
Teleconference to Discuss Complete Response Item, October 6, 2010 - MenHibrix

 
Date:
October 6, 2010  

Subject:
Teleconference to Discuss Complete Response Item 67 c, d, and e (adding --b(4)-- content as QC release tests for the MenHibrix final container)  

Participants:
CBER: 
Jennifer Bridgewater (Consumer Safety Officer)
Daron Freedberg (Chemist, DBPAP/LBP)
Rajesh Gupta (Deputy Director, DPQ)
Tina Roecklein (Consumer Safety Officer)
David Staten (Project Manager) 
Liz Sutkowski (Head of CMC Review Branch 3) 
Joseph Temenak (Project Manager) 
Willie Vann (Supervisory Chemist, DBPAP/LBP)

GSK: 
Nancy Cauwenberghs, Director, Technical Regulatory Unit 
Jean-Francois Dierick, Manager, QC Biochemistry 
Jody Gould, Director, Vaccines, North American Regulatory Affairs 
Kalliopi Grigoriadou, Scientist, Technical Regulatory Unit 
Dominique Labbe, Expert Scientist, Analytical R&D 
Olivier Laloux, Director, Analytical R&D 
Christophe Lenfant, Senior Project Manager, Analytical R&D 
Norris Pyle, Assistant Director, Vaccines, North American Regulatory Affairs 
Catherine Vigano-Wolff, Scientist, Technical Regulatory Unit 
Xavier Raquet, Senior Scientist, Technical Regulatory Unit

Product: 
MenHibrix STN 125363, submitted August 12, 2009

Purpose of Meeting: 
The purpose of the meeting was to discuss GSK’s planned response to Item 67 (c, d, + e) from the Complete Response Letter dated June 11, 2010. Specifically, the requested addition of –b(4)---- content as a QC release test for Hib, MenC and MenY on the MenHibrix final container vaccine.

Discussion: 

GSK provided CBER with information on the planned response (Attachment 1) and a slide presentation of that information (Attachment 2). GSK presented the information, outlining why a test for –b(4)---- content has not been able to be developed due to issues with specificity, sensitivity, accuracy and robustness. In place of –b(4)-- content testing, GSK is proposing (b)(4) by -----(b)(4)----- for QC release and stability. The test has been shown to detect degraded conjugate and to correlate with –b(4)--

CBER noted that there are two approved quadravalent products that currently have a –b(4)-- content test on the final container. GSK highlighted that there are key differences between Menhibrix and the approved products that prevent the accurate testing of –b(4)-- in the Menhibrix final container. As explained by GSKBio, the following specific Menhibrix characteristics explain the technical limitations for the development of a valid –b(4)-- for Hib, Men C and MenY on the final container vaccine:
•MenHibrix is lyophilized in the presence of sucrose, which interferes in -------------(b)(4)------------------------------------ used for the quantification of Hib, PSY and PSC
•Menhibrix conjugates are made from large size --------------------(b)(4)---------------------. The resulting conjugates have a large size (up to -----------------------------------(b)(4)-------------------------------------------------------.

Various ---------(b)(4)-------- have shown that –b(4)---, especially those of ----------------------(b)(4)-----------------------------. Consequently, the –b(4)-/conjugates separation techniques have poor accuracy. 

In terms of –b(4)- detection, several approaches have been tested which all have shown either lack of specificity and/or sensitivity. For instance, interferences of PSY- and sucrose prevent the specific quantification of PSC. CBER asked for more details regarding the dialysis for quantification of free PSY by ----(b)(4)----. GSKBio has highlighted that despite the fact that around (b)(4) of the total sucrose content is eliminated after (b)(4), its residual content is still too high to allow PSY quantification based on its –b(4)--content.

From all data generated, it was also highlighted that the most appropriate quantification methods (---(b)(4)--- for Hib and (b)(4) for PSY) have poorly informative sensitivity.

GSKBio explained that the -----(b)(4)----- assay can be implemented as a routine release test on the final container vaccine for release and stability. In this assay, ---------------------------(b)(4)------------------------------------------------ are consequently not detected by this assay. A correlation experiment was conducted in which conjugated (b)(4) were subjected to ---(b)(4)--- conditions and then formulated into the final vaccine (Attachment 2, slide 5). ------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------- test results and consequently, the ability of ---(b)(4)--- to detect --(b)(4)-- conjugates in the final product. The high sensitivity of -----(b)(4)----- to detect conjugate ---(b)(4)--- is also clearly demonstrated where for instance a (b)(4) increase in free Hib content corresponds to (b)(4) shift in the ---(b)(4)--- response.

CBER asked if GSK had performed (b)(4) studies in final container vaccine followed by testing via the -------(b)(4)-------. GSK highlighted that the –b(4)--- measured in the -------(b)(4)------- shown in Attachment 2-(slide 5) are more representative of the product than -(b)(4)------------as they are directly generated from --------(b)(4)---------. Also as stated above, in this assay, the conjugate is detected via a -----------(b)(4)-------------------------are consequently not detected by this assay.

CBER and GSK discussed various other aspects of the testing that had been performed to date. The take away messages from this meeting were:
•CBER will evaluate GSK’s planned response to have -----------(b)(4)----------- in place of a –b(4)--- content as a QC release test for Hib, MenC, and MenY on the final container vaccine once all information is submitted in the complete response. GSK’s response must contain all details and justifications upon which CBER will make their determination.
•CBER encourages GSK to continue to look for a suitable method for conducting a –b(4)-----content test for Hib, MenC, and MenY on the final container vaccine.

Follow-Up/Actions: 

GSK will ensure the complete response contains the following:
•All details and justifications as to why ----------(b)(4)----------- is a suitable method for detecting --------(b)(4)---------.
•All details regarding the failed attempts to qualify a QC release test for –b(4)- content on Hib, MenC, and MenY in the final container vaccine and the corresponding justification as to why such a test for –b(4)-- content cannot be developed for MenHibrix.
•As agreed during the teleconference, GSK will provide information as to the PS content used in the clinical trials.
