
 
  


FDA-483 Review - Atryn



 
Memorandum

From: Roman Drews, HFM-392 

Subject: Review of GTC’s responses to FDA-483 observations made during the 
pre-licensing inspection conducted between 4/10/2008 and 4/18/2008 for the 
manufacture of Antithrombin (Recombinant) [ATryn] bulk drug substance 

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

Through: Timothy Lee, HFM-392
 Acting Chief, Laboratory of Hemostasis/DH/OBRR 

I reviewed the responses from GTC Biotherapeutics, Inc. (GTC) dated July 28, 
2008 to the observations listed in Form FDA-483 (in bold font) issued on April 
18, 2008. My review is summarized as follows:
  Observation: The Standard Operation Procedure (SOP) for the investigating out 
  of specification test results (SOP-006-QC) outlines principles of retest and 
  re-sampling plans (8.4) but fails to specify the predetermined retesting 
  procedures (e.g. maximum number of retests to be performed on a sample) 

GTC submitted an updated version of SOP-0006-QC for investigation of 
out-of-specification (OOS) test results that incorporates the predetermined 
re-testing/re-sampling procedures. The re-testing procedure specifies maximum 
number of testing (-b(4)- tests) for the particular type of release assays 
(e.g., Potency, --b(4)------------- based method, and ----b(4)-----------) and 
also provides retesting limits for the remaining assays, 
---b(4)-------------------- method, used in the manufacture of ATryn. The SOP 
also outlines the criteria for reporting, evaluation of data, and closing the 
out-of-specification investigations. The changes are acceptable 
----------------------------------------b(5)----------------------------------------------------------------------b(5)---------------------------------------------------------------------b(5)-----.
  Observation: The SOP for the rATIII-thrombin inhibitory activity (SOP-0071-QC) 
  specifies acceptance criteria for the standards and test articles. There is, 
  however, no written procedure governing the number of tests that can be 
  performed where the acceptance criteria are not met and before the test can be 
  classified as invalid. 

The firm submitted a copy of the revised SOP -0071-QC. The revisions include a 
new section in the document specifying the number (-b(4)-) of invalid results 
obtained before initiating a failure investigation. Also, the SOP contains 
detailed criteria to classify tests as valid or invalid including statistical 
analysis of the standard curve and control samples such as the probability value 
for regression--b(4)--, probability for non-parallelism -b(4)-, and coefficient 
variation -b(4)-. For the release of Drug Substance, -b(4)- tests are performed 
from the -----b(4)---------------------- is reportable. Drug product release 
consists of -b(4)- distinct tests of b(4) distinct vials (b(4) tests total). 
Each vial must be evaluated independently against the specification. I found the 
modified criteria to be acceptable.
  The images of -b(4)----------- used to assess 
  ------------b(4)-------------------------------- impurity in the batches 
  #---------b(4)---------------- show significantly --------b(4)------------- of 
  the tested samples when compared to the rATIII reference standard. However, 
  according to SOP-0083-QC to verify Limit of Detection of the performed assay 
  and measure -b(4)- in the drug substance, the 
  ---------------------------b(4)-------------------------------------------------------------------------------------------------------------------------------------.v


The --- b(4)----------------- is established by -b(4)------- technique 
semi-quantitatively comparing the -b(4)- signal to the signal of rATIII present 
in milk samples and dilutions of standard for rATIII content. The rATIII 
---b(4)---------------------------------------------------------------------------------------------------------------n
to calibrate assay and provide assurance that ------------b(4)---------- in the 
milk sample is not underestimated due to technical deficiency. The examples of 
the analyzed batches listed in Observation 3 demonstrate that due to the 
---b(4)--------- (signal) of rATIII in the tested milk samples when compared to 
that of standard rATIII, the reported ------b(4)------------- impurity was most 
likely underestimated. In response to this observation, GTC submitted a modified 
version of SOP-0083-QC which includes the following requirement for the assay 
validity 
“---------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------”.a
I found it to be acceptable.
  The protocols for column and filtration system lifetime studies were not 
  established. 

GTC submitted prospective process validation protocol (VZL-0079-PVP) to document 
consistent functioning of reusable membranes and chromatography resins over 
their respective lifecycles during the manufacture of ATryn drug substance at 
----------b(4)--------------------------------. The protocol encompasses 
performance of 
-------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.k
The analysis with pre-defined with acceptance criteria for filtration steps 
during the ----b(4)------------------------ testing include: 
-------------------------------------------------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------.e
The pre-defined performance parameters for Chromatography Columns are: 
------------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.p
The details of study including acceptance criteria are provided in tabulated 
form and I found them acceptable. The data generated over previous campaigns 
will be trended, reviewed, and submitted to the referenced protocol. The maximum 
lifetime (number of cycles) for the aforementioned operation units have been 
prospectively established based on the outcome of small-scale and developmental 
studies, including effect of the aging on the viral removal performance and 
there were reviewed under the BLA. 
-------------------------------------------------b(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
 

 