Zen in the Art of Parametric Release

B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Zen in the Art of Parametric
Release (a regulatory
perspective)
Marla Stevens-Riley, Ph.D.
CDER
Office of Pharmaceutical Science
Division of Microbiology for ANDA Review
PDA 9th Annual Global Conference on Pharmaceutical Microbiology
October 20, 2014
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Disclaimer
Opinions expressed in this presentation are
those of the speaker and do not necessarily
reflect the views or policies of the FDA
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Outline
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Our organization
Parametric release (PR) defined
Benefits of PR
History
Guidance for a PR program
Current use
Deconstructing PR
PR submission challenges
Implementation of PR
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OPS Division of Microbiology
(for ANDA review)
Lynne Ensor, Ph.D.
Division Director (Acting)
CDR Paul Dexter, M.S.
Deputy Division Director (Acting)
Marla Stevens-Riley, Ph.D.
Yarery Smith, Ph.D.
John Arigo, Ph.D.
Team Leader
Team Leader (Acting)
Team Leader (Acting)
Team 1
Dupeh Palmer, Ph.D.
Eric Adeeku, Ph. D.
Nandini Bhattacharya, Ph.D.
Wendy Tan, Ph.D.
Nutan Mytle, Ph. D.
Amena Frias, Ph. D.
Team 3
Team 2
Lisa Shelton, Ph.D.
Yeissa Chabrier-Rosello, Ph.D.
Maria Cruz-Fisher, Ph.D.
Peggy Kriger, Ph. D.
Yuansha Chen, Ph. D.
Microbiology Project Managers
Sonni (Song) Kim
Eileen Monaghan
Jesse Wells, Ph.D.
George Arhin, Ph.D.
Helen Ngai, Ph.D.
Jonathan Swoboda, Ph.D.
Julie Nemecek, Ph.D.
Haijing Hu, Ph. D.
Administrative Support
Melody Lescalleet
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Parametric Release Defined
• Commercial release of a finished drug
product without the performance of a
sterility test but rather by the meeting of
pre-determined acceptance criteria for
critical process parameters
• Product is considered sterile and meets
CFR 211.165a and 211.167a
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Parametric Release Defined
TS Sterility Testing wait 14 days
• Waiting for results
• Product is held in facility while waiting
• Potential sterility test failures-false or otherwise
TS PR Requirements no waiting
• Immediate release
• No sterility testing prior to release
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Benefits of Parametric Release
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Saves money-no sterility testing
Saves time-no waiting for sterility results
Saves space-no holding while waiting
Manufacturing flexibility—product to
market quickly if there is a need?
• Better process understanding and control?
• Better sterility assurance?
• Less stress?
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History of Parametric Release
• First approved in 1985-1 company
• When was the second company
approved?
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
History of Parametric Release
• Why a gap of over 10 years?
• Reluctance by industry?
• Lack of regulatory information?
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Guidance for PR
• Guidance for Industry: Submission of Documentation
of Applications for Parametric Release of Human and
Veterinary Drug Products Terminally Sterilized by Moist Heat
Processes (2010)
 Provides guidance to industry on submission content
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M072180.pdfGuidance for PR
• Compliance Policy Guide: Sec. 490.200 Parametric
Release-Parenteral Drug Products Terminally Sterilized by
Moist Heat (2012)
 Provides guidance to FDA staff
http://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm312974.htm
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Guidance for PR
• Additional regulatory assistance:
– Request meetings with the FDA
• Contact project managers
– Submit questions to the FDA for a formal
response
• Considered “Controlled Correspondence”
• Email: [email protected]
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Use of Parametric Release
• How many pharmaceutical companies are
currently approved for parametric release
of 1 or more drug products in CDER?
a. 0-3
b. 4-6
c. 7-9
d. 10-12
e. 13+
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Use of Parametric Release
How many pharmaceutical companies have
been approved for parametric release in
CDER after the publication of our guidance?
