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Vaccines, Blood & Biologics

Final DBSQC Review Memo, April 20, 2012 - MenHibrix


Date: April 20, 2012

To: Joseph Temenak, HFM-481
Chair, BLA Review Team

From: Rajesh K. Gupta, Ph.D., HFM-680
Deputy Director, Division of Biological Standards and Quality Control (DBSQC)

Through: William McCormick, Ph.D., HFM-680
Director, Division of Biological Standards and Quality Control (DBSQC)

Subject: STN 125363 – Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, Hib-MenCY-TT, MenHiberix®, Review of Drug Substance and Drug Product Analytical Procedures

Cc: William McCormick, Ph.D., HFM-680
Willie Vann, Ph.D., HFM-437

On 12 August 2009, GSK submitted a Biologics License Application (BLA) for Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine. Division of Biological Standards and Quality Control (DBSQC), then Division of Product Quality (DPQ), reviewed the analytical methods, associated validation protocols and reports and specifications on the Drug Substance and Drug Product in the original submission and amendments listed below.

STN 125363/0, Sections 3.2.S.4.2, 3.2.S.4.3, 3.2.P.5.2, 3.2.P.5.3, Documents related to Methods in Section 3.2R
STN 125363/0.1 (amendment received 08/27/2009), List of SOPs, validation protocols and validation reports for the Drug Substance and Drug Product
STN 125363/0.3 (amendment received 02/08/2010) Additional method validation documents, Batch analysis data on clinical lots
STN 125363/0.4 (amendment received 03/03/2010) Additional method validation documents
STN 125363/0.7 (amendment received 04/21/2010) Additional methods related documents, responses to specific question related to methods and supply of reagents for in-support testing

Methods Reviewed

Drug Substance, Polysaccharide-TT Conjugates (Hib-TT, MenC-TT and MenY-TT)

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Drug Product

  • Sterility Test by -----(b)(4)-----------
  • Identity Meningococcal C conjugate and Identity Meningococcal Y by (b)(4)
  • Identity Haemophilus influenzae type b antigen by (b)(4)
  • Hib Polysaccharide content by (b)(4)
  • PSC-PSY contents by (b)(4)
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  • ----------------------(b)(4)-----------------------------------------------------------
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  • Endotoxin Content by ---------(b)(4)------------
  • General Safety or Abnormal Toxicity

On May 7, 2010, DPQ’s review memo was submitted and comments from that review memo were communicated to the sponsor in a complete response (CR) letter on June 11, 2010. GSK provided response to these comments in an amendment 0.12, received on April 15, 2011. GSK’s responses to the DPQ’s comments were reviewed and a memo dated August 26, 2011 with additional comments was submitted. These comments were summarized in a memo dated September 6, 2011 as “Letter-Ready comments” and were communicated to the sponsor in another CR letter dated September 21, 2011. GSK responded to these comments in an amendment 0.21, received on December 1, 2011. Additional clarification and information was requested from the sponsor on February 23, 2012, to which GSK responded by an amendment 0.25, received on March 1, 2012.

In an amendment 0.12, GSK had committed to perform additional method validation studies in response to DPQ’s comments communicated in the first CR letter dated June 11, 2010. These additional validation reports were also submitted in the amendment 0.21 (Reviewers from DPQ: Rajesh K. Gupta, Lokesh Bhattacharyya, Alfred Del Grosso, James Kenney, Manju Joshi, Karen Campbell, Hsiaoling Wang and Brandon Duong).

This memo provides review of GSK’s responses to comments communicated in the CR letter dated September 21, 2011, to additional validation reports submitted in amendment 0.21 and information in other amendments related to methods submitted after DPQ’s last review memo of August 26, 2011.

Additionally, DBSQC completed testing of representative samples from monovalent conjugate bulks and final container to evaluate safety and potency of the product. Tests important for the quality and manufacturing consistency of the product were selected in discussion with the CMC reviewers from DBPAP. Separate memos for in-support testing have been submitted to the STN 125363 file.

Submissions Reviewed in this Memo

STN 125363/0.14 (amendment received 08/25/2011), Qualification reports for reagents used for in-support testing
STN 125363/0.19 (amendment received 10/26/2011) Proposal for comparability protocols and ----(b)(4)--- assay on Drug Product
STN 125363/0.21 (amendment received 12/01/2011) Responses to the CR letter dated September 21, 2011 and additional method validation documents from commitments made in amendment 0.12
STN 125363/0.24 (amendment received 01/31/2012) Validation report on ---(b)(4)---- assay performed on Drug Product
STN 125363/0.25 (amendment received 03/01/2012) Response to DBSQC Information Request of February 23, 2012
STN 125363/0.26 (amendment received 04/03/2012) Validation reports on polysaccharide assays on Drug Product

Recommended Action

The responses and data submitted by the GSK in response to DPQ’s comments communicated as part of the CR letter on September 21, 2011 and additional information and documents related to analytical methods submitted in other amendments were reviewed. All questions and comments related to analytical methods have been addressed to the satisfaction of DBSQC’s reviewers. Based on DBSQC’s review of all the information and documents submitted to support analytical methods for testing of Drug Substance and Drug Product and related specifications for the Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, MenHibrix®, and test results on representative samples meeting product specifications, I recommend approval of this application.

Review and Comments on GSK’s Response to the CR Letter (Amendment 0.21) and Data submitted in other Amendments

DBSQC’s comments from memos of August 26, 2011 and September 5, 2011 that were communicated to the sponsor in the CR letter dated September 21, 2011, and subsequent information request communicated by an email on February 23, 2012 are given in regular font with the comment number from the CR letter. GSK’s responses submitted in amendments 0.21 and 0.25 are provided in italics font and DBSQC’s final review of the responses and conclusion are provided in bold font.

Regarding Qualification Reports for Reagents used for in-support Testing

In response to CBER’s request, GSK submitted qualification reports for all reagents used during testing of representative samples in an amendment 0.14. All qualification reports have been adequate.

Regarding Comparability Protocols to –(b)(4)-- Critical Reagents and Reference Standards



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15 pages redacted due to (b)(4)

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