRI TR No. 30 Training Course 2012.

41. 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

42. Raw Material, In-Process and 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

43. 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

44. 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

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

46. 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

47. Manufacturing Facility Design Product Tracking & Control
Product Segregation
Four elements to help prevent the risk of a mix-up of processed/non-processed & sterile/non-sterile product:
Manufacturing Facility Design
Equipment Design
Load Monitors  
Product Tracking & Control
A means of preventing the possibility of a mix-up between processed/non-processed and sterile/non-sterile product should be developed. The following product segregation solutions, or their combination, may be used to mitigate this risk and should also be supported by comprehensive procedures:
Slide taken from PDA TRI TR No. 30 Training Course 2012.

48. 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 Picture courtesy of PDA.

49. 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

50. Product Segregation Example

51. Product Tracking and Control
A validated, automated product tracking and control system 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
NOTE: Not in the US - Additional features for these systems may include human error prevention mechanisms that may prevent the use of non-calibrated sterilizers or non-validated sterilization processes.
Product Tracking and Control
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 processed and non-processed product. Additional features for these systems may include human error prevention mechanisms that may prevent the use of non-calibrated sterilizers or non-validated sterilization processes.
It is the responsibility of the applicant of a parametric release submission to provide justification for the product segregation, monitoring and control system.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

52. Manufacturing Process
Product movement through the manufacturing process should be controlled through product status (e.g., processed/unprocessed or sterile/non-sterile) segregation
Product movement through the manufacturing process should also be controlled through product status (e.g., processed/unprocessed or sterile/non-sterile) segregation. The use of water in a manufacturing process and facility should be carefully controlled to minimize the potential for water in the environment to facilitate microbiological contamination of equipment or facilities used in the manufacturing of pharmaceutical and medical device products
Slide taken from PDA TRI TR No. 30 Training Course 2012.

53. Ongoing Process Monitoring and Control
After qualification & validation, an ongoing monitoring and control program should be set in place
Once equipment qualification and process validation are completed, it is essential that an ongoing monitoring and control program be in place to ensure the validated state of the sterilization process. Procedural controls that include load disposition procedures, a comprehensive change control program, requalification and revalidation requirements as well as planned preventative maintenance should be established.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

54. Load Release Procedural controls: Load disposition procedures
Comprehensive change control program
Requalification
Repeated validation
Planned preventative maintenance
Release or rejection of a load (with respect to the sterilization process) should be based on meeting sterilization specifications (based on quality units)
Slide taken from PDA TRI TR No. 30 Training Course 2012.

55. Quality Unit Parameters for Load Disposition*
Product bioburden is within limits, where required
The validated load pattern was used
The sterilizer has a current validation
Sterilizer system suitability evaluations have met established requirements
Sterilization load monitor (if used) meets acceptance criteria
Critical operational parameters have been achieved
Release or rejection of a load (with respect to the sterilization process) should be based on meeting sterilization specifications. The following should be confirmed prior to release of each sterilized load by the Quality Unit:
Product bioburden is within limits, where required
The validated load pattern was used
The sterilizer has a current validation
Sterilizer system suitability evaluations have met established requirements
Sterilization load monitor (if used) meets acceptance criteria
Critical operational parameters have been achieved. Failure to meet critical operational parameters results in rejection of the load.
NOTE: The sterility test cannot be used to overrule failure of a critical operational parameter to release a product.
Failure to meet critical operational parameters, key operational parameters or performance attributes requires investigation to determine root cause with input from personnel with relevant experience such as sterilization engineering and/or microbiology.
When key parameters are not met, the rationale for load disposition must be approved by the Quality Unit.
When manual intervention of a microprocessor control system is allowed, the intervention should be documented and evaluated. Rationale for load disposition should be documented with input from personnel with relevant experience such as sterilization engineering and/or microbiology.
A system should be in place that ensures the following:
All planned maintenance and routine checks have been completed
All instrumentation was in calibration
* The sterility test cannot be used to overrule failure of a any load disposition parameter to release a product.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

56. Sterilization Load Release
The Quality Unit determines load disposition based on:
Sterilization load monitors meeting acceptance criteria
Critical operational parameters being met
A system should be in place that ensures the following:
All planned maintenance and routine checks have been completed
All instrumentation was in calibration
A system should be in place that ensures the following:
All planned maintenance and routine checks have been completed
All instrumentation was in calibration
Key and critical operational parameters are reviewed in the sterilization cycle record through either a redundant manual review (two separate, trained individuals), where one of the reviewers represent the Quality Unit; or a validated automated parameter review system with the same degree of resolution and sensitivity as the redundant manual review. Use of a validated parameter review system includes high level Quality Unit oversight to ensure cycle conformance.
The Quality Unit determines load disposition based on:
Sterilization load monitor meets acceptance criteria
Critical operational parameters have been achieved. Failure to meet critical operational parameters results in rejection of the load.
NOTE: The sterility test cannot be used to overrule failure of a critical operational parameter to release a product.
Note:
Slide taken from PDA TRI TR No. 30 Training Course 2012.

