Journal
COMPUTERS & CHEMICAL ENGINEERING
Volume 125, Issue -, Pages 558-568Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.compchemeng.2019.01.022
Keywords
Monoclonal antibodies; Glycosylation; Chinese hamster ovary cells; Design space identification; Global sensitivity analysis; Kinetic modeling
Funding
- Biotechnology and Biological Sciences Research Council BioProNET network in Industrial Biotechnology
- Engineering and Physical Sciences Research Council [EP/K038648/1]
- EPSRC [EP/K038648/1] Funding Source: UKRI
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The manufacture of protein-based therapeutics presents unique challenges due to limited control over the biotic phase. This typically gives rise to a wide range of protein structures of varying safety and in vivo efficacy. Herein we propose a computational methodology, enabled by the application of constrained Global Sensitivity Analysis, for efficiently exploring the operating range of process inputs in silico and identifying a design space that meets output constraints. The methodology was applied to an antibody-producing Chinese hamster ovary (CHO) cell culture system: we explored >8000 feeding strategies to identify a subset of manufacturing conditions that meet constraints