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Record of Telephone Conversation, September 28, 2012 - Flublok
Submission Type: BLA Submission ID: 125285/0 Office: OVRR
Protein Sciences Corporation
Telecon Date/Time: 28-Sep-2012 09:24 AM Initiated by FDA? Yes
Telephone Number: Communicated via e-mail
1. Information Request
Author: TIMOTHY FRITZ
CMC and pharmacovigilance
FDA Participants: Timothy Fritz
Non-FDA Participants: Penny Post
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
From: Fritz, Timothy
Sent: Friday, September 28, 2012 9:24 AM
To: 'Penny Post'
Subject: CBER Information Request STN 125285
Attachments: CBER Information Request_28 Sept 2012 STN 125285.pdf
Dear Dr. Post-
Our review of Protein Sciences Corporation’s submission STN 125285 (Flublok) is ongoing. We have the following requests for additional information:
1. In your 21 November, 2011, submission to STN 125285 (Amendment 49), you provide revised drug substance and drug product release specifications. Please provide a table to show Drug Product Specifications.
2. In your 17 February, 2012, submission to STN 125285 (Amendment 52), you state that because –b(4)-----------------interferes with the –b(4)------------------------ assay, results are obtained from a b(4) dilution of sample. Since this reduces the sensitivity of your assay –b(4)-, please collect samples for --------------------- –b(4)-------------------------------------------------------------------------------
3. In our November 12, 2010 information request, CBER advised Protein Sciences to formulate with monovalent bulks that had potency b(4)--- the potency measured at time of release, in place of instituting a fixed shelf life for each strain. Please note that monovalent bulks should only be used to formulate final product within the same season that they are manufactured, even if potency is acceptable in a subsequent influenza season. To obtain approval to use monovalent bulks for subsequent seasons, you will need to submit a supplement containing data to demonstrate quantitative and qualitative attributes of the monovalent bulk throughout the targeted period.
4. Stability of monovalent bulks for each strain should be evaluated routinely as described in your written procedures, with investigations conducted when lots are less stable than anticipated. Since these procedures were reviewed some time ago, we request that you submit an outline of your stability protocols for monovalent bulks and final product to the file. The outline should note number of lots tested each season, conditions that require additional lots to be placed on stability, identify the tests conducted and frequency of testing.
5. The fill process flow chart you provided by e-mail on 17 September 2012, appears inconsistent with information provided in your March 27, 2012, submission (Amendment 55).
a. The information in your March 27, 2012, submission provides data for tests conducted on samples collected at –b(4)---------------- “to determine the allowable hold time for trivalent bulk prior to filling” (section 4.2 page 7 of 16). Please clarify whether samples from the trivalent bulk or filled vials were used for the potency, b(4), bioburden and endotoxin tests that support hold time, and explain how the –b(4)----------- -- samples were generated for PV5, PV6 and PV7 considering these fills were likely to have been completed in b(4).
b. For validation runs PV5, PV6, and PV7, please provide the time at which formulation began, and the time the last vial was filled.
c. Please state whether the trivalent bulk is held for a significant amount of time prior to filtration and filling. If it is held, please explain why, and whether mixing occurs throughout this period.
d. Please explain whether the trivalent bulk is filtered into a secondary container from which the vials are filled.
6. We recommend future strain change supplements include at minimum:
a. Virus certificate of origin
b. Information currently provided in Section 3.2.S.2.3.8, “WVB plus rHA insert”. This should include:
i. A table showing the plasmid clone, recombinant baculovirus clone and P3 WVB lot numbers.
ii. The nucleotide and corresponding protein sequence of rHA inserts in the WVB, pointing out silent mutations.
iii. Alignment of the amino acid sequence with the reference (please provide the database and accession number, or source, of the reference).
iv. –b(4)------ of the WVB.
v. CoA for the WVB.
c. Antigenic analysis of the rHA when the sequence is not identical to the recommended strain.
d. Demonstration that potency reagents (reference antigens and antisera) are available and suitable for accurately measuring potency.
e. Labeling information.
We acknowledge that most of this information was provided in your 22 June, 2012, submission to STN 125285 (Amendment 56). Please submit images and analyses of SRID gels to demonstrate suitability of both the reference antigen and antiserum for measuring the potency of rHA manufactured for the 2012/13 season. This should include titration of reference antigen and at least one fresh preparation of H3 and B rHAs, together with the total protein concentration, and –b(4)-------.
7. We acknowledge the commitment in your original BLA submission to perform a large, Phase 4, comparative safety and immunogenicity study (PSC07/09) following Flublok approval. Does PSC still intend to conduct this study? If so, please inform us of any updates to this study plan.
Please provide your response as an Amendment to STN 125285. In your reply, we recommend that you restate our request 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 Chair, Dr. Timothy A. Fritz, at 301-796-2640.
Timothy A. Fritz, Ph.D.
1451 Rockville Pike
Rockville, MD 20852
1451 Rockville Pike
Rockville, MD 20852
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