
    
 
  


CMC related information request, December 7, 2011 - Gintuit




  

 
 

CMC related information request for STN BLA 125400 (12/07/11) 

 
  Please direct FDA to the appropriate part(s) of the BLA that describes the 
  proposed identity assay for your product. This should include a detailed 
  justification as to how the proposed identity assay meets the criteria as 
  defined in 21 CFR 610.14. In your response, please address how this identity 
  assay is able to distinguish Apligraf from other product(s) being manufactured 
  in the same facility.

 
  During the CTGTAC meeting on Nov. 17, 2011, reference was made by OI to a 
  donor tissue screening process in which approximately 1 in 5 tissue samples 
  pass screening and are carried forward for cell bank production. Please 
  provide details for this screening process including the SOPs and 
  specifications.

 
  During the CTGTAC meeting on Nov. 17, 2011, it was noted by the AC panel that 
  each mature construct can be derived from two different donors (one donor for 
  each cell strain). Consequently, there can be different donor pairings between 
  keratinocyte and fibroblast cell strains used to form the mature constructs. 

 
    Please provide data if and/or how donor pairing of cell strains impacts 
    product quality. For example, if pairing of a particular fibroblast cell 
    strain from one donor when combined with keratinocytes strains from other 
    donors led to differences in potency, barrier function, cytokine expression, 
    etc.
    Please verify that that new keratinocyte and fibroblast strains are not used 
    together to form a mature construct for cell strain qualification (i.e. 
    there is only variable (new cell strain) being evaluated at once).

 
  During the CTGTAC meeting on November 17, 2011, you indicated that no direct 
  correlation analyses had been performed between the cell bank qualification 
  data collected from mature constructs using biological assays such as VEGF, 
  MTT, cytokines expression and in vivo mouse model and the equivalent 
  ---b(4)------ results.

 
    Please provide a summary table that includes the cell bank qualification 
    results/data for all cell strains that have been released to date for 
    Apligraf manufacture
    From the data set defined in part a, please provide correlation analyses 
    between VEGF levels, MTT results and in vivo mouse model results and    
    --b(4)---------------results
    Please verify if any quantitative data is available for the cytokine 
    expression levels measured by RT-PCR for cell strain qualification. If 
    available, please provide a correlation analysis between cytokine expression 
    levels and the ---b(4)------------ results.

 
  Please direct FDA to a table that summarizes the lot release testing results 
  for all manufactured Apligraf units that were released from a time period 
  beginning with the initiation of the first IDE trial for the oral indication 
  to the present. For the data set defined in this time period, please 
    provide:A trend analysis for each lot release test over the specified time 
    period
    A release specification and justification that is supported by statistical 
    analysis of the data set (for quantitative release specifications only)


 
  Please direct FDA to the portions of the BLA demonstrating the following 
  assays have been validated for specificity as per ICH Q2 (R1):Morphological 
    analysis (MCB release testing, final product release testing)
    Isoenzyme analysis (MCB release testing, WCB release testing)
    Karyology (Cytogenetic) analysis (MCB release testing)
    Involucrin content (WCB release testing)
    Cytokine profile (-b(4)- release testing)

 

   
 

