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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

DPQ Comments

MEMORANDUM

Date:March 30, 2009
To:Dr. Lewis Markoff, HFM-451
From:William McCormick, Ph.D., HFM-407
Through:Dr. Norman W. Baylor, Office Director OVRR/CBER
Subject: Summary Review of STN 125280/0/0: Intercell Biomedical Ltd, – Japanese Encephalitis Vaccine, Inactivated, Adsorbed; Review of Drug Substance and Drug Product Analytical Procedures, and Lot Release Protocol template.

DPQ has completed review of sections of the BLA for Japanese Encephalitis Vaccine STN 125280 trade name IXIARO submitted for license by Intercell AG. Sections reviewed included 3.2.S. Drug Substance and 3.2.P. Drug Product specifications, analytical procedures and associated method validation protocols and reports.

Reviews of the intermediate, DS and DP specifications, analytical procedures and the associated validation protocols and reports were performed by the staff of Division of Product quality (Reviewers from DPQ: Alfred del-Grosso, Brandon Duong, James Kenney, Sarah Larson, Manju Joshi, Muhammad Shahabuddin, Rama Velicheti and Rajesh K. Gupta, until recused).

 Methods Reviewed:

Intermediates/Early Stages

Test for Adventitious Viruses
Mycoplasma

Drug Substance

----------(b)(4)----------------
------------
-----------------
--------- Assay, Inactivation test
----------(b)(4)-------------

Drug Product

Sterility
---(b)(4)--
Potency
--------(b)(4)-----------
General Safety

The following concerns were raised by Intercell in section 3.2.S.4.2.3 Drug Substance ---(b)(4)----------------------------- of the original Application.

“It should be noted that this method is not considered fully satisfactory for determining --------(b)(4)----------- in Drug Substance because the limit of quantification of the assay -(b)(4)- is close to the expected --------(b)(4)---------- in Drug Substance (-----(b)(4)----), resulting in a low precision of about 20% at this -(b)(4)- level. A new method, with a more appropriate lower limit of quantification is in final phase of development and validation (------------(b)(4)---------- Assay), described in Section 3.2.P.5.2.8.”

Concerns about follow-through on these recommended changes to the assay are further described in the method review memo authored by reviewer Dr. Del-Grosso and uploaded to the file (dated Feb 3, 2009). It is recommended that completion of assay qualification and validation and initiation of use of the changes to the method be addressed by Supplement submission within 3 months as a Post-Marketing Commitment (PMC). Until this PMC is completed it is expected that assay variability near the limit of quantitation is expected to contribute to a number of Out of Specification results that may increase product failure rate. When lots are found unacceptable, it may be a consequence of the assay limitations instead of actual product characteristics. In this situation, when lots are found acceptable using the current version of the assay, we will have adequate assurance that they are indeed acceptable. It is therefore acceptable to use the assay as originally submitted until the PMC is completed and approved.

Amendment 10 was reviewed for changes to the specifications for the Control of Drug Product which indicated the following pending recommendations stated by Intercell:

“Note: Test and specification will be introduced for the following parameters (see Section 3.2.P.2.3.3.5): Identity, -----------------------------(b)(4)----------------------------- in Drug Product.Otherwise, all methods were found to be suitable for intended use.”

It was observed that the specification for -----------------(b)(4)------------------- was too large and a recommendation to lower the spec was made. Initially a specification of ---(b)(4)---- was discussed but this was raised to -(b)(4)- as the data provided did not support the lower specification. Initial confirmatory testing performed within the CBER DPQ lab did not meet specification. Subsequent investigation revealed an error in assay performance due to the inappropriate -------(b)(4)------- standard. Retesting confirmed acceptability of all lots tested.

Amendments 16, 24 and 27 were reviewed in order to follow up on requested changes to the Lot Release Protocol and to clarify requirements for ID testing, -----(b)(4)----- assay, and assay determining --------------(b)(4)------------------.

-(b)(4)-- lots were tested as requested by the review committee and found to be confirmed to meet product release specifications. Test result memos have been uploaded to the BLA file.

Testing Plan for post licensing Lot Release has been completed, and Lot Release Protocol has been found to be acceptable.

DPQ reviewer team concur that approval of this BLA is recommended.


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