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has been filtered to remove contaminating organisms is pumped into the 
fermenter to provide necessary oxygen for growth. Metabolic heat is 
removed by a cooling jacket. Modern instrumentation monitors and controls 
variables such as fermenter temperature, air flow, pressure, pH, dissolved 
oxygen, feed rates of various nutrients, and composition of exhaust gases. 
Operating pressures are modest and are nominally about 5 psig. 
Antibiotic fermenters are designed primarily to protect the fermen- 
tation from contaminating organisms. To adapt them to fermentations with 
recombinant organisms, we have modified them to contain the fermentation 
organism more completely. This was readily accomplished by filtration or 
incineration of the exhaust gases, containment of the agitator seal, 
sampling and inoculating with a closed system, and followed, 
by thermal or chemical sterilization of the fermenter contents before 
processing. Detailed operating procedures are used and the equipment and 
procedures are thoroughly validated before the system is used for fermen- 
tations with recombinant organisms. A schematic representation of both 
types of fermenters is attached. 
Monitoring of the operating system is carried out continually and con- 
sists of microbiological sampling of the exhaust systems after filtration, 
sampling of the operator environment, and frequent integrity testing of 
the filtration systems. In over 2,000 hours of operation with fermentors 
containing recombinant organisms, we have never recovered the recombinant 
organism from the enviornment even though it is regularly monitored. 
After thermal or chemical kill, a sample of each fermentation batch is 
plated on a culture medium to monitor effectiveness of the procedures. 
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