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Vaccines

Review of Drug Substance and Drug Product Analytical Procedures - July 17, 2009 - Hiberix

MEMORANDUM

 

Date:July 17, 2009
  
To:Jay Slater, M.D. HFM-422
Chair, Hiberix BLA Review Team
  
From:Rajesh K. Gupta, Ph.D., HFM-407
Deputy Director, Division of Product Quality (DPQ) and Acting Lab Chief, PQLS
  
Through:William McCormick, Ph.D., HFM-407
Director, Division of Product Quality (DPQ)
  
Subject:STN 125347: – Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), Hiberix® – Review of Drug Substance and Drug Product Analytical Procedures

Review of the analytical procedures and the associated validation protocols and reports was performed by the staff of Division of Product quality (Reviewers from DPQ: Rajesh K. Gupta, Alfred Del-Grosso, James Kenney, Manju Joshi, Karen Campbell, Hsiaoling Wang, Nora Etz, Joe Progar, and Brandon Duong).

SUBMISSIONS REVIEWED

STN 125347/0, 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 125347/0.4 (amendment received 5/1/2009)

STN 125347/0.9 (amendment received 6/15/2009)

Amendment 125347/0.9 also contains GSK responses to CBER Information Requests, “A”, “B”, “C” and “D”, that were made to obtain samples, reagents and additional information/clarification on various test methods. These methods were set up at CBER to perform testing in support of the BLA. GSK’s responses to these requests were adequate, except those related to the validation or adequacy of the test methods. Comments on the validation and adequacy of methods are provided below along with other comments from the review of the methods.

METHODS REVIEWED

Drug Substance

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

Drug Product

  • Identity Haemophlus influenzae type b -----b(4)------
  • Sterility Test by ---------b(4)-------------
  • ---b(4)-------------------------------------
  • Water content ---------b(4)-----------
  • Endotoxin ---b(4)-------------------------------------
  • ---b(4)-------------------------------------
  • ---b(4)-------------------------------------

RECOMMENDED ACTION

The data submitted to support the analytical methods used for testing of drug substance and drug product of Haemophilus influenzae type b conjugate were reviewed and found to ensure the quality of this product. Based on this review, I recommend approval of this product with a number of post-marketing commitments (listed below) to ensure consistent performance and compliance of analytical methods with the current regulations and ICH guidelines.

REVIEW SUMMARY AND POST MARKETING COMMITMENTS

Analytical procedures and the associated validation protocols and reports for the drug substance and drug product were reviewed.  A number of concerns and questions about the methods in the original submission were communicated to the sponsor.  During the BLA review process, the sponsor submitted amendments providing clarification and additional documentation.  There still remain a number of outstanding issues, which CBER requests these be addressed within 6 months of the BLA approval. These issues are listed below.

  1. ---------------------------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

             

1 Page determined to be not releasable: b(4)

 

 

DETAILED REVIEW AND COMMENTS

 

  1. Methods Validation:

CBER Comments provided in the Information Request of May 21, 2009

You provided summaries of method validations. In order for FDA to perform a complete review, validation protocols with experimental design and pre-determined criteria on various validation parameters and validation reports describing results from the validation protocol should be provided for all methods used for release testing of drug substance and drug product. Based on the method validation summaries provided in the submission, the following comments are provided that should be addressed while submitting validation protocols and validation reports.

GSK’s response provided in amendment 125347/0.9 

Provided in Table 1 (Table not reproduced in this review memo) are the method validation protocols and reports for all methods used for release testing of the drug substance and drug product. Note that a compendial method verification report for sterility testing on the drug substance is provided in Section g under “Tests on Drug Substance”, and compendial method verification reports for sterility and endotoxin testing in the drug product are provided in Section a and Section d respectfully under “Tests on Drug Product”.

CBER’s Evaluation: The response is adequate. Please see below comments on validation documents listed in Table 1 (not reproduced in this review memo) for specific methods.

