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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

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Thank you

Marla Stevens-Riley, Ph.D.

Master Microbiology Reviewer

Division of Microbiology Assessment

CDER/OPQ/OPF

FDA