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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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483 Response Review Memo - PLI (Atryn)


From: Chiang Syin, Ph.D., Chief, CBER/OCBQ/DMPQ/MRB II, HFM-676
Subject: 483 response review memo - review of --b(4)-------------- facility’s 483 response to the pre-licensing inspection conducted between ----b(4)-------------------- for GTC antithrombin alfa bulk manufacture
To: Establishment Inspection File (EIF)
File: BL STN 125284/0
Through: Laurie P. Norwood , Deputy Director, DMPQ, HFM-670

I have reviewed and evaluated -b(4)-- updated response dated January 22, 2009 to the Form FDA-483 List of Observations (in bold) issued on --b(4)---- as follows.

  1. Observation: There was no written procedure for reprocessing. However, three lots, ---------b(4)------------------------------------------ were reprocessed. In addition, lot --b(4)---, has undergone --b(4)---- nanofiltration after --b(4)------- nanofilter failed the initial integrity testing.

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. -b(4)- has drafted a policy document and procedural SOP (SOP QA-GEN-079, Policy on Product Rework and Reprocessing and SOP QA-GEN-080, Reprocessing Procedure) to include process risk assessment, review of regulatory requirements, documentation requirements, and product disposition requirements.

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.--b(4)- committed that any further product reprocessing activities will be performed according to the requirements of the newly-implemented program.

During the telecon held on 1/21/09 between CBER and -b(4)--, it was agreed that the policy document QA-GEN-079 will be further revised to specify that the reprocessing should be subject to regulatory review and the implicated lot(s) will not be distributed into commerce until regulatory agency review is completed. A copy of the updated SOP will be submitted to FDA when effective; target date for completion is January 30, 2009.

  1. Observation: There were no leachable and extractable testing performed for --b(4)--- materials used in buffer preparation.

--b(4)- initially agreed to implement an extractable/leachable assessment policy which will include risk assessment, safety assessment, and model solvent study design. -b(4)- will perform generic family-approach studies for leachables and extractables for storage -b(4) used in buffer preparation activities by June 15, 2008 and studies completed by October 31, 2008.

Regarding the -b(4)- in use for ATryn processing, the supplier has provided a substantial regulatory support package certifying conformance to USP standards including Class VI toxicity, USP <661> physiochemical properties, and USP <88> in-vivo biological reactivity. This information will supplement the in-house studies.

-b(4)--- provided an update during the 1/21/09 telecon that SOP QA-GEN-082, Leachable/Extractable Assessment had been implemented at the --b(4)----------- site. However, evaluation of the storage -b(4)- used in buffer preparation activities is still ongoing. And -b(4) proposed that any necessary model solvent studies will be completed by March 31, 2009 and a copy of the resulting information submitted to FDA when complete.

  1. Observation: The current batch record does not require to specify on the elution profile when the material eluted from the chromatography columns was collected. Also, the criteria for the determining comparability of the process chromatograms to reference chromatogram are not specific with regards to elution peak profile and appearance. The two batches of rATIII drugs substance -----b(4)----------------------- with documented deviations in the chromatography column chromatograms were not released by GTC Biotherapeutics.
-b(4)- has revised the process batch records with GTC’s input to provide specific instruction to --b(4)------- chromatograms with the ---b(4)----- of product elution. More specific instruction will be added to the records to define comparability of process chromatograms to reference chromatograms and training for all applicable manufacturing personnel will be performed to ensure this comparison is performed consistently. Any deviations in product profile will be considered Major deviations requiring full investigation to include documentation by GTC of final batch outcome. The revised ATryn batch records (43-029, 45-029, 55-029) were submitted to FDA via e-mail on January 22, 2009.
  1. Observation: The --b(4)-- gauge on the Air Handling Unit, -b(4)--, which covers the Manufacturing -b(4)- for Antithrombin III bulk purification operations, was found not working on 4/15/08. The gauge was not covered under the daily function and alarm checklist, and the last maintenance was performed on 11/28/07.

After further review it has been determined that the gauge cited in the observation is not a primary indicator of system performance. Instead, this gauge measures ----------b(4)----------------------------------- in order to detect potential filter clogging. A robust preventative maintenance program for the system filters ensures that the filters are routinely changed prior to clogging; evidence of satisfactory system performance is also monitored through the environmental monitoring program. As a result of this review, this gauge has been reclassified as Reference Only, not requiring daily review.

A CAPA (PR32557) was opened to capture instrument criticality review and perform all necessary documentation revisions. The criticality assessment is ongoing as the number of utility system instruments is substantial (thousands). It is estimated that this process will be completed by May 31, 2009.

  1. Observation: The ----------------b(4)---------------------------------------- for the final bulk drug substance were required to be filled within -b(4)- after --b(4)------ according to SOP PF-CLN-017. However, the ---b(4)------- were found to be labeled with an expiration date of -b(4)--.
The procedure for -------------b(4)-------------------------------- used in the ATryn process, --b(4)--, has be updated by June 30, 2008 to include specific instructions for labeling --b(4)---------------- with a -b(4)-- expiration date, consistent with SOP PF-CLN-017. Deviation PR#28482 has been initiated to review the batch history and confirm that all --b(4)------ were used within the -b(4)----- expiry. Upon further review it has been determined that the --b(4)------ expiration dating study performed by -b(4)---- was not specific to the -----b(4)-----------; --b(4)------- will perform an expiration dating study for this container. The ---b(4)-- study is on target for completion prior to the next scheduled ATryn campaign but will be performed earlier if the -b(4)-- manufacturing schedule allows. This study will be conducted according to -b(4)-- protocol VP-228, Addendum 1 and a copy of the resulting report will be sent to FDA upon completion.

The written statements of corrective actions, which have been taken to correct the deficiencies noted during the pre-approval inspection, appear to be adequate and complete. 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 bulks on the basis of the pre-licensing inspection provided that all other considerations are in compliance with applicable regulations and standards.