Monday, August 11, 2008
P122
Process Development for Pilot Scale Production of Nodusmicin
High throughput screening of approximately 208,000 samples from AMRI’s natural product collection identified Nodusmicin as a compound of interest in a targeted antibacterial screening initiative. Consequently, a process to produce sufficient Nodusmicin for subsequent studies, including lead optimization and SAR, was required. AMRI fermentation scientists implemented statistically designed experiments to optimize fermentative production of Nodusmicin. We utilized our experience with related natural products, biosynthetic pathways, available literature, and rationally designed experiments drawn from biochemistry and precursor analyses to aid in rational experimental design. Initial attempts were focused upon producing several hundred milligrams of compound and ultimately fermentation titers approaching 0.2 g/L Nodusmicin were achieved in 20L fermentations. This process was scaled up to 500L fermentations in our pilot scale facility. Downstream processing steps were designed to eliminate the need for chromatography. This process was supportive of over 50 grams of Nodusmicin per month for further pharmaceutical studies. This presentation is a review of the critical discoveries made while developing this pilot scale process, which include medium development, statistically designed experimentation, strain improvement and downstream processing improvements.
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