Recombinant DNA Advisory Committee - 03/1-2/93 
o Post production run culture and testing 
o Lot release test of transduced cells (ex vivo ) 
Discussion 
With regard to Dr. Gunter's presentation. Dr. Post asked if 5% refers to a production 
lot. Dr. Gunter responded that 5% of the production lot is the recommended testing 
volume. Dr. Post inquired whether there is any correlation between the size of a 
production lot and a patient dosage. Dr. Gunter stated that the FDA is not correlating 
dosage with the size of a production lot at this time. However, as investigators progress 
to Phase II and Phase III trials and the size of the production lots increases, the FDA 
will reevaluate these criteria. 
Dr. Parkman noted that there are clinical settings in which ex vivo testing of transduced 
cells would not be possible prior to administration, i.e., transduced hepatocytes. There 
are instances in which either the patient is undergoing a surgical procedure or cell 
survival is limited ex vivo. Dr. Gunter agreed with Dr. Parkman's comments and said 
that there will be instances where there will be no choice but to proceed with 
administration of the transduced cells prior to the completion of the proposed assays. 
Dr. Gunter stated that the FDA will consider any valid, rational, scientific argument 
against any of the FDA's recommendations. 
Dr. Parkman asked about the proposed limit of RCR detection. If one production lot is 
equal to 5 patient doses, what is the level of detection? Dr. Anderson answered that the 
limit of detection would be 4 RCR particles. Dr. Miller suggested that the limit of RCR 
detection should approach 0. Dr. Anderson said that the theoretical limit of RCR 
detection is 0 particles per production lot, assuming that the lot will be cultured for a 
sufficient period of time after harvest. However, the practical limits of detection will 
actually be less than 1 RCR particle per production lot. If a single RCR particle is 
detected in any assay, the lot will be discarded. Dr. Miller said that the calculations do 
not accurately reflect the level of detection because the testing volume will be only 5% 
of an entire production lot. Testing this volume only guarantees that there are less than 
20 RCR particles per production lot. 
Dr. Chase stated that the calculations should not be interpreted based on sample 
volume, because this is not a solid object. The probability of contamination is not the 
same as the fraction of the area that is sampled. Dr. Anderson agreed with the 
statement made by Dr. Chase and added that carrying a post-production run out for 
twice the period of time in which an RCR breakout would occur, brings the level of 
detection to 0 per production lot. Dr. Chase stated that although the desired goal of 
detection is 0 particles per production lot, you can never be certain that it is absolutely 0. 
Recombinant DNA Research, Volume 17 
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