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Vaccines, Blood & Biologics

Record of Telephone Conversation, July 23, 2012 cont - Flucelvax


Submission Type: BLA    Submission ID: 125408/0    Office: OVRR
Influenza Vaccine (MDCK Cells)
Novartis Vaccines and Diagnostics, Inc.
Telecon Date/Time: 23-Jul-2012 09:47 AM        Initiated by FDA? Yes
Telephone Number:
Communication Categorie(s):
1. Advice
2. Information Request
Telecon Summary:
Product testing, process validation, submission timing.
FDA Participants: Timothy Fritz
Non-FDA Participants: Matthew Gollwitzer
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Telecon Body:
Dear Mr. Gollwitzer-
CBER’s review of Novartis’ submission STN 125408 is ongoing. Below we provide answers to Questions 3 and 5 of your May 25, 2012 e-mail. We are also providing a response and comments to your proposal to waive Residual Infectious Virus testing of     --------(b)(4)-------- and your proposal to remove Mycoplasma testing of viral harvests. Finally, we are providing advice regarding final container potency testing and the submission timeline provided by Kaia Agarwal to Wellington Sun via e-mail on July 11, 2012.
Question 3: As discussed in the March 07 teleconference with CBER, Dr. Gupta made a recommendation to re-classify the trivalent bulk as sterile.  Furthermore, it was Dr. Gupta’s expectation that NVD would ship sterile trivalent bulk with 2012 strains.  Considering the start of commercial manufacture in June 2012, NVD will not be able to meet the timelines for sterility and requests either to waive such requirement based on recent CFR amendment or incorporate this method post-licensure starting from 2013 flu season.  Does CBER find this acceptable?
CBER Response: Based upon your current testing scheme, we agree with your proposal to waive the sterility release test for trivalent bulk.
Question 5: NVD would like to submit an annual update for 2012 season flu strains.  This could be submitted by July-Aug timeframe prelicensure and/or post-licensure in Oct for expedited approval.  NVD is seeking advice on CBER expectations for submission timing for the annual update.
CBER Response: Novartis may submit updated information for the 2012-2013 influenza strains pre-licensure as an amendment to STN 125408 or post-licensure as a Prior Approval Supplement (PAS). We cannot guarantee an expedited review if the information is submitted as a post-licensure PAS. In addition to Routine Release Testing of Working Seed Viruses data, information to be submitted should include:
  • source documentation and passage history for establishment of working seeds
  • (b)(4) test results for ---------(b)(4)--------------------------- for reassortants passaged ----(b)(4)-------
  • CBER identity confirmation letters for working virus seeds used for production
  • updated labeling items
Please note that your proposed timing of August 12, 2012, to submit an amendment to STN 125408 containing 2012-2013 influenza strain information may result in this amendment being classified as a major amendment. We encourage you to submit this information as soon as possible.
Regarding your April 26, 2012 response to Comment #6 of our March 13, 2012 Information Request:
CBER Response: We do not agree with your proposal to waive the Residual Infectious Virus test in the -----(b)(4)---------- and cannot comment on discontinuing this test after licensure. Including this test in the ---(b)(4)----- and reporting the results in the Lot Release Protocol is consistent with other US-licensed inactivated influenza vaccines.
Regarding your June 19, 2012 (Sequence 12) response to Comment 11 of our May 4, 2012 Information Request:
Novartis Response: The tailing effect of positive responses at (b)(4) end dilutions is displayed in the (hypothetical) graph (Figure 1.11.1-1), which is based on the statistical conditions of a Poisson distribution.
CBER Response: The theoretical explanation you have provided in response to Question 11a shows that ---------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  Data presented in Document No. 231299 indicate that all tests produce positive results at ---------(b)(4)-----. Your theoretical explanation does not fully explain the experimental results with all strains.  Please comment.
Novartis Response: The amount of the virus inoculum in the two methods was different. As defined by the ------(b)(4)---------, the test in -------(b)(4)--------------- applied a total sample volume of ----------(b)(4)-----------------------------------------.  The ------(b)(4)------------- method uses a total sample volume of ---------------(b)(4)--------------------------------------------.  Therefore, due to the higher sample volume used, the ----(b)(4)---------------- test is more sensitive than the test used for embryonated egg vaccines.
CBER Response: We agree that testing ----------------(b)(4)-------------------------------------------- method may provide ---(b)(4)---------- assurance of absence of residual infectious virus than the (b)(4) methods performed in ----(b)(4)----------.  However, this assumption is based on similar levels of sensitivity of detecting live virus using --------------------(b)(4)----------------.  Please provide data on the comparative sensitivity of -------(b)(4)------------------------------ using virus preparations made in MDCK cells.  This information should be submitted within the next 2 weeks. CBER is willing to discuss this issue further by telecon, if necessary.
Regarding your June 19, 2012 (Sequence 12) response to Comment 10b of our May 4, 2012 Information Request:
CBER Response: We understand Novartis’ concerns regarding using the indicator cell method for Mycoplasma testing of viral harvests. Your control cell Mycoplasma testing provides some assurance for viral harvests. We recommend that Novartis develop and implement a --(b)(4)---- Mycoplasma test for viral harvests for the 2013-2014 influenza season. CBER is willing to assist Novartis in the development of this test.
Regarding the timeline provided by Kaia Agarwal to Wellington Sun via e-mail on July 11, 2012; specifically, your proposed timing for submission of samples for in-support testing:
We recommend that all lots of monovalent bulk for the 2012-2013 influenza strains (3 lots each of each of the 3 strains) and 3 lots of formulated trivalent bulk for the 2012-2013 be submitted to CBER for in-support testing no later than August 17, 2012. Samples received after this date may delay approval of STN 125408.
Regarding final container potency testing:
We recommend that a potency test be added to final container release tests.
Please submit the requested information as an amendment to STN 125408. We recommend that you restate each item and follow it with your explanation or clarification. Use of this format helps organize the relevant information and provides a self-contained document that facilitates future reference.
If you have any questions, please contact the Regulatory Project Manager, Drs Brenda Baldwin or Timothy Fritz, at 301-796-2640 or via e-mail.
Thank you.
Timothy A. Fritz, Ph.D.
WOC2 HFM-478
1451 Rockville Pike
Rockville, MD 20852
Phone: 301-796-2640
Fax: 301-827-1597
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