Current Topics For Sterile Generic Drug Products

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1 Current Topics For Sterile Generic Drug Products Marla Stevens-Riley, Ph.D. Team Leader Division of Microbiology for ANDA Review FDA/CDER GPHA CMC Workshop June 4, 2014

2 Disclaimer Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA 2

3 Presentation Overview Division of Microbiology for ANDA Review Product Quality Microbiology Defined Current Topics: Post-use constitution and/or dilution prior to storage Bioburden sampling of the bulk solution Biological Indicators (BIs) Supplement cover letters 3

4 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. Team Leader Yarery Smith, Ph.D. Team Leader (Acting) John Arigo, Ph.D. Team Leader (Acting) Team 1 Dupeh Palmer, Ph.D. Eric Adeeku, Ph. D. Nandini Bhattacharya, Ph.D. Nutan Mytle, Ph.D. Wendy Tan, Ph.D. Team 2 Lisa Shelton, Ph.D. Yeissa Chabrier-Rosello, Ph.D. Siba Bhattacharyya, Ph.D. Maria Cruz-Fisher, Ph.D. Peggy Kriger, Ph.D. Team 3 Jesse Wells, Ph.D. George Arhin, Ph.D. Helen Ngai, Ph.D. LCDR Scott Steffen, Ph.D. Julie Nemecek, Ph.D. Jonathan Swoboda, Ph.D. Administrative Support Melody Lescalleet 4

5 Product Quality Microbiology Defined Microbiology of manufacturing processes Part of Chemistry, Manufacturing & Controls (CMC) Focus on validation of manufacturing processes and tests that will be used for commercial production and release of a specific drug product Quality by Design Do not focus on processes that were used for the manufacture of the exhibit batch 5

6 Current Topics: The Bottom Line Post-Constitution and/or dilution prior to storage support the labeling of the product Bioburden sampling of the bulk solution know the microbial quality after hold times and prior to filtration steps Biological Indicators use the appropriate BI for the specific process Supplement cover letters provide more details 6

7 Post-constitution and/or Dilution prior to Storage Why is this a concern? When a drug product container is opened and entered There is a RISK of contamination Inadvertent contamination Could be low or high levels, but mostly likely low If immediately used without further manipulation: Less opportunity for contamination, less opportunity for any contaminants to grow less risk to patient If manipulated, stored, then used: Greater opportunity for contamination, greater opportunity for any contaminants to grow greater risk to patient 7

8 Post-constitution and/or Dilution prior to Storage Manipulation: Constitution of drug product with a sterile solution Addition of a sterile diluent to the drug product Storage (after manipulation; prior to patient administration): In same container or new container Temperatures Durations As storage time increases at any temperature, risk of microbial growth may increase 8

9 Post-constitution and/or Dilution prior to Storage What is our current thinking? Product labeling is recommended to be supported by scientific studies Studies to demonstrate that the drug product does not support adventitious microbial growth (NMT 0.5 Log 10 increase) using the diluents and storage conditions indicated in the labeling What are some supporting references? ICH Q8-Pharmaceutical Development-Section II.E ICH Q1A(R2) Stability Testing of New Drug Substances and Products, Section

10 Post-constitution and/or Dilution prior to Storage Are studies required for multiple-dose products? Maybe Multiple-dose products should pass antimicrobial effectiveness testing (AET) per USP<51> or equivalent Products may contain preservative Products (API typically) may be inherently antimicrobial However, typically AET is performed with the antimicrobial component at the concentration allowed for release or stability, whichever is lower, or less 10

11 Post-constitution and/or Dilution prior to Storage Are studies required for multiple-dose products (cont.)? When a product is diluted prior to patient use, the preservative or antimicrobial component may be diluted to a concentration lower than that used in the AET Therefore, additional studies may be needed to demonstrate that the drug product (and all other components) constituted and/or diluted as indicated in the package insert does not allow for an increase in microbial growth under the storage duration and temperature 11

12 Post-constitution and/or Dilution prior to Storage Overall recommendations: Perform risk assessment of the likelihood that adventitious microbial contamination will grow in the drug product after manipulation and storage per the conditions indicated in the package insert/labeling Assess duration of storage Assess temperature of storage Assess diluents indicated Assess use of any additional containers for storage 12

13 Post-constitution and/or Dilution prior to Storage Overall recommendations: For multiple dose products: Evaluate existing AET studies to compare the concentrations of the preservative or inherently antimicrobial ingredient (and other excipients) used in those studies with the resulting concentration of the same ingredients after diluting as indicated in the package insert/labeling 13

14 Bioburden Sampling of the Bulk Solution What is bioburden? Microbial contamination in bulk drug solution or drug product Bacteria, yeast/mold On components or within ingredients when received Imparted by personnel during handling or from equipment surfaces during manufacturing processes Can bioburden affect product quality? YES!! 14

