Updates Regarding the OGD
Division of Microbiology
&
ANDA Sterility Assurance Review
Dr. Lynne A. Ensor
U.S. Food & Drug Administration
Center for Drug Evaluation & Research
Office of Pharmaceutical Science/Office of Generic Drugs
Division of Microbiology
Acting Division Director/Deputy Division Director
2013 GPhA/FDA Fall Technical Conference
October 29, 2013
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This presentation reflects the views of
the presenter and should not be
construed to represent FDA’s views or
policies.
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OGD Division of Microbiology
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
Secondary Reviewer
Team Leader (Acting)
Team 1
Team 2
Dupeh Palmer, Ph.D.
Eric Adeeku, Ph. D.
Jonathan Swoboda, Ph.D.
Vacant
Vacant
Lisa Shelton, Ph.D.
George Arhin, Ph.D.
Nandini Bhattacharya, Ph.D.
Vacant
Vacant
Microbiology Project Managers
LCDR Craig Kiester
Sonni (Song) Kim
Team 3
Jesse Wells, Ph.D.
Helen Ngai, Ph.D.
LCDR Scott Steffen, Ph.D.
Vacant
Vacant
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Additional Division Activities
• Reorganization of OGD & GDUFA implementation
• Creation of OPQ
– Integrated Team-Based Review pilot
• Drug Shortage & Recalls
– Prevented 282 in 2012 (75% sterile injectables & predominantly generics)
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•
•
•
•
Site Inspection Risk Management Experts
Pharmacy Compounding
QbR
Recruitment/training
Presentations (internal & external)
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FY’13 Priorities
• GDUFA Implementation & Microbiology
Queue
• Expedited reviews
– Drug shortages
– Extenuating circumstances beyond applicant’s control
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Common Deficiencies
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Terminal Sterilization
• Incomplete information/description regarding
production loads vs. validation loads
– Please provide a description of if/how the validation
load(s) relates to the production load(s)
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Validation of
Sterilization/Depyrogenation
• Results provided from only 1 run for
sterilization/depyrogenation validation.
– Results from three consecutive successful runs are
recommended. If initial validation results are years old, it is
recommended that results from the most recent revalidation/qualification study are submitted
• Hundreds of pages of raw data without a
narrative are provided.
– Provide a narrative or study summary with any data
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Validation of Sterilization/
Depyrogenation (2)
• The requalification information only includes the
frequency, but not the type of studies
– Provide a summary of any/all requalification studies
(i.e., bracketing, HD/HP/microbial challenge, etc.).
• It is unclear how validation loads compare to
production loads
– Are loads minimum, maximum, fixed or worst-case?
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Bulk Drug Solution Bioburden
• No alert or action levels for bulk drug solution
bioburden
– Recommend setting bulk drug solution bioburden
alert and action levels for the solution prior to any
filtration step.
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Sterilizing Filtration of Drug Solution
• During the filtration sterilization validation study it is
unclear if/how the positive control (0.45 um rated filter)
was included in the bacterial retention studies and/or
positive control results are not provided
– It is recommended that the 0.45 um rated filter is challenged parallel
with the test (0.22 um rated) filters
• Viability data for B. diminuta in the drug solution are not
provided with the bacterial retention study results
– Please provide this information with bacterial retention study summaries
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Container Closure Integrity Testing
• The container closure system used for
validation study is not stated and/or dimensional
specifications are not provided
– Please indicate the manufacturer of the components used in
validation testing
– If different components are used than those proposed for
production, please indicate the inner neck diameter
specifications of the vials and/or are different from proposed drug
product vial, or stoppers are not identical/equivalent (i.e., same
formulation and dimensions, but perhaps different coating) to the
proposed drug product stoppers.
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Antimicrobial Effectiveness Testing
• Antimicrobial Effectiveness testing results are
not provided for the drug solution formulated
with preservative at the lowest specified
concentration, or not provided at all for multidose drug products that are preservative-free.
- Provide AET summary and results for the drug product
containing the minimum API concentration (either release or
stability [lowest])
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Drug Product Labeling
• The drug product label does not indicate if
the product is intended to be single or
multiple dose. The volume of the drug
product could allow for multiple dose.
– Clearly indicate single or multiple dose
– If multi-dose, please provide AET summary and
results (per USP <51> or equivalent)
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Drug Product Labeling (2)
– Microbiological quality following product
penetration
– Post-reconstitution or dilution
– Risk assessment data to support the
proposed post-penetration holding
parameters per product labeling
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Product Labeling
– Risk assessment study & data
• Maximum hold duration during worst-case holding
conditions/diluent
• Minimum inoculum (≤100 cfu/mL)
–
–
–
–
USP <51> strains
Typical skin flora
Nosocomial infection causing organism(s)
Psychrophilic organism(s)
• Acceptance criteria
– No growth (LT 0.5 log10)
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References
• Guidance for Industry for the Submission of
Documentation for Sterilization Process Validation
in Applications for Human and Veterinary Drug
Products
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072171.pdf
• Guidance for Industry: Sterile Drug Products
Produced by Aseptic Processing – Current Good
Manufacturing Practice
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf
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References (2)
• Guidance for Industry: Container and Closure
System Integrity Testing in Lieu of Sterility
Testing as a Component of the Stability Protocol
for Sterile Products – 2008
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM146076/pdf
• Guidance for Industry: Pyrogen and Endotoxins
Testing: Questions and Answers - 2012
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm314718.htm
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References (3)
• Guidance for Industry: Comparability Protocols
– Chemistry, Manufacturing, and Controls
Information – Draft 2/03
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070545.pdf
• Guidance for Industry: Changes to an Approved
NDA or ANDA – 2004
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm077097.pdf
• Guidance for Industry: ANDA Submissions –
Refuse-to-Receive Standards - 2013
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM370352.pdf
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Technical Questions
• How to submit Control Correspondences
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsa
ndTobacco/CDER/ucm120610.htm
• Mail to:GenericDrugs@FDA.HHS.Gov
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Contact Information
Lynne A. Ensor, Ph. D
240-276-8827
lynne.ensor@fda.hhs.gov
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