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Vaccines, Blood & Biologics

CMC Review Memo, May 15, 2012 - MenHibrix


Date: May 15, 2012

From: Michael P. Schmitt, Ph.D., Chief, LRSP/DBPAP/OVRR

Through: Jay Slater, M.D., Director, DBPAP/OVRR

To: File, BLA 125363/0/21

Product: MenHibrix (Meningococcal Group C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine)

Subject: CMC Review Memo – GSK’s response to FDA’s Complete Response (CR) Letter, issued September 21, 2010.


STN 125363/21 (Amendment received 11/30/2011)

GSK responded to the second CR letter issued by CBER (September 21, 2010) on November 30, 2011. This review memo covers only item 6 in the CR letter dated September 21, 2011.


On August 12, 2009 GlaxoSmithKline Biologicals submitted a BLA for Meningococcal Group C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, which has the proprietary name MenHibrix. Clinical development of this vaccine was conducted under IND (b)(4). The vaccine contains N. meningitidis serogroup C and Y polysaccharides (PSC and PSY, respectively) and H. influenzae type b capsular polysaccharide (PRP), with each covalently attached to tetanus toxoid. The final vaccine product is lyophilized and provided in (b)(4) glass vials, and is reconstituted prior to injection with a saline diluent in ----(b)(4)-----------. The final vaccine contains 2.5 mg PRP-TT, 5 mg PSC-TT and 5 mg PSY-TT in a 0.5 ml dose. The vaccine is indicated for immunization of toddlers 6 weeks through 15 months for the prevention of invasive disease caused by N. meningitidis serogroup C and Y and H. influenzae type b.

On June 11, 2010, CBER submitted the first CR letter to GSK for the MenHibrix BLA. I was responsible for three items in this CR letter. The firm responded to CBER’s questions on April 15, 2011. While the firm provided acceptable responses to two of my comments, they did not adequately address concerns to my third comment contained in item 25c in the CR letter (see item 25c below). CBER submitted a second CR letter to the sponsor on September 21, 2011 to address unresolved issues. I had one item in the second CR letter, item 6. Item 6 was related to the firm’s insufficient response to item 25c of the previous letter. CBER received a response to the second CR letter on November 30, 2011.


Below is item 25c included in the first CR letter dated June 11, 2010.

25c We note that the initial (b)(4) testing done at Rixensart on the purified TT is for monitoring purposes only (Table 99, m3.2.S.2.4-section 3.2). In order to maintain manufacturing process consistency, we request that you develop a specification ----------(b)(4)-------- for the (b)(4) analysis on TT prior to –(b)(4)- purification at Rixensart. In addition, we request that you revise the –(b)(4)--- currently performed on the purified TT held in storage to a “quality decision test” instead of a monitoring purposes only test. Please comment.

Below is a summary of the sponsor’s response to item 25c:

The firm did not accept our assessment that a specification was needed for this manufacturing step and they indicated that the test should be maintained as a monitoring test rather than a quality decision test. The firm believed that appropriate controls and testing are in place at steps ---------(b)(4)--------------------------- to guarantee process consistency. The firm indicated that although no specification is provided for monitoring tests, consistency ranges are specified within the Action and Alert levels that are in place to ensure consistency of manufacturing (Action and Alert levels were not provided for this step in the BLA). The firm indicated that these ranges are reviewed and adapted (if needed) on a regular basis according pre-defined rules. The firm noted that monitoring test results that fall outside of the pre-defined consistency range will result in an investigation if Action Levels are exceeded.

  • We found the sponsors response to be inadequate and submitted the following item in a second CR letter

Item 6 in the second CR Letter dated September 21, 2011:

You provide the in-process quality decision and monitoring tests for each step of the TT purification and ---(b)(4)----- process performed at Rixensart (Table 1 in your response to Question 25 of the CR Letter dated 11 June 2010). We do not concur with the ----(b)(4)------------------------------- testing performed at the ----(b)(4)------------- as a ----(b)(4)----------------. While we acknowledge that the ----(b)(4)----------- are essential to maintain process consistency, CBER also believes that establishing a predefined specification in the --(b)(4)---- content of the purified TT (b)(4) immediately ------(b)(4)-------- purification is equally important in maintaining process consistency. We note that stability studies with the TT (b)(4) clearly indicate that ----(b)(4)--- TT significantly –(b)(4)----- over time. Please establish specifications for the TT –(b)(4)--- content at the step –(b)(4)-- just prior to the -------(b)(4)-------- of TT that occurs at Rixensart. Also, please revise this test to a quality decision test rather than a monitoring test.

Sponsors response to item 6 above, received November 30, 2011:

The company agrees to revise the ------------(b)(4)------------------ testing performed at the (b)(4) step of the Hib-TT and MenC/Y-TT processes to a quality decision test rather than a monitoring test. The steps and the timings at which a test for the -------(b)(4)-------- will be place during --------(b)(4)------- of the TT and ---------(b)(4)--------- are provided in Table 1 and Table 2 for the Hib-TT and Men-TT processes respectively. For a description of the analytical method used to measure the --------(b)(4)---------, please refer to modules m3.2.S.2.4 Controls of Critical Steps and ---(b)(4)--- Hib-TT (submitted February 8, 2010 in sequence 0003), Menc-TT (submitted August 12, 2009 in sequence 0000) and MenY-TT (submitted February 8, 2010 in sequence 0003).

The statistical approach used to calculate the specifications for the ------(b)(4)------- at the (b)(4) step of the Hib-TT process is based on process performance indices as described in the answer to Item 16.

The statistical evaluation of the specification for the -----------(b)(4)------------- has been performed based on the data provided in Table 3and Table 4 for the Hib-TT and Men-TT processes, respectively. All lots used to establish the specification are representative of the commercial manufacturing process described in module m.3.2.s.2.2 Description of

Manufacturing Process and Process Controls related to each drug substance. The average and standard deviation values are shown, as well as the process capability indexes.

Based on this statistical evaluation, the proposed specification is --------------------------------------------------------------------(b)(4)---------------------------------------------------------- of the Hib-TT and MenC/Y-TT processes.

As requested in Item 11a, the ------(b)(4)---------- test will also be implemented in the QC release program of the purified TT bulk. Please note that the analytical methods used for the QC release of the purified TT bulks and for in process testing mentioned in Table 1 and Table 2 are not identical. Differences in the (b)(4) methods are detailed in Table 5. Due to those differences in the analytical procedures, the results obtained with these (b)(4) methods in terms of -----(b)(4)----------- should not be compared. In addition, as a result of the different procedures, the specification applied on the TT purified bulk (please refer to the answer to Item 11a) and the specification applied at the (b)(4) step of the Hib-TT and MenC/Y-TT processes are different.

CBER’s response:

The sponsor’s response to item 6 is acceptable. There were, however, internal discussions at CBER regarding the statistical approach that used process performance indices to determine the specification for --------(b)(4)------- for TT. This methodology was ultimately found to be acceptable.


The sponsor’s response to item 6 is adequate. All of my issues from the first and second CR letters have been addressed. I have no further comments. Therefore, I recommend approval of this BLA.

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