Recombinant DNA AtJvisory Committee - 09/14-15/92 
consent document. 
Dr. Post requested that the investigators provide further information regarding co- 
cultivation of the cells with the producer cell lines. This procedure may complicate the 
issue of helper virus contamination. What is the stroma that will be in the long-term 
bone marrow culture? 
Dr. Murray called on Dr. Paul Aebersold of the FDA to present a brief summary of the 
FDA meeting held in the morning regarding safety testing for replication competent 
retroviral vector supernatant preparations. 
Presentation--Dr. Aebersold 
Dr. Aebersold of the Division of Biological Investigational New Drugs, FDA, noted that 
protocols previously approved by the RAC and FDA were approved prior to recent 
observations in monkeys that developed lymphomas. This new data suggests that 
replication competent retroviruses possibly could be pathogenic in primates. The FDA is 
concerned about the implications of these findings and whether it should initiate testing 
beyond previous requirements. 
On the other hand, when dealing with industrial scale production of biological agents, it 
is not possible to exhaustively test entire production lots. For example, a production run 
of 200 flasks would require a final scale up to 20,000 flasks in order to obtain a final 
S + /L' readout of the entire preparation. Quality control testing is not exhaustive testing, 
only representative aliquots. Therefore, quality control testing can never assure that no 
replication competent viruses exist. The focus of the FDA's discussions is how to sample 
a production run for testing, what assays will be performed on these aliquots, the 
percentage of producer cells that should remain in long-term culture, and whether the 
producer cells should be cultured with a permissive cell line for retroviral replication, 
including xenotropic viruses. It has been proposed that the co-cultivation assay 
procedure may be a more sensitive method for detecting helper virus contamination; 
however, this result has not been verified in a side-by-side comparison. In the future, the 
FDA will probably require supernatants to be assayed on a cell line that is sensitive to 
xenotropic viral replication such as the Mus dunni murine cell line which supports 
xenotropic virus replication. In addition, the FDA may require co-cultivation testing of 
an aliquot of the producer cells. However, neither of these assays would absolutely 
assure that there are no replication competent viruses in a clinical lot. Although the 
FDA will probably be initiating more stringent standards for the assay of replication 
competent helper viruses, it is unclear what action will be taken on existing clinical lots. 
Dr. Post inquired as to the FDA's requirements on existing protocols. Dr. Aebersold 
stated that he could not respond to Dr. Post's question because this issue is not a simple 
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