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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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483 Response Review Memo

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.

  1. 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.

  1. 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.