o 5. The long time lag between preparation of large scale exception 
requests and receipt of approval by the Director of NIH for 
changes to plasmids for previously approved polypeptide products 
and equipment/protocols causes delays in the delivery of product 
benefits to the public, increases product costs and adds nothing 
to the safety considerations. The local IBC should be 
authorized to approve such requests for changes to plasmids. 
Discussion: To shorten the significant time lag between beginning the 
preparation of written 10-liter culture exception requests, the 
subsequent approval by the local IBC, then submission to the RAC which 
only meets quarterly and final receipt of written approval by the 
Director of NIH, we suggest that the local IBC be permitted to authorize 
such work above 10 liters when the particular fermentation equipment, 
operating procedures, and polypeptide products (if any) of the 
recombinant organism have been previously approved by the Director for 
the same containment levels as requested in the new exception request. 
For example, Genentech has been approved by the Director for the large 
scale fermentation of specific EK1 host vector systems in a P2 laboratory 
with certain fermentors. We have now made several changes to the 
plasmids to increase yields of the same polypeptide products. The new 
recombinant DNAs have been well characterized and shown to be free of 
harmful sequences. The host vector systems will be grown in the same 
fermentor systems with operating protocols previously approved by the 
Director. However, even after approval by the local IBC, it will be 
necessary to submit the exception requests for the new plasmids for the 
same products to the Director via the RAC. This procedure not only 
dilutes the busy RAC agenda but introduces a two to four month delay in 
every product developmental schedule for each modified plasmid for the 
same products with no gain in safety. In summary, we request that new 
large scale culture requests which are modifications of approved 
submissions, particularly at the PI HV1 and P2 HV1 levels, only require 
local IBC approval with written notification of ORDA in cases where the 
fermentors, polypeptide products, and protocol have already been approved 
by the Director in a previous submission. 
We believe that the RAC and its working group which drafted the proposed 
large scale Guidelines have made a sincere and thoughtful effort to 
provide a list of safe specifications and procedures. However, some of 
the requirements add little to the desire for safety from potential risk 
and by extrapolating laboratory Guidelines, are quite impractical for 
large scale production of beneficial products from recombinant 
microorganisms. The appointment of an advisory group having extensive 
design and operating experience with large scale fermentation equipment 
would be highly desirable as we move further into large scale development 
and production with recombinant cultures. 
Sincerely , 
Brian T. Sheehan, Ph.D. 
Vice President, Manufacturing 
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