building a better sterility assurance application · 15 references •guidance for industry (2008):...
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Building a Better Sterility Assurance Application
Marla Stevens-Riley, Ph.D. Master Microbiology Reviewer
Division of Microbiology Assessment
Office of Process and Facilities
Office of Pharmaceutical Quality
CDER/FDA
May 2017
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Disclaimer
The views and opinions expressed in this presentation are those of the authors and do not necessarily represent official policy
or position of the Food and Drug Administration
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Overview
Goal:
–Build a Better Sterility Assurance Submission
Topics:
–Common deficiencies
–References
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Common Deficiencies
• Conflicting information
– Between narrative summaries in different modules
– Between narrative summaries in different sections
– Between summaries of reports and the details in the reports
Example:
P.3.3-Line 4 and Filling machine Z
P.3.5-Line 10 and Filling machine X
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Common Deficiencies • Absence of rationale or justification
– Validation supports the specific commercial production process
– Validation not always identical to production
– Explain how validation study supports the commercial production process
Example:
P.3.3-10 mL vial for commercial production
P.3.5-Depyrogenation validation using 2 mL vial
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Common Deficiencies • Absence of information for items received as
sterile or depyrogenated or both
– Another entity performing a process
– Applicant responsible for:
• Identifying entity performing process
• Describing the process
• Indicating location of validation information
• Referencing DMF and providing LOA, if necessary
– Place validation in the application, if possible
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Common Deficiencies • Failure to indicate the sterilization method of
the product filter – Filters can be sterilized by autoclave, steam in place,
or purchased as sterile
– Describe proposed commercial sterilization process
– Provide validation of the sterilization process
– Reviewer cannot assume filter in an equipment load
Example:
P.3.5- autoclave validation load: filter housings, filter, scoops, manifolds, bowls
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Common Deficiencies
• Bioburden monitoring (bulk solution) is not described – Routine performance is not described
– Point(s) of monitoring is not described
– Monitoring location is not adequate
– Bioburden monitoring =knowledge of microbiological quality
Compound hold filter 1 hold filter 2 filling
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Common Deficiencies
• No pressure or vacuum conditions were used in container closure integrity testing
– For microbial ingress and dye ingress testing
– These conditions remove air bubbles, particulates, dried product
– These conditions “simulate” shipping conditions
– Expectations are flexible
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Common Deficiencies
• Unacceptable incubation conditions for Biological Indicators
– G. stearothermophilus incubation is 7 days
– Commercial BIs available with reduced incubation times of 24-48 hours
– Certificate of analysis refers to FDA guidance; however, guidance pertains to health care facilities
– Concern is low levels of sub-lethally injured spores
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Common Deficiencies
• Media fills are not representative of maximum production conditions
– Container closure system
– Duration
– Interventions
– Environmental monitoring
– Rejected or discarded units
– Explain. Explain. Explain.
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Common Deficiencies
• Incorrect use of pooling for endotoxins testing
– Pooling allowed for units of 100 mL or less
– Pool no more than 3 units
– Must divide the maximum valid dilution (MVD) by the maximum number of pooled units
– Concern that that high levels of endotoxin in one unit will be diluted out
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References
• Guidance for Industry (1994): Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064983.htm
• Guidance for Industry (2004) : Sterile Drugs Products Produced by Aseptic Processing-Current Good Manufacturing Practice
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm
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References • Question-Based Review (QbR) for Sterility
Assurance Evaluation of an ANDA (2011)
– QbR for Sterility Assurance of Terminally Sterilized Products: Frequently Asked Questions
Detailed product quality microbiology information
begins on page 6
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm120971.htm www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM276170.pdf
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References
• Guidance for Industry (2008): Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM146076.pdf
• Guidance for Industry (2012): Pyrogen and Endotoxins Testing: Questions and Answers
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm314718.htm
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References
• Guidance for Industry and FDA Staff (2007): Biological Indicator (BI) Premarket Notification [510(k)] Submissions
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071261.htm
• International Organization of Standardization (ISO) Sterilization of health care products-biological indicators-Part 1: General Requirements 11138-1:2006/(R)2010