Use of quality by design elements in process characterization

Major elements of a Quality by Design (QbD) approach were employed in the process characterization program for a recombinant protein produced in E. coli. The effort started with a risk-based assessment of process parameters for inclusion in the experimental design.  Statistical design of experiments (DOE) was used to evaluate selected parameters for impact on product quality and subsequent downstream clearance of product- and process-related impurities. Characterization of the limit of in vitro cell age and univariate studies to extend proven acceptable ranges (PARs) to support future investigations of manufacturing excursions were also performed. In addition to characterization of the fermentation steps, the overall strategy included qualification of the scale-down model (SDM) used to perform the experiments and validation of media and stock solution hold times.