Accelerating process improvement through integrated bioprocessing

Dow AgroSciences is the agribusiness subsidiary of The Dow Chemical Company engaged in the development of new agricultural solutions to help growers increase crop productivity in a sustainable manner. One such product is derived from an agriculturally relevant natural product produced by a species of Streptomyces. Development of a commercially viable fermentation route for this product requires meeting desired economics, successful scale-up and maximizing the productivity. The Dow AgroSciences’ development program involves the highly integrated applications of classic strain improvement by random mutagenesis, engineering biology, and fermentation process development. New strains and fermentation process improvements are vetted in bioreactors at multiple scales and the performance of the downstream process is evaluated. Process performance results guide subsequent strain and process improvement targets resulting in a highly integrated development program. This process uses a filamentous Actinomycete bacterium in a complex media resulting in a viscous, shear-thinning broth. Consequently, mass transfer limitations at small-scale can mask high yielding strains or deliver false positives. Careful analysis of cultivation parameters identified key factors impacting scale-up predictability. Using robust experimental designs, an improved process was designed that better predicts performance at manufacturing scale. This presentation will review how these approaches contributed to a rapid acceleration in productivity gains resulting in a 75% improvement in titer over a one-year period with successful scale-up to 30 kL bioreactors.