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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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BLA Mid-Cycle Review Memo - Atryn

Memorandum

From: Chiang Syin, Ph.D., Chief, CBER/OCBQ/DMPQ/MRB II, HFM-676
Subject: BLA Mid-Cycle Review Memo, for Atithrombin alfa, for the prevention and treatment of thromboembolic events
To: BLA Files, STN 125284/0 Antithrombin alfa
GTC Biotherapeutics, Inc. (License # 1794)
Through: John A. Eltermann, Jr. , Director, DMPQ, OCBQ, HFM-670
Recommendation: Information request

Background:

GTC Biotherapeutics (GTC) has submitted the BLA for antithrombin alfa (ATry n), a sterile, terminal heat-treated product that is intended for intravenous infusion, when reconstituted and diluted. The active ingredient is a recombinant DNA derived product expressed in and purified from the milk of transgenic goats, in which the human antithrombin gene has been stably integrated. This BLA was submitted in eCTD format under a rolling BLA mechanism until the final module is received by CBER on August 8, 2008 to trigger the review milestones with the first Action Due date of February 7, 2009.

We conducted in April 2008 the pre-licensing inspections at GTC facility (------b(4)----------------------------------------) and ----b(4)------------------ facility (--------------------b(4)---------------------------------------- ready for shipping to the -------b(4)------------- facility in Netherland for the final product manufacture. Form-483s were issued to both GTC and -b(4)-- at the conclusion of the inspections. ----b(4)------------ facility in --b(4)-----, the Netherlands was inspected in late ---b(4)---------- by CDER for a NDA product. The responses to 483 observations are pending.

I initiated a telecon on November 13, 2008 with Mr. Dick Scotland, Exec. VP of GTC and advised him that I’ll request more information.

Information Request:

  1. Please provide a summary of the batch production record for antithrommbin alfa drug substance lot -b(4)- and a tabulation of the bioburden data, which was committed during our pre-licensing inspection by GTC to collect and submit to CBER.  
  2. Please provide a summary and tabulation of data generated during the ATryn process valdiation study performed at -----b(4)---------------- following the facility renovation.
  3. We noted in the submission that the final product lot ---b(4)----- manufactured by ----b(4)------------------ has not been released by GTC. As this is the lot manufactured after facility renovation, we are concerned whether there is any product comparability issue. In our discussion on November 13, 2008, you have suggested that this is only limited to the testing for the ----------b(4)-------------- step. Please provide a detailed investigation report and any corrective actions implemented to address the testing problem.