15 Bioburden Sampling of the Bulk Solution How can bioburden affect the product? Excessive microbial by-products can degrade or adulterate the product Living and dead bacteria are a concern: Exotoxins Endotoxins Cellular debris Overwhelm and/or pass through filters contaminated product Ineffective terminal sterilization process contaminated product 15

16 Bioburden Sampling of the Bulk Solution How to control bioburden? Understand the microbiological quality bulk solution during the manufacturing process Likelihood to support growth Points for contamination Holding conditions conducive for growth Aspect of QbD Sample the bulk solution At the appropriate point in the manufacturing process Specific for each product 16

17 Bioburden Sampling of the Bulk Solution What is the appropriate sampling point? Depends on product and the process Sampling prior to filtration and after any hold period provides protection from microbial byproducts AP product: Compounding hold 48 hrs (sample here) 0.22 µm sterilizing grade filter filling machine TS product: Compounding hold 24 hrs (sample here) filling machine terminal sterilizer 17

18 Bioburden Sampling of the Bulk Solution Overall recommendations for sampling: If there are filtration steps prior to sterilization by filtration or terminal sterilization, we recommend sampling prior to filtration and after any hold period Provides knowledge of the microbial quality of the solution prior to any sterilization step Additional sampling at other points may be necessary 18

19 Biological Indicators What are Biological Indicators? Microorganisms used to challenge the effectiveness of a sterilization process After exposure to the process, BIs are incubated to assess if there are survivors Commercially purchased or prepared in-house Spores embedded on paper strips, in solution, in sealed ampoules Different organisms for different sterilization processes 19

20 Biological Indicators What is the concern? Use of inappropriate BI for validation of a moist heat sterilization process used in a pharmaceutical manufacturing setting What is meant by inappropriate BI? Less than optimal organism to challenge the specific process Less than optimal form of BI for the process Use of a BI that is not designed to monitor sterilization in a pharmaceutical facility (but designed for use in health care facility) 20

21 Biological Indicators How would a BI designed for use at a health care facility be chosen for use at a pharmaceutical manufacturing facility? Possibly because of the reduced incubation time desire for quick results Typically G. stearothermophilus is incubated for 7 days; however, this BI is available with incubation times as short as hours The BIs marketed with the shorter incubation times may have been designed to monitor sterilization at a health care facility, not a pharmaceutical facility 21

22 Biological Indicators What is the difference between the BIs with reduced incubation times and traditional incubation times? Criteria by which the reduced incubation time may have been determined There is a chance that the reduced incubation time was based on criteria provided in a Center for Device and Radiologic Health (CDRH) Guidance for BIs intended for use in health care facilities Guidance for Industry : Biological Indicator (BI) Premarket Notification [510(k)] Submissions (2007) 22

23 Biological Indicators What are the criteria in the guidance? Minimum incubation time is the greatest number of days to obtain more than 97% positive BIs (based on the 7 day incubation time) Refer to Attachment II of the CDRH guidance for additional information What does this mean? Traditionally, 7 days at C per ANSI/ISO :2006/(R)2010 Time frame assures low numbers of injured spores have a chance to grow 23

24 Biological Indicators Why are we concerned about the criteria in the CDRH guidance? Reduced incubation time may be too short to detect low numbers of sub-lethally injured spores Low numbers of sub-lethally injured spores may never grow to a point of visualization if a reduced incubation time is chosen Furthermore CDRH Guidance states: This document does not address the following sterilization process indicators or related products: BIs intended for use in a manufacturing setting. 24

25 Biological Indicators Overall recommendations: Understand the BI needs for the specific process Have a chat (perhaps coffee) with the BI manufacturer; assess their method/data for determining the reduced incubation time it may be adequate Or, use a 7 day incubation for G. stearothermophilus subjected to moist heat sterilization processregardless of form What you are doing may be appropriate, but check! 25

26 Supplement Cover Letters Why are supplement cover letters important? Cover letters explain all post-approval changes and are necessary for complete assessment of the filing category Appropriate level of detail facilitates: Granting CBE-0 or CBE-30 process Assignment process Review process Without adequate details, process slows Phone calls needed, which take time and are resource intensive 26

27 Supplement Cover Letters What type of details are recommended? A list of every proposed change or reference to an associated document with this information clearly described A list of any ANDAs/NDAs that may already be approved for the same change (provide approval date, if possible) or at least submitted to Agency Indication of approved vs changing information. Can refer to another document. CBE-30s are based on what is currently approved. Time intensive to search for old submissions and reviews to verify information. 27

28 Acknowledgements John Metcalfe, Ph.D., Senior Microbiology Reviewer- New Drug Microbiology Staff Lynne Ensor, Ph.D. Division Director (Acting)- Division of Microbiology for ANDA reviews Paul Dexter, Ph.D. Deputy Division Director (Acting)-Division of Microbiology for ANDA reviews 28

29 Thank You Marla Stevens-Riley, Ph.D. White Oak Bldg th Floor marla.stevens-riley@fda.hhs.gov 29

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