
 
  


483 Response Review Memo - ATryn


 
Memorandum

From: Chiang Syin, Ph.D., Chief, CBER/OCBQ/DMPQ/MRB II, HFM-676

Subject: 483 response review memo - review of GTC Biotherapeutics’ 483 response 
to the pre-licensing inspection conducted between 4/10/2008 and 4/18/2008 for 
antithrombin alfa manufacture

To: Establishment Inspection File (EIF)
File: BL STN 125284/0

Through: Laurie P. Norwood , Deputy Director, DMPQ, HFM-670

GTC Biotherapeutics, Inc. will be the sole license holder for antithrombin alfa 
and is responsible for maintaining source material productions, process 
validation, QC and final release testing of the drug substance and drug product 
manufacture. I have reviewed and evaluated GTC’s revised response dated July 27, 
2008 to the Form FDA-483 List of Observations # 5 and #6 (in bold) issued on 
April 18, 2008. The product reviewer, Dr. Roman Drews of DH/OBRR, will address 
the observations # 1-4 separately.
  There was no approved reprocessing and reworking protocol. However, three 
  lots, -----------b(4)----------------------------------------, were 
  reprocessed. In addition, lot ---b(4)-----, has undergone ----b(4)-- 
  nanofiltration after --b(4)----------b(4)----- nanofilter failed the initial 
  integrity testing. Currently this is only a written policy with no specific 
  included. 


Reprocessing of the above-listed batches included dilution and --b(4)--- 
activities (batches ---------b(4)-----------) and ---b(4)------, dilution, and 
--b(4)--------------- activities (batch --b(4)-----). All activities were 
documented via planned deviations to the batches and using batch specific 
reprocessing protocols, mutually approved by -b(4)- and GTC in advance of the 
reprocessing activities. The nanofiltration is routinely performed using a 
----b(4)------- for antithrombin alfa. For batch --b(4)---------, the 
nanofiltration unit could not be post-use integrity tested due to a mechanical 
failure. The decision was made to perform a --b(4)--- nanofiltration using a new 
unit; this unit passed post-use filter integrity testing.

GTC has submitted a reprocessing protocol, TR-0327-PRO (Protocol for 
Reprocessing of Materials during the Manufacture of antithrombin alfa Drug 
Substance) to include the conditions for reprocessing such as --b(4)---- is only 
allow when there is a filter integrity failure. GTC has committed no reworking 
will be performed and a prior approval supplement (PAS) will be submitted with 
supporting data for regulatory review for future reprocessing.
  Besides the 0.22 micron sterilizing filters, there was no leachable and 
  extractable testing performed for the equipment and --b(4)---- materials used 
  in ATIII purification process including purification 
  -----b(4)---------------------------------------. 

GTC provided a Validation Project Plan (VPP) under VAL-0080-PLN. This plan 
defines the requirements for the evaluation of potential extractables and/or 
leachables from the product contact --b(4)---- components of the process 
equipment, filters and chromatography media used to manufacturing antithrombin 
alfa drug substances and products, and the risk assessment. GTC proposed to 
implement and complete the study before the next manufacturing campaign, 
currently scheduled ------------b(4)---------------------------.

I found the draft protocols and proposed corrective actions to be adequate. All 
corrective actions should be verified during the next routine GMP inspection of 
the firm.

Therefore, I recommend that the facility be considered for approval for the 
production of antithrombin alfa on the basis of the pre-licensing inspection 
provided that all other considerations are in compliance with applicable 
regulations and standards.
 

 
