Digital twin of a continuous chromatography process for mAb purification: Design and model‐based control

Abstract

Model‐based design of integrated continuous train coupled with online process analytical technology (PAT) tool can be a potent facilitator for monitoring and control of Critical Quality Attributes (CQAs) in real time. Charge variants are product related variants and are often regarded as CQAs as they may impact potency and efficacy of drug. Robust pooling decision is required for achieving uniform charge variant composition for mAbs as baseline separation between closely related variants is rarely achieved in process scale chromatography. In this study, we propose a digital twin of a continuous chromatography process, integrated with an online HPLC‐PAT tool for delivering real time pooling decisions to achieve uniform charge variant composition. The integrated downstream process comprised continuous multicolumn capture protein A chromatography, viral inactivation in coiled flow inverter reactor (CFIR), and multicolumn CEX polishing step. An online HPLC was connected to the harvest tank before protein A chromatography. Both empirical and mechanistic modeling have been considered. The model states were updated in real time using online HPLC charge variant data for prediction of the initial and final cut point for CEX eluate, according to which the process chromatography was directed to switch from collection to waste to achieve the desired charge variant composition in the CEX pool. Two case studies were carried out to demonstrate this control strategy. In the first case study, the continuous train was run for initially 14 h for harvest of fixed charge variant composition as feed. In the second case study, charge variant composition was dynamically changed by introducing forced perturbation to mimic the deviations that may be encountered during perfusion cell culture. The control strategy was successfully implemented for more than ±5% variability in the acidic variants of the feed with its composition in the range of acidic (13%–17%), main (18%–23%), and basic (59%–68%) variants. Both the case studies yielded CEX pool of uniform distribution of acidic, main and basic profiles in the range of 15 ± 0.8, 31 ± 0.3, and 53 ± 0.5%, respectively, in the case of empirical modeling and 15 ± 0.5, 31 ± 0.3, and 53 ± 0.3%, respectively, in the case of mechanistic modeling. In both cases, process yield for main species was >85% and the use of online HPLC early in the purification train helped in making quicker decision for pooling of CEX eluate. The results thus successfully demonstrate the technical feasibility of creating digital twins of bioprocess operations and their utility for process control.

Realization of digital twin for dynamic control toward sample variation of ion exchange chromatography in antibody separation

“…In recent years, with the maturation of the first principle model for IEC, process development based on the mechanistic model has become increasingly common (Babi et al, 2022; Chen, Yao, et al, 2022; Hahn et al, 2015; Osberghaus et al, 2012; Pirrung et al, 2017), which can not only save a significant amount of wet experiments but also yield higher purity and recovery compared to traditional optimization methods such as the design of experiments. Furthermore, mechanistic models have found applications in real‐time process control (Gomis‐Fons et al, 2020; Rischawy et al, 2022, 2023; Tiwari et al, 2023). By connecting the mechanistic models to the input and output of different steps (such as protein capture, polishing, pH adjustment, etc.…”

Methodology for fast development of digital solutions in integrated continuous downstream processing

“…The development of these digital solutions becomes an important part of the process development and needs to be accounted for early in the development chain. Lab-scale automated continuous bioprocesses have been reported (Steinebach et al 2017, Feidl et al 2020, Gomis-Fons et al 2020B, Rathore et al 2021, Schwartz et al 2022, Tiwari et al 2022. The software used in these experimental platforms were very different from locally developed PLC to commercial process automation SCADA systems.…”

Methodology for fast development of digital solutions in integrated continuous downstream processing

“…The development of these digital solutions becomes an important part of the process development and needs to be accounted for early in the development chain. Lab‐scale automated continuous bioprocesses have been reported (Feidl et al, 2020; Gomis‐Fons et al, 2020, Gomis‐Fons, Schwarz, et al, 2020; Rathore et al, 2021; Schwarz et al, 2022; Steinebach et al, 2017; Tiwari et al, 2022). The software used in these experimental platforms were very different, ranking from locally developed PLC to commercial process automation SCADA systems.…”