P37: Increasing Geldanamycin Production by Medium Modification and Process Improvement

Monday, November 7, 2011
Capri Ballroom (Marriott Marco Island)
T. Tully, R. Doyle, R. Schild, P. Sharma, M. Gando and A. Goswami, Bristol-Myers Squibb, New Brunswick, NJ
Geldanamycin is a macrocyclic polyketide produced by Streptomyces hygroscopicus.  Geldanamycin and its analogues are of clinical interest based upon their inhibition of Heat Shock Protein-90 and thus for their potential use as anti-cancer agents.  A previously established fermentation protocol for the production of geldanamycin was evaluated for further improvement of yield and process knowledge.  The current work focused on examining different conduction and raw material options, and identifying key and critical fermentation parameters.  A series of medium component changes were employed, not only as part of a process improvement strategy, but also to facilitate better consistency and accessibility of raw materials while developing a BSE-TSE compliant medium.  One aspect of the fermentation that was actively explored was the nitrogen feed, which when modified from an extended low level feed over the course of ca. 7 days to a shortened feed over a more limited 3 day span, resulted in significantly higher levels of geldanamycin formation.  Additional work was also carried out to thoroughly evaluate parameters for inoculum transfer, especially where larger fermentors requiring multiple flask and tank stages for scale up would be required. Compared with geldanamycin yields of ca. 3.7 g/L for the starting process, yields as high as 9.3 g/L were eventually achieved.
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