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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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CMC related information request, December 7, 2011 - Gintuit

 

CMC related information request for STN BLA 125400 (12/07/11)
 
  1. 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.
 
  1. 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.
 
  1. 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. 
 
    1. 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.
    2. 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).
 
  1. 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.
 
    1. 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
    2. 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
    3. 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.
 
  1. 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:
    1. A trend analysis for each lot release test over the specified time period
    2. A release specification and justification that is supported by statistical analysis of the data set (for quantitative release specifications only)
 
  1. Please direct FDA to the portions of the BLA demonstrating the following assays have been validated for specificity as per ICH Q2 (R1):
    1. Morphological analysis (MCB release testing, final product release testing)
    2. Isoenzyme analysis (MCB release testing, WCB release testing)
    3. Karyology (Cytogenetic) analysis (MCB release testing)
    4. Involucrin content (WCB release testing)
    5. Cytokine profile (-b(4)- release testing)