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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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:

  1. 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)-----.
  1. 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.
  1. 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)-------------------------------------------------------------------------------------------------------------------------------------.
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)--------------------------------------------------------------------------------------------------------------- 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)-----------------------------------------------------------------------------------------------------------------------------------------”. I found it to be acceptable.
  1. 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)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. The analysis with pre-defined with acceptance criteria for filtration steps during the ----b(4)------------------------ testing include: -------------------------------------------------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------. The pre-defined performance parameters for Chromatography Columns are: ------------------------------------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. 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)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.