
 


483 Response Review Memo - PLI (Atryn)


Memorandum

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.
  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.
  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.
  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.
  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.
  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.
 