Tests on Drug Substance

Documents Reviewed

m3.2.4.2 Analytical Procedures (Hib-TT, GSK Biologicals) and

m3.2.S.4.3 Validation of Analytical Procedures (Hib-TT, GSK Biologicals)

 

  1. -----------b(4)----------------

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

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

  • -----------------------------------------b(4)---------------------------------------------.

 

13 Pages determined to be not releasable: b(4)

 

 

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

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

  1. -----b(4)------------

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

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

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

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

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

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

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

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

Tests on Drug Product

Documents Reviewed

m3.2.P.5.2 Analytical Procedures – Hiberix™ GSK Biologicals and

m3.2.P.5.3 Validation of Analytical Procedures – Hiberix™ GSK Biologicals

  1. Sterility tests (section 1.1 and 2.3 of m3.2.P.5.2) (-------b(4)------------------ with -b(4)- and by ------------b(4)--------------------) for both Final Bulk and Final Container

Test is performed according to the current ---------------b(4)----------------------- ----------------------------------------------------------------------------------------- and to 21 CFR (Method of analysis 610.12 Sterility) and to current ---b(4)----- Sterility Tests.

CBER Comments provided in the Information Request of May 21, 2009

Please provide a method verification report demonstrating that specified organisms have been selected for bacteriostatis and fungistatis testing of the product matrix.

GSK’s response provided in amendment 125347/0.9 

A method verification report for sterility testing in the Hiberix final container vaccine is provided in Attachment 8.

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

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

 

CBER’s Evaluation: The report provided does not have enough details with regard to number of various organisms used (from a --------b(4)-----) for bacterostatis and fungistatis studies to confirm the number of organism were --b(4)-----. Please commit to provide this information on number of organisms used (from a -----b(4)-------) for bacterostatis and fungistatis studies.

 

  1. Identity by --b(4)--- (section 2 of m3.2.P.5.3)

The Haemophilus influenzae type b polysaccharide (Hib) conjugated with tetanus toxoid (TT) is identified by an ----------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

CBER Comments provided in the Information Request of May 21, 2009

This is a qualitative test and requires demonstration of specificity to confirm its suitability for intended use. Little information was provided in the summary, except a brief statement on the specificity of the method.  Please provide a validation protocol with experimental design and specifications for evaluation of specificity of the method and a validation report describing results from the validation protocol.

GSK’s response provided in amendment 125347/0.9 

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

 

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

  1. ---------------------------b(4)--------------------------------------------

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

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

 

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

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

 

1 Page determined to be not releasable: b(4)

 

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

 

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

  1. --------------------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

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

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

 

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

 

  1. Endotoxin content by ----b(4)------ method) (section 2.6 of m3.2.P.5.2).

Endotoxin is measured by the ----b(4)------------- method as described in the current -----------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

CBER Comments provided in the Information Request of May 21, 2009

Please provide a method verification report or a detailed test procedure that describes the verification criteria results for the standard curve and that demonstrates that the drug substance does not inhibit or enhance the

---b(4)--------- reaction.

 

GSK’s response provided in amendment 125347/0.9 

A method verification report for endotoxin testing in the Hiberix final container vaccine is provided in Attachment 9.

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

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

 

CBER’s Evaluation: The response is adequate.

 

  1. ------------------------b(4)----------------------------------------------------------------------------------------

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

 

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

1. -----------------------------------b(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

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

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

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

 

 

3 Pages determined to be not releasable: b(4)

 

 

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

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

 

CBER Evaluation:  The response is adequate

 

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

2. --------------------------------b(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

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

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

 

CBER Evaluation:  The response is adequate

 

  1. Water content by ----b(4)------

 

The test is performed according to ------------------b(4)-------------------------------------------------------------------------------------. The water content is determined by the -------b(4)---------- method. This method is based on the ------------b(4)----------------------------------------.

 

CBER’s Comments

The method and validation summary provided are adequate for the intended use.

 

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