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Vaccines, Blood & Biologics

CR Response Review, May 13, 2012 - MenHibrix

Date:May 13, 2012
To:File for 125363/0

James E. Keller, Ph.D.


Michael Schmitt, Chief

Subject:MenHibrix Product Review Memo, Response to CR Items for Tetanus Toxoid Manufacturing and Testing
Sponsor:GlaxoSmithKline (GSK)

MenHibrix CR Response Review Background

On 12 August 2009, GSK submitted a Biologics License Application (BLA) for Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine. The proprietary name is MenHibrix. On 11 June 2010, CBER issued a complete response (CR) Letter to the firm. The firm responded to this letter on 15 April 2011. The response was considered inadequate. Therefore, on 21 Sept 2011, CBER issued a second CR Letter. The firm provided responses to the second CR Letter on 30 Nov 2011 (Amend 21). Information Requests (IR) were sent to the firm on March 20, 2012 and onMay 02, 2012. A teleconference was held with the firm on May 03, 2012. The subject of these communications was to discuss concerns regarding the firm’s responses to CR Items 11a and 12. The firm responded to item 11a on 04-April 2012 (Amend 27) and to item 12 on 09-May 2012 (Amend 31). The firm has adequately addressed my concerns related to tetanus toxoid manufacturing and testing. I have no other outstanding issues. My review is below.

CMC Review of GSK’s CR Letter Response Dated 30 November 2011

We do not concur with your implementation of the following tests as monitoring tests. Please add these tests as QC Release Tests:
a. ------------b(4)-------------------------------------------------------------------------------------------------

Question 11a had an additional three subset requests submitted by CBER to GSK in an IR dated 20 March 2012, as follows:

For the validation of the –b(4)- method used at –b(4)- to quantify –b(4)---------- in Purified TT, please provide the following information from the validation report:

-----b(4)-------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Review of the firm’s response to Question 11a from CR Letter Response and IR Response

-----b(4)----- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

We do not concur with a b(4) month shelf life for Purified TT as proposed in the BLA. Please revise the expiration date to reflect the real time stability data (i.e., --b(4)--- In addition, please provide a specification for the test ----b(4)----------------------------------------------- performed during the stability protocol.

The firm and CBER had several interactions regarding this issue. On 30 Nov 2011 and subsequently on 04-April 2012 (Amend 27) the firm indicated that –b(4)------ stability data supported a hold time greater than –b(4)----. However, CBER noted that the next stage of manufacture requires ----b(4)----------------------------------------------------------- content has –b(4)------------------------------ Therefore, CBER disagreed with the firm’s proposal to set expiry of purified ---b(4)---------------. CBER also disagreed with the proposed stability specification of “greater than –b(4)--------------” and communicated to the firm that the specification would have to be greater than ---b(4)-------------

The firm explained that stability testing and in-process testing to ----b(4)-------------------------------------------- test methods. The firm said that the –b(4)---- method used to track -b(4)--------- during stability testing generated –b(4)-------------- values that were about -b(4)--- than % values obtained using the in-process –b(4)----- method. According to the firm –b(4)----- in the stability –b(4)--- assay was equivalent to ---b(4)----------------- during PS-TT manufacture. The firm submitted –b(4)------------ data obtained from b(4) TT lots using both –b(4)---- methods to demonstrate the b(4) shift in –b(4)--------- values. The b(4) lots each contained about –b(4)----------- according to the stability –b(4)---- assay and showed about ---b(4)------------- when measured using the in-process –b(4)---- assay. The firm did not directly test whether the same % shift also occurs for lower –b(4)-------content; for example, they did not demonstrate that –b(4)-------------- during stability testing was equivalent to –b(4)--- during in-process testing.

On May 02, 2012 CBER sent an IR to the firm. On May 09, 2012 the firm agreed to accept –--b(4)--- stability for purified TT bulk along with a revised release specification of “not less than ---b(4)--------------. They also submitted the following language for a PMC:

---b(4)------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

The –b(4)---- dating for –b(4)------, the revised release specification of “not less than --b(4)-------------, and the PMC stated above are acceptable.


The firm has addressed all of the outstanding CMC Tetanus Toxoid issues. Therefore I have no additional CMC concerns and recommend approval of MenHibrix.

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