Updates Regarding the OGD Division of Microbiology & ANDA Sterility Assurance Review Dr. Lynne A. Ensor

Transcription

1 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,

2 This presentation reflects the views of the presenter and should not be construed to represent FDA s views or policies. 2

3 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. Team Leader Team 1 Dupeh Palmer, Ph.D. Eric Adeeku, Ph. D. Jonathan Swoboda, Ph.D. Vacant Vacant Yarery Smith, Ph.D. Secondary Reviewer Team 2 Lisa Shelton, Ph.D. George Arhin, Ph.D. Nandini Bhattacharya, Ph.D. Vacant Vacant John Arigo, Ph.D. Team Leader (Acting) Team 3 Jesse Wells, Ph.D. Helen Ngai, Ph.D. LCDR Scott Steffen, Ph.D. Vacant Vacant Microbiology Project Managers LCDR Craig Kiester Sonni (Song) Kim 3

4 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) Site Inspection Risk Management Experts Pharmacy Compounding QbR Recruitment/training Presentations (internal & external) 4

5 FY 13 Priorities GDUFA Implementation & Microbiology Queue Expedited reviews Drug shortages Extenuating circumstances beyond applicant s control 5

6 Common Deficiencies 6

7 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) 7

8 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 8

9 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? 9

10 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. 10

11 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 11

12 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. 12

13 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]) 13

14 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) 14

15 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 15

16 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 log 10 ) 16

17 References Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice 17

18 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 Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers

19 References (3) Guidance for Industry: Comparability Protocols Chemistry, Manufacturing, and Controls Information Draft 2/03 Guidance for Industry: Changes to an Approved NDA or ANDA Guidance for Industry: ANDA Submissions Refuse-to-Receive Standards

20 Technical Questions How to submit Control Correspondences ndtobacco/cder/ucm htm Mail 20

21 Contact Information Lynne A. Ensor, Ph. D lynne.ensor@fda.hhs.gov 21