Scale-up methodologies for Escherichia coli and yeast fermentation processes.

Abstract

Scale-up techniques from the literature have been compiled and reviewed for applicability to Escherichia coli and yeast processes. The consistency of design and operating parameters for the pilot scale vessels in an existing fermentation pilot plant, ranging in nominal volume from 100 l to 19,000 l, was established and compared favorably with approaches found in the literature. Differences were noted as a function of parameters such as fermentor scale, vessel geometry, agitator type/size and ungassed/gassed power input. Further analysis was conducted using actual fermentation data for historical and recent development processes collected over a 10-year-period, focussing on operating conditions at peak culture oxygen uptake rates. Scale-up estimates were performed based on geometric similarity, agitator tip speed, gassed power per unit volume and mixing time. Generally, scale-up calculations from the 280 l scale were most similar to the parameters of installed equipment. Scale-up from the 30 l laboratory scale typically underpredicted parameters with scale-up from the 280 l scale being most appropriate. The 19,000 l fermentor installation was notably different in geometric similarity from the 280 l-1900 l scales since its design was meant to accommodate a wide range of operating volumes. Analysis of historical and recent processing performance was conducted for single cell bacterial or yeast fermentations which challenged peak operating conditions of the fermentors. Identification of key issues associated with scale-up for these specific pilot plant vessels was believed to be critical to efficient process development, clinical material production, and expected process transfer to a manufacturing facility.