a. 0
b. 1
c. 2
d. 3
e. 4+
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Deconstructing Parametric
Release
• Recommendations for a PR program:
– Process understanding:
• Validated terminal sterilization (TS) cycle
– Process control:
• Environmental monitoring of product (bulk
bioburden) and components, flow of materials
– Specific PR submission information:
• Documentation
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Deconstructing Parametric
Release
• Specific PR submission information
– Control Strategy: tell us your story
– Risk Assessment: face your potential failures
– Commitments: take the leap
– Revised batch records: make the connection
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Deconstructing Parametric
Release
• Specific PR submission information:
– Control Strategy:
• Methods to monitor validated production TS cycle
• Critical process parameters (CPP) and acceptance
criteria
• Load monitor
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Deconstructing Parametric
Release
• Specific PR submission information:
– Risk Assessment:
• Discussion of points of potential failure (risk to
sterility) and efforts to mitigate problems
• Experience historical data from using TS cycle,
specific load size/arrangement, sterilizer, container
closure system, facility
– Results from sterility testing
– Results from terminal sterilization
– Results from bioburden monitoring
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Deconstructing Parametric
Release
• Specific PR submission information:
– Commitments
• Load monitor result is one of the CPPs
• If there is failure to meet the acceptance criteria of
any CPPs, the batch cannot be released
• Cannot use sterility test for release if failure of any
CPPsmeeting the CPPs substitutes for sterility
testing
• Regardless of how the batch is released, any
batch tested must meet reference test for sterility 18
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Deconstructing Parametric
Release
• Specific PR submission information:
– Revision of batch records
• Release records revised to indicate PR as the
method to achieve sterility
• Release records contain or refer to SOP or
document with requirements and commitments of
PR and the criteria for the CPPs
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Challenges
• 1) Use of a sterilization load monitor
– Devices included in production load that indicate
exposure to sterilization
– Reading of monitor satisfies the requirement for a
laboratory test for sterility (21 CFR 211.167a)
– Load monitor readout/result is one of the CPPs
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Challenges
• 1) Use of a sterilization load monitor
– For a submission: describe load monitor
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Identity-what is it
Function-what it measures and how
Location and rationale/justification-in load, on cart
Data demonstrating that monitor works in the
specific load with the specific cycle
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Challenges
• 1) Use of a sterilization load monitor
– Types:
• Biological indicator-in chamber or product
• Physical indicator- immersed in the product in
container (provides F0)
• Chemical indicator- see ANSI (2008)
– FDA PR Guidance (2010): “In certain circumstances a
Class 3 indicator may be appropriate; however, a Class 5
indicator is recommended for most situations.”
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Challenges
• 1) Use of a sterilization load monitor
– What types have been approved for PR?
• Chemical indicators
– Class III  in older submissions and often used in
conjunction with probes in product
– Class V (integrators)  in newer submissions
• Physical indicators immersed in product
• Approximately 50% of firms using chemical
indicators and 50% using physical indicators
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Challenges
• 2) Historical data/experience
– Successful execution of the specific TS cycle
• With the drug product solution
• With the container closure system of product
• At the specific location/facility
– “General guideline”  data from approx. 1 yr
or 10 batches covering passage of time
– Data (failures and successes) results from TS, sterility
testing, bioburden monitoring
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Challenges
• 2) Historical data/experience:
– What if you do not have historical data for the
drug product?
– Can an application receive approval for PR
without historical data?
Maybe!
• Firms can submit data from TS of similar product,
similar container closure system, similar sterilizer,
similar cycle, at the same facility
• “Similar” determined by review divisions
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Parametric Release
Implementation
Are you interested now?
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Parametric Release
Implementation
• How to file?
– Already approved product:
File a Prior Approval supplement (PAS)
Follow the PR guidance for information to submit
 Historical data from the TS, sterility testing, and
bioburden monitoring during commercial
manufacture and release using the sterility test
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Parametric Release
Implementation
• How to file?
– Unapproved product: but have experience
with another similar product*
File an original submission
Follow the PR guidance for information to submit
Historical data from TS, sterility testing, and
bioburden monitoring of similar product
*similar: cycle, sterilizer, load(s), container/closure
system, product
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Recap of Parametric Release
– Validated terminal sterilization cycle
– Process control and understanding
– PR specific items:
• Critical process parameters identified
• Load monitor identified
• Submission information
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Control strategy
Risk assessment and historical data
Commitments
Revised records
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Where is the Zen?
• Definition: Enlightenment can be attained through
meditation, self-contemplation, and intuition
• Theme of the book: “Through years of practice, a
physical activity becomes effortless both mentally and
physically, as if the body executes complex and difficult
movements without conscious control from the mind”
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B1 - Parametric Release
Presented by: Marla Stevens-Riley, PhD
Thank you
Marla Stevens-Riley, Ph.D.
[email protected]
240-402-8796
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