57. 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

58. Change Control
Changes to the manufacturing process, product, and equipment should be periodically reviewed as a quality system check.
Changes should be periodically reviewed to determine if the cumulative effect of all changes made since the last qualification has the potential to affect cycle efficacy.
As part of the quality system, a comprehensive change control program that governs changes to the manufacturing process, product and equipment should be in place prior to implementation of a parametric release program. All changes should be assessed to evaluate the potential affect on cycle efficacy and product quality. Depending upon the change, some or all of the original validation must be completed to demonstrate that the change has not affected cycle efficacy or product quality. The change control program should ensure all repairs, modifications and testing have been approved by individual(s) with appropriate (e.g., sterility assurance engineering and/or microbiology) competency.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

59. Change Control Program
Repairs
Modifications
Testing
Validation of components by qualified sterility assurance personnel
Depending upon the change, some or all of the original validation must be completed to demonstrate that the change has not affected cycle efficacy or product quality. The change control program should ensure all repairs, modifications and testing have been approved by individual(s) with appropriate (e.g., sterility assurance engineering and/or microbiology) competency.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

60. 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

61. 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

62. Risk Assessment---Risk is Everywhere
Conditional Risk
Suggestions welcomed
Image courtesy of xkcd.com

63. 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

64. When a new product/process is being considered for Parametric Release
Risk Assessment for PR
When a new product/process is being considered for Parametric Release
A risk assessment should be conducted during process development
 A well-justified risk assessment is instrumental for parametric release to preclude the potential to produce and release a non-sterile product. If a new product or process is being considered for parametric release, then a risk assessment should be conducted during process development.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

65. Risk Assessment for PR
If existing product or process is being considered for PR
Risk assessment should leverage successful historical data
A modified FMEA is included in the Appendix (modeled after TR-44 QRM of Aseptic Processes) to assess the decision to move to parametric release.
If an existing product or process is being considered for parametric release, then the risk assessment should include historical data (e.g., bioburden data, sterile batch release history, qualification and requalification summaries).
Image courtesy of samedanltd.com
Slide taken from PDA TRI TR No. 30 Training Course 2012.

66. 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!!

67. 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

68. Successful qualification data
Production History
Successful qualification data
Pre-sterilization bioburden data including spore heat resistance characterization
Previously submitted application numbers and approval dates for products terminally sterilized in their final container
A description of the differences between the approved and proposed process should also be provided.
Summary of prior knowledge of the manufacturing process (production history)
Pre-sterilization bioburden data including spore heat resistance characterization
Successful qualification data
Previously submitted application numbers and approval dates for products terminally sterilized in their final container
In cases where the same manufacturing process, container system type, and sterilization program are used, the successful history of sterile product release of a current formulation can be used to support a parametric release submission for a new formulation with similar expected bioburden. It can be demonstrated that pre-sterilization bioburden levels are very low and independent of the formulation with the use of pharmaceutical grade compounds and components, robust environmental control and solution filtration prior to filling with a microbial retentive filter.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

69. Risk Analysis Qualitative Risk Ranking Chart
Risk Factors
Qualitative Ranking
Severity
Occurrence
Detection
High
Impact of the unwanted event to product quality is severe
Occurrence is often
The process failure will almost certainly escape detection prior to product release
Medium
Impact of the unwanted event to product quality is moderate
Occurrence is periodic
Controls may detect the existence of a process failure prior to product release
Low
Impact of the unwanted event to product quality is low
Occurrence is seldom
The process failure is obvious and readily detected prior to product release
Severity, occurrence, and detection were considered in the estimation of risk for each cause and process failure. Assignment of qualitative risk ranking (Low, Medium, High) was used and are provided in Table B-1.
Slide taken from PDA TRI TR No. 30 Training Course 2012.

