Connected mechanistic process modeling to predict a commercial biopharmaceutical downstream process

Abstract

Mechanistic modeling has shown to contribute greatly to the process understanding of chromatography and filtration processes. However, these are mostly considered individually and not connected for an entire downstream process. In this study, mechanistic models were connected to describe an entire downstream process of a Fab fragment. For the capture step, a transport-dispersion model (TDM) combined with an extended Langmuir isotherm was applied. Depth filtration was modeled with a combined pore blocking model. The polishing ion exchange chromatography steps were described by a TDM combined with the colloidal particle adsorption model. The tangential flow filtration model accounts for both the Donnan effects and flow limitations. The presented downstream process model could predict online and offline data recorded at 12,000 L manufacturing scale. Process variations of 23 manufacturing batches were adequately reproduced by the model based on the consideration of input process parameter variations.