• Rischawy, Federico
• Kluters, Simon
• Saleh, David
• Studts, Joey
• Wang, Gang
• Hubbuch, Jürgen
• Müller, Benedict

Abstract

<jats:title>Abstract</jats:title><jats:p>Mechanistic modeling of chromatography processes is one of the most promising techniques for the digitalization of biopharmaceutical process development. Possible applications of chromatography models range from in silico process optimization in early phase development to in silico root cause investigation during manufacturing. Nonetheless, the cumbersome and complex model calibration still decelerates the implementation of mechanistic modeling in industry. Therefore, the industry demands model calibration strategies that ensure adequate model certainty in a limited amount of time. This study introduces a directed and straightforward approach for the calibration of pH‐dependent, multicomponent steric mass action (SMA) isotherm models for industrial applications. In the case investigated, the method was applied to a monoclonal antibody (mAb) polishing step including four protein species. The developed strategy combined well‐established theories of preparative chromatography (e.g. Yamamoto method) and allowed a systematic reduction of unknown model parameters to 7 from initially 32. Model uncertainty was reduced by designing two representative calibration experiments for the inverse estimation of remaining model parameters. Dedicated experiments with aggregate‐enriched load material led to a significant reduction of model uncertainty for the estimates of this low‐concentrated product‐related impurity. The model was validated beyond the operating ranges of the final unit operation, enabling its application to late‐stage downstream process development. With the proposed model calibration strategy, a systematic experimental design is provided, calibration effort is strongly reduced, and local minima are avoided.</jats:p>

Topics

• impedance spectroscopy
• phase
• experiment
• polishing
• chromatography