



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:
  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.
  Please provide a summary and tabulation of data generated during the ATryn 
  process valdiation study performed at -----b(4)----------------following the 
  facility renovation.
  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.
 

 