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1.      MCB isoenzyme and karyology (cytogenetic) analysis

 

a.       Please provide the complete set of testing results for the isoenzyme 
and karyology (cytogenetic) analysis performed by 
--b(4)-------------------------------------------------------------- for all HDF 
and HEP MCB banks. These data should include results for all parameters 
evaluated at each passage for each cell type.

 

b.      Please also comment on any trends identified in the data set and their 
relevance, for example, if there were any observed changes in the karyology of 
keritinocytes.

 

c.       Please clarify which passage number is used for each cell type and 
describe the passage in reference to stage of manufacture (e.g. number of 
passages prior to use, passage of use, and senescence). There are 
inconsistencies in the BLA application for this information.

 

2.      Please provide further details regarding tumorigenicity testing of the 
MCBs          [--b(4)---------------------------], and if available, the SOP and 
the assay validation report (including a validation summary table). If formal 
analytical method validation per ICH guidelines has not been performed for this 
assay, please provide a rationale and any qualification data that demonstrate 
this assay is suitable for its intended use and will provide consistent and 
reliable results.

 

3.      Please provide a more in-depth justification for the acceptance criteria 
–b(4)----- for the collagen biosynthesis assay for HDF WCB release testing, 
especially as it relates to values obtained during previous manufacture. For 
example, in Table 7 of –b(4)------Apligraf Manufacturing--b(4)- (retrospective 
process validation report for cell banking), the mean value for Collagen 
Biosynthesis (--b(4)---) was –b(4)--, approximately –b(4)----------- than the 
acceptance criteria. The justification should describe how the current 
specification, with a seemingly acceptance criteria, provides sufficient control 
of manufacturing quality and consistency.

 

4.      Similary, please provide a more in-depth justification for the 
acceptance criteria of --b(4)--- for the involucrin assay for HEP WCB release 
testing, especially as it relates to values obtained during previous 
manufacture.

 

5.      The laboratory listed as the donor testing facility under 
FEI----b(4)------- could not be located in the Human Cell and Tissue 
Establishment Registration (HCTERS) database. Please verify the FEI# is correct 
and/or provide further information for the laboratory which conducts the donor 
testing.
 

   
 
