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Vaccines, Blood & Biologics

Record of Telephone Conversation, August 24, 2012 - Flucelvax


Submission Type: BLA    Submission ID: 125408/0    Office: OVRR
Influenza Vaccine (MDCK Cells)
Novartis Vaccines and Diagnostics, Inc.
Telecon Date/Time: 24-Aug-2012 09:00 AM        Initiated by FDA? Yes
Telephone Number: ---(b)(4)--------
Communication Categorie(s):
1. Advice
Telecon Summary:
Residual virus testing, lot release protocol.
FDA Participants: Rajesh Gupta, Lokesh Bhattacharyya, William McCormick, Karen Campbell, Zhiping Ye, James Kenney, Muhammad Shahabuddin, Timothy Nelle, Brenda Baldwin, Timothy Fritz
Non-FDA Participants:
Matthew Gollwitzer – Regulatory Affairs Manager
Umang Shah- Regulatory CMC
Kerstin Platz – Regulatory CMC
Karsten Kattmann – Segment Head, Marburg Tech Ops
Stefan Knapp - Head QA
Manfred Brunen – FCC Technology Transfer
Jens Gregersen – FCC Technology Transfer
Diana Hammer – Quality Control
Holger Kost – Head of QC
Markus Schweitzer – Quality Operations Manager
Bernhard Knapp – QP – Quality Release
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Telecon Body:
A telecon was scheduled to discuss Novartis’ June 19, 2012, response to items 11a and 11b of CBER’s May 4, 2012, information request regarding the residual infectious virus testing. In addition, Novartis’ proposed changes to the Flucelvax Lot Release Protocol (LRP) were discussed.
We indicated that some of the information provided by Novartis appeared contradictory. Novartis clarified that they had tested --------------(b)(4)------------------------------- and that this was why 100% of the experiments were positive for all 3 strains. CBER requested that Novartis provide the validation protocol and testing reports and to indicate which lots, titer and dilution of virus were tested.
Novartis provided a theoretical explanation of why the ----(b)(4)---------- method should be more sensitive than the ----(b)(4)------------- method for detecting residual infectious virus. We noted that Novartis had not provided actual data showing the comparability between the 2 methods and suggested 2 possible options for demonstrating comparability:
Option 1:
If Novartis is unable to demonstrate that the test for residual infectious virus performed in –(b)(4)-- cells is not at least as sensitive as the test performed in          ----(b)(4)----------, Novartis will need to test the first 3 ----(b)(4)------- lots from each annual influenza season for residual infectious virus in both the --------------(b)(4)------------. All 3 lots for all seasonal strains must pass the test in both substrates.  Subsequent lots during the season can be tested by the ---(b)(4)--- method only.
Option 2:
Alternatively, if Novartis can provide validation data demonstrating that the sensitivity of the residual infectious virus test performed in ---(b)(4)--- is at least as great as the test performed in ---(b)(4)----------, then Novartis may release             ----------(b)(4)----------------------------- by the test performed in ----(b)(4)------ only.  We suggested that a possible experiment to validate the sensitivity of the assay (which should be demonstrated for at least 3 strains representing H1N1, H3N2 and B types) was as follows:
-----(b)(4)-------- lots (at least 3 lots for each strain) spiked with serial dilutions of the same strain of MDCK cell grown influenza virus of known concentration                   ---(b)(4)----------- should show at least similar or higher sensitivity in detecting spiked virus by the ---(b)(4)-- test as compared to the ------(b)(4)------- test.  As per theoretical explanation provided during the call that the sensitivity of –(b)(4)------- is significantly higher than the ----(b)(4)-----------, they can perform the test at one spike level of ----(b)(4)---- and show that such spike cannot be detected by (b)(4), but readily detected by ---(b)(4)-------.
We informed Novartis of the critical nature of this data and of the need that this information be provided prior to licensure. Novartis suggested that the scientific basis for residual virus testing of ----(b)(4)---- was not the most sound. We replied that we were discussing this issue internally but that, until a decision was reached, the ----(b)(4)----- should still be tested and that we needed to take a conservative approach to the testing. Novartis said that they would work to provide the data as soon as possible.
Lot Release Protocol (LRP)
Based on our comments, Novartis provided via e-mail on August 23, 2012, a revised LRP and Mycoplasma testing template together with a request to discuss the following specific topics:
  1. Format of the Mycoplasma in Control Cell (indicator method) (see page 6 of NVD final draft based on FDA feedback on July 25, 2012)
  2. Reporting of the ----(b)(4)------- result - to be included in the annual strain change supplement starting 2013-14
  3. ---------(b)(4)--------------------- SRD testing ---------------(b)(4)------------------------------------------
Regarding item a) We said that we would need time to review the LRP and Mycoplasma template before providing a response. Regarding item b) We said that we needed to discuss further internally and would provide a response as soon as possible. Regarding item c) We informed Novartis that we found their proposal ----(b)(4)----- SRD testing                  ----------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------.
We informed Novartis that they could provide CBER with trivalent bulk samples for concurrent testing. Novartis acknowledged the option of performing concurrent testing and said that they would ensure that they had the appropriate template to include with the samples.
Additional Discussion
We said that Novartis should discuss the intended overage for the final product with CBER and that their overage plan and subsequent stability results should be submitted as a supplement.

Page Last Updated: 12/19/2012
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