Technologies and Approaches for Reliable Scale-up of Complex Secondary Metabolite Fermentations

Reliable scaled-down fermentation platforms that are predictive of large-scale performance and simultaneously detect incremental improvements in yield can be challenging for mycelial (viscous, shear-thinning) fermentations, especially those utilizing industrial grade medium.  Inherent differences across scales often have a physiological impact and make linear scaling impractical.  Small scale micro titer plates and shake flasks used for mutant selection are often subject to mass transfer limitations that can mask higher yielding strains or give false positives.  Amongst these challenges, there is a consistent trend across the Industry to increase experimental throughput and accelerate the scale-up process.  Scale-down models must be predictive, but also should have low variance to maximize throughput and statistical power.  Model variance and scale-up criteria must be well defined in order to develop robust experimental designs that maximize predictability and reduce scale-up time.  This presentation will describe not only methods that have been employed at Dow AgroSciences to detect and overcome scale-up limitations but will also examine experimental considerations to improve statistical significance and experimental throughput.