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Vaccines, Blood & Biologics

Recommendation to waive a pre-licensing inspection-Atryn


From:Chiang Syin, Ph.D. , Chief, OCBQ/DMPQ/MRBII, HFM-676
To:BLA File: STN 125284/0
Subject:Recommendation to waive a pre-licensing inspection for the contract filling of Antithrombin alfa at ----------b(4)-----------------------, Netherlands site.
Sponsor:GTC Biotherapeutics, Inc. (License # 1794)
Product:Antithrombin alfa
Through:Laurie Norwood, M.S., Deputy Director, CBER/OCBQ/DMPQ

Clearance Routing

Laurie P. Norwood, M.S.
Deputy Director
Division of Manufacturing and Product Quality
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research


Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research




I recommend to waive the pre-licensing inspection of ---------------b(4)--------------------------------- Manufacturing Facility (b(4)), a contract filling facility located in --b(4)-----, The Netherlands, for Antithrombin alfa, a transgenic goat-derived recombinant human antithrombin to be aseptically filled, lyophilized, and heat-inactivated in 20 mL vials at -b(4)- under GTC Biotherapeutics’ BLA .

Brief History

GTC Biotherapeutics, Inc. submitted a BLA for ATryn ® (antithrombin alfa) for Injection, which is a sterile, terminally heat-treated product that when reconstituted and diluted, as directed, is intended for intravenous infusion. The active moiety in ATryn is antithrombin alfa, a recombinant DNA-derived product expressed in and purified from the milk of transgenic goats into which the human gene for antithrombin has been stably integrated.

GTC currently has two major contract manufacturing facilities: ---b(4)------------ facility (--b(4)-----) for bulk manufacturing and formulation, then the formulated bulks are shipped to ----b(4)---------------- facility (--b(4)----, Netherlands) for aseptic fill, lyophilization and heat inactivation of final container product. CBER has previously conducted a pre-licensing inspection at ----b(4)------ facility for ATryn bulk manufacturing process and formulation in --b(4)----.

----b(4)--------------- is a subsidiary of ---b(4)-----------------, and the ---b(4)----- Manufacturing Facility manufactures aseptically filled liquid and lyophilized drugs for human use. The firm is the approved manufacturing site for ---b(4)---------------------------------------- under --b(4)------, which they have been manufacturing for over 10 years. This is the only product that the firm is approved to manufacture for the US market. The firm also contract fills various clinical drugs for the EU.

Supporting Information

The recommendation for inspection waiver is based on the criteria as outlined in CBER SOPP 8410 “Determining When Pre-Licensing/Pre-Approval Inspections (PLI/PAI) are necessary.” As stated in the aforementioned SOPP, it is CBER’s policy that a pre-licensing inspection will generally be necessary for a BLA if any of the following criteria in bold are met:

  1. The facility does not hold an active US license.
    ----b(4)------------------- currently hold a U.S. licensed product, ---b(4)-----------------------, under --b(4)---.
  2.  The facility has not been inspected in the last two years by the FDA.
    The most recent FDA pre-approval inspection was conducted on --b(4)------ – ---b(4)------ by Caryn McNab and Steven A. Gonzales of ORA for major changes to the facility and equipment for ----------b(4)----------------------.
  3. The establishment is performing significant manufacturing step(s) in new (unlicensed) areas using different equipment (representing a process change). This would include areas that are currently dedicated areas that have not been approved as multi-product facilities/buildings/areas.
    As indicated in the BLA (STN 125284), --b(4)------------ Manufacturing Facility is approved as the manufacturing site for -----------------b(4)-----------------------------------------) and multiple non-US licensed products or clinical materials. The facility produces multiple parenteral drug and biological products through a -b(4)- fill line using shared equipment (such as -------------------b(4)----------------------------------------------------------------------------------------------------------------------------) to produce ATryn. The only dedicated equipment is the ---b(4)--------------- which is used for terminal heat-treatment of the lyophilized product.
  4. The previous inspection revealed significant GMP deficiencies in areas related to the processes in the application/supplement (similar processes) or systemic problems, such as QC/QA oversight.
    During the most recent pre-approval inspection, -----b(4)--------------------- was cited for multiple FDA 483 items. However, the firm’s corrective actions to the 483 items were deemed adequate and this inspection was classified as Voluntary Action Indicated (VAI). No significant GMP deficiencies or systemic problems were identified. The last post-approval inspection of this facility was conducted in 1997, and it was classified as NAI.
  5. The manufacturing process is sufficiently different (new production methods), specialized equipment or facilities) from that of other approved products produced by the establishment.
    As stated earlier that the only ATryn specific equipment is the ---b(4)----------------- and -----b(4)----------------- shares a --b(4)---- filling line and their multiple-product manufacturing equipment for all aseptically filled, parenteral drugs and biologics. Major equipment such as ---b(4)----- and --b(4)------ remained unchanged during facility renovation. The results obtained from pre-renovation and post-renovation ATryn lots were comparable and all met the pre-set specifications of the final product.

Waiver Recommendation:

Based on the information provided in the Biologics License Application Supplement, and the previous inspection report, I recommend waiving the pre-licensing inspection for -----b(4)------ located in ----b(4)--------, Netherlands.

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