Proper CMC Submission -API Ramnarayan Randad, Ph.D. DMF Review Staff/OGD June 4, 2014 GPhA/FDA Bethesda, MD 1
Type II Drug Master Files (DMFs) and GDUFA Generic Drug User Fee Amendments (GDUFA) July 9, 2012 (FDASIA PDUFA, GDUFA, BsUFA). Type II DMF -one-time user fee Pass Completeness Assessment Available for Reference -Oct 2014, ww.fda.gov/gdufa DMF team pilot 2010 Affects ANDA submission Risk of causing an RTR ANDA applicant is notified (email) of the DMF status 2
Completeness Assessment (CA) GDUFA requires Type II API DMFs to undergo an initial CA to ensure that the DMF is complete. Agency Guidance (10/1/2012), that include recommendation on information that should be included in the DMF. CA checklist follows CTD format: Has 62 questions DMFs that pass initial CA are published on the FDA s public Web site as available for reference (www.fda.gov/gdufa). 3
Format of the Checklist Administrative/General Information (question 1-11) 2.3.S QOS (question 12) 3.2.S.1 General Information (question 13-15) 3.2.S.2 Manufacture (question 16-36) 3.2.S.3 Characterization (question 37-40) 3.2.S.4 Control of Drug Substance (question 41-45) 3.2.S.5 Reference Standards or Materials (question 46-51) 3.2.S.6 Container Closure System (question 52-54) 3.2.S.7 Stability (question 55-58) 3.2 R Regional info (question 59-61) 4
CA Review Process DMF holder Actions DMF holder pays the DMF fee DMF holder sends notification to DMFOGD@fda. hhs.gov DMF holder submits amendment ANDA applicant who references this DMF FDA Actions Generate CA queue and prioritize. Issue Incomplete letter to DMF holder.* No *Notification of Incomplete status is sent to ANDA applicant if the DMF has been referenced by a submitted ANDA under filing review. Is DMF Eligible for Admin CA? No Assign to reviewer for full CA Is DMF Complete? Yes DMFs listed as available for reference on FDA website Yes 5
How is the Generic Industry doing with CAs? Overall Industry is adapting very well. Some metrics: DMFs for Full CA complete on the first cycle: 17% DMFs for Full CA complete by the second cycle: 88% Average response time (first cycle): 45 days CTD format and Electronic- CTD submissions greatly facilitate the process efficiency 6
Clarifications on DMF [Common Queries] API is a substance or a mixture when the substance is unstable or cannot be transported on its own. DMF for a mixture (e.g. API plus an excipient) can qualify as the API under GDUFA. We ask that a justification be submitted to the DMF when this claim is made. Note that these situations also have important facility fee implications. The CA requires that a DMF be for a single API produced by a single manufacturing process. 7
Clarifications (continued) DMF should be limited to one process although multiple manufacturing sites for a single drug process is permitted. Certain process alternatives/changes may be permissible with sufficient supportive information provided. e.g.: Validated reprocess/rework procedures Micronization leading to different particle sizes Addition of a stabilizing antioxidant for stability purpose Alternate crystallization procedure to produce a different polymorph Minor process variation that is the same chemical transformation with little risk to the impurity profile Factors which are indicative of a second process Significant process alternation resulting in different impurity profile and requiring different control strategy Different starting materials Different Intermediates 8
Clarifications (continued) What is the stability data requirement to pass the CA? Do the provisions of the new stability guidance apply? The guidance requirements apply to the full scientific review. To pass the CA the firm needs to demonstrate that stability studies have started (i.e. one batch with a time point beyond initial). 9
Policy Change for FY 2015 DMF must be Available for Reference at the time of ANDA submission or the ANDA will be Refuse to Receive For FY 2013 and 2014 this was not the case DMF holders had the entire ANDA filing window to become Available for Reference Firm s will need to coordinate DMF fee payment and ANDA submission to allow the DMF to pass the CA (we recommend 6 months) 10
Average time to CA Completion by Payment Month (Full CA, first cycle) 350 300 250 200 Backlog > 400 Initial Bolus Cleared Backlog : 78 Backlog > 300 200 160 120 Large influence of the bolus on timelines Impact was partially muted do to hiring 150 100 50 0 80 40 0 September 2013 bolus has been cleared so another downward trend is expected # of Paid DMFs Avg Days of 1st CA Review
Avoid an RTR due to the DMF-Suggestions Make sure the DMF is on the Available for Reference list prior to ANDA submission Communicate with the DMF holder so they know the ANDA submission timeframe. Pay the DMF fee six-months in advance of the planned ANDA submission date This will allow sufficient time for two cycles of CA review (if needed) Submit a high-quality DMF (preferably in ectd format) 12
Avoid an RTR due to the DMF- Be Proactive! Know if the DMF is eligible for an administrative CA Make sure the choice of starting materials is appropriately justified For older DMFs, know whether a complete update needs to be submitte and submit ahead of payment! Make sure FDA has the current contact information (fax number) Respond to Incomplete letters as quickly as possible (30 days or less is ideal) Provide notification of amendment as instructed on the fax cover sheet! Contact us with CA status requests if the DMF is not on the list or you have not received a DMF Incomplete 13 communication (DMFOGD@FDA.HHS.GOV)
Resources from Oct 1, 2012 40 35 30 25 20 15 10 5 0 Growth in DMF Staff Since Oct 1, 2012 Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Large increase in resources since Oct 1, 2012 14 GDUFA hires in FY2013 25 GDUFA hires in 2014 Total review Staff of 61 by end of 2014 Increased capability to cope with large and variable workload. Will result in much lower and predictable CA timelines
Thank you 15