Date: September 1, 2011
From: Michael P. Schmitt, Ph. D.
Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic, and Allergenic Products, HFM-437
Through: Drusilla Burns, Ph.D.
Chief, Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic, and Allergenic Products, HFM-434
To: File, BLA 125363/12
Product: MenHibrix (Meningococcal Group C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine)
Subject: CMC Review Memo – GSK’s response to the FDA Complete Response (CR) Letter, submitted to the firm on June 11, 2010.
STN 125363/12 (Amendment received 4/15/2011)
The sponsor responded to the FDA CR letter on April 15, 2011. This review memo covers only my specific questions that were included in the CR letter.
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 proposed 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.
CBER submitted a CR letter to GSK regarding this original submission BLA on June 11, 2010. The firm responded to CBER’s questions on April 15, 2011. I had three questions or comments in the CR letter. I had two additional questions in my review memo that were not part of the CR letter, since they were addressed through internal discussions at CBER.
Below are the original five items included in my review memo.
Questions and comments for sponsor:
- You have not stated how you will inform CBER when new --(b)(4)-- of C. tetani are produced If you propose to report ----(b)(4)---- changes in your annual report, please submit a detailed comparability protocol for replacement and reporting of future ----(b)(4)---- changes. Alternatively, after approval of this BLA you may submit a future comparability protocol supplement for replacement of -------(b)(4)-------.
- We note that you have previously produced C. tetani -------(b)(4)-------- using ------(b)(4)-------. We strongly recommend that all future ------(b)(4)------ and ------(b)(4)-------- be produced from ----------(b)(4)---------------. Please explain how you will derive future -------------(b)(4)---------------.
- We note that during Tetanus Toxoid manufacturing in building (b)(4) many of the monitoring test results failed to meet your predefined Alert limit or Action limit specifications. Although we understand that these specifications were initially determined for manufacturing in building (b)(4), we recommend that you establish updated Alert and Action limits for monitoring tests throughout the manufacturing process for the purified TT produced in (b)(4). Please provide updated Alert and Action limits for the TT manufacturing process or provide a proposal on how you will revise these specifications in the future. Please specify the number of lots you will use in establishing updated specifications.
- Please specify the exact date when TT manufacturing was initiated in building (b)(4).
- 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)----------- at Rixensart. In addition, we request that you revise the (b)(4) test currently performed on the purified TT held in storage to a “quality decision test” instead of a monitoring purposes only test. Please comment.
Items 1, 3, and 5 above were included in the CR letter. Question 2 was not included in the letter, since it was noted that manufacturers on rare occasions are permitted to produce ----(b)(4)---- from -------(b)(4)-------. Comment 4 was also not included in the CR letter, since it was determined that all Tetanus Toxoid lots manufactured after 2005 were produced in (b)(4).
The acceptability of the firm’s response to items 1, 3, and 5 is indicated below:
Memo item 1 is answered in response to question 35 in the CR letter:
In my view, the firm provided an acceptable response to this question with regard to the information they provided in their CP for the preparation of C. tetani ----(b)(4)----. Most of the information provided in the CP is derived from the original BLA. I did not review the information regarding the preparation of the ----(b)(4)---- for Hib, MenC or Men Y.
Memo item 3 is answered in response to question 33 in the CR letter:
The firm provided an acceptable response to this question. In their response, they indicated that alert and action levels for in process monitoring tests throughout the manufacturing process for Tetanus (b)(4) production were re-calculated in 2010 in the (b)(4) facility. All commercial and consistency lots were included in the calculation and at least (b)(4) data points were used to determine each step in the process. A data Table (Table 1) is provided in their response that shows the results of these revised calculations.
Memo item 5 is answered in response to question 25C in the CR letter:
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 downstream and prior to conjugation 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.
CR Letter Response for question 25c:
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 monitoring test. While we acknowledge that the downstream steps are essential to maintain process consistency, CBER also believes that establishing a predefined specification in the ------(b)(4)----- of the purified TT (b)(4) immediately prior to --(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)---- significantly ---(b)(4)--- over time. Please establish specifications for the ----(b)(4)---- content at the step --(b)(4)-- just prior to the ---(b)(4)--- purification of TT that occurs at Rixensart. Please revise this test to a quality decision test rather than a monitoring test.
I do not recommend approval at this time. GSK has not provided an adequate response to question 25c.