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Kurian, Varghese

Luo, Yu

Ogunnaike, Babatunde A.

Radhakrishnan, Devesh

Robinson, Anne

Song, Liqing

Wells, Evan A.

English

Engineering Conferences International

Tuesday, April 25, 2023                               Session 4: Analysis and Control of Cell Culture-based Manufacturing ADVANCED CONTROL OF GLYCOSYLATION AND TITER IN FED-BATCH  MONOCLONAL ANTIBODY PRODUCTION  Anne Skaja Robinson, Department of Chemical Engineering, Carnegie Mellon University  Anne.Robinson@cmu.edu Yu Luo, University of Delaware; Glaxo Smith Cline (current address) Devesh Radhakrishnan, University of Delaware; BioMarin Pharmaceutical Inc. (current address) Evan A. Wells, Carnegie Mellon University; Janssen Pharma (current address) Liqing Song, Carnegie Mellon University; Glaxo Smith Cline (current address) Varghese Kurian, Department of Chemical and Biomolecular Engineering, University of Delaware Babatunde A. Ogunnaike, Department of Chemical and Biomolecular Engineering, University of Delaware    Key Words: process control, state estimation, quality by design, Open Platform Communications  Therapeutic monoclonal antibodies (mAbs) are currently produced commercially in fed-batch cultures using media recipes and protocols based primarily on heuristics. The main production objectives are maximizing mAb titer (productivity) and achieving desired glycan distributions (quality attribute). The distribution of glycans is a critical quality attribute (CQA) of mAb manufacturing because it can either promote or inhibit the desirable therapeutic effects of mAb drugs. However, controlling glycosylation is challenging because it is a complex, non-template driven process that takes place within the cell. Consequently, the variables available for influencing glycosylation are far fewer than the controlled variables such that the process is challenging to model. In addition, on-line sensors do not currently exist for characterizing glycan distribution frequently enough for effective on-line control. Nevertheless, recent advances in both glycosylation modeling and glycan assays have improved the possibility of implementing model-based control of glycosylation in place of the current heuristics-based approach.  Here we present an overall model-based strategy for meeting productivity and product quality requirements in the manufacture of mAbs. The proposed multivariate cascade control system consists of two nested control loops. The outer loop, which is responsible for controlling product attributes such as mAb titer, cell density, and the relative abundance of dominant glycans, uses a model predictive controller (MPC) to determine the setpoints for the inner loop. The inner loop, in turn, employs multiple PI controllers to sustain the cell culture by maintaining the levels of nutrients, pH, temperature, and dissolved oxygen, at desired values. Because measurements of glycan distribution are not available frequently enough, the outer loop incorporates a state observer, which uses available sensor measurements and model predictions to reconstruct the complete system state that the MPC uses, along with the process model, to determine the desired control policies. We interface our controller software with the sensors and actuators in the bioreactor through the Open Platform Communications (OPC). As a first step toward implementing on-line control of industrial fed-batch mAb manufacturing processes, we evaluate via simulation, the performance of the outer-loop MPC and demonstrate the capability of the overall system to satisfy complex production objectives, as a first step toward the ultimate goal of creating an advanced control system for fed-batch mAb manufacturing processes.    Related references from our laboratories: 1) Y Luo, V Kurian, BA Ogunnaike (2021) Bioprocess systems analysis, modeling, estimation, and control, Current Opinion in Chemical Engineering 33, 100705 2) E Wells, L Song, M Greer, Y Luo, V Kurian, B Ogunnaike, AS Robinson (2020) Media supplementation for targeted manipulation of monoclonal antibody galactosylation and fucosylation, Biotechnology and Bioengineering 117 (11), 3310-3321 3) D Radhakrishnan, EA Wells, AS Robinson (2018) Strategies to enhance productivity and modify product quality in therapeutic proteins, Current opinion in chemical engineering 22, 81-88    

ADVANCED CONTROL OF GLYCOSYLATION AND TITER IN FED-BATCH  MONOCLONAL ANTIBODY PRODUCTION

https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1029&context=ccexviii&type=additional

ADVANCED CONTROL OF GLYCOSYLATION AND TITER IN FED-BATCH MONOCLONAL ANTIBODY PRODUCTION

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Engineering Conferences International