70. Risk Evaluation Risk Prioritization Ranking Chart
Detection RPR ranking (Low (green), Medium (yellow), High (red))
Low (High likelihood failure will be detected)
Medium
High (It is not likely failure will be detected)
Occurrence
High
This cause is likely to occur, but when it does it will be detected. Risk is Medium
This cause is likely to occur and may be detected. Risk is High
This cause is likely to occur and is not likely to be detected. Risk is High
This cause could occur and will be detected. Risk is Low to Medium Risk.
This cause could occur and may be detected. Risk is High
The cause may occur and it will not be detected. Risk is High.
Low
This cause is not likely to occur and if it does it will be detected. Risk is Low
The cause is not likely to occur and if it did it may be detected. Risk is Low or Medium.
The cause is not likely to occur and not likely to be detected. Risk is High
Risk evaluation was performed using a qualitative risk prioritization ranking (RPR) determined in the analysis.
A combination of occurrence and detection values was used in the risk prioritization chart to determine the current RPR
The acceptability of each failure cause was determined using the RPR
A Medium RPR required investigation for further mitigation and then a final determination was made as to its acceptability
Risk Evaluation
Risk evaluation was performed using a qualitative risk prioritization ranking (RPR) determined in the analysis. Since the occurrence of non-sterile liquid product is considered unacceptable due to patient risk, severity is always rated as high and not included in the risk prioritization ranking chart. Therefore, the RPR was performed based on likelihood of detection and occurrence frequency. Table B-2 uses color-coding to depict the RPR ranking (Low (green), Medium (yellow), High (red)).
The assessment of the manufacturing and sterilization process is shown in the modified FMEA in Table B-3. Qualitative values (Low, Medium, and High) were assigned to each failure (unwanted event) for frequency of occurrence and likelihood of detection. A combination of occurrence and detection values were used in the risk prioritization chart to determine the RPR. The acceptability of the mitigation for each unwanted event was evaluated using the RPR determined after implementation of the risk mitigation step(s). The decision to adopt a parametric release program should be based on the risk mitigation strategy and its overall effectiveness in preventing the manufacture and release of non-sterile product.
In the example provided, all initial medium or high risks, with the exception of one in Section 2.1, were reduced to a “low” RPN through the application of risk mitigation step(s).
In some cases, multiple risk mitigation steps were required to reduce the RPN to “low”. In one case, after the application of all possible risk mitigation steps, a “medium” RPN was not able to be further reduced to “low”. Further evaluation of the medium risk item was performed along with the development of a rationale to support the acceptability of the “medium” risk as summarized in the Table B-2 Comments Column for Reference Number 2.1.
The following assessments were made:
Personnel: potential failures caused by not utilizing competent sterilization engineering and microbiology personnel were evaluated for sterilizer equipment design, sterilization cycle design, and sterilization process design
Product Design: potential microbial barrier integrity failures were evaluated
Sterilizer System: the potential failure to detect temperature instrumentation drift was analyzed
Sterilization Process: bioburden control, product segregation and sterilization operating parameter review accuracy and failures were evaluated
Validation: failure related to the use of uncertified biological indicators was analyzed
Load release: potential failure related to the lack of segregation of processed and non-processed product along with inadequate sterilization record review
Environmental and ingredient microbiological impact
Slide taken from PDA TRI TR No. 30 Training Course 2012.

71. Risk Assessments Personnel Product Design Sterilizer System
Sterilization Process
Validation
Load Release
Environmental & Ingredient Microbiological Impact
The following assessments were made:
Personnel: potential failures caused by not utilizing competent sterilization engineering and microbiology personnel were evaluated for sterilizer equipment design, sterilization cycle design, and sterilization process design
Product Design: potential microbial barrier integrity failures were evaluated
Sterilizer System: the potential failure to detect temperature instrumentation drift was analyzed
Sterilization Process: bioburden control, product segregation and sterilization operating parameter review accuracy and failures were evaluated
Validation: failure related to the use of uncertified biological indicators was analyzed
Load release: potential failure related to the lack of segregation of processed and non-processed product along with inadequate sterilization record review
Environmental and ingredient microbiological impact
Slide taken from PDA TRI TR No. 30 Training Course 2012.

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

73. Risk Assessment Disposition
“…approval of the parametric release program will be based on how well the firm has addressed the risks to product sterility.”
Guidance for Industry Submission Documentation in Applications for Parametric Release for Human and Veterinary Drug Products Terminally Sterilized by Moist Heat-FDA, 2010.

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

75. 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

76. 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

77. Radiation Sterilization rogram
Validation 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 rogram

78. 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

79. 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??

80. Closing Thoughts on Parametric Release
Moist Heat Sterilization Programs: Parametric Release vs. Sterility Test
Closing Thoughts on Parametric Release
Robust
Ster.
Program!!
Deficient
Ster.
Program!!
Risk Assessment/Mitigation
Achievement of Critical Parameters
Enhanced Segregation/Load Monitor
Micro/Eng Qualifications
Science-Base Sterilization Program
Leveraging of History/Experience
Integrity Validation
Sterility
Test
There really is only
one scientifically sound and robust sterilization program approach and that must include the elements highlighted in this session for Parametric Release!
The Sterility Assurance – O – Meter!

81. Closing Thoughts on Parametric Release
Now is the Time to Break the Sterility Test Release Paradigm……
Closing Thoughts on Parametric Release
Develop Sterilization Program Elements
Develop Sterilization Program Elements
Risk Assessment/Mitigation
Achievement of Critical Parameters
Enhanced Segregation/Load Monitor
Micro/Eng Qualifications
Science-Base Sterilization Program
Leveraging of History/Experience
Integrity Validation
Risk-base/Scientific Approach
“Minimalist” Approach
Release Approach?
Release Approach?
Parametric
Release
Sterility Test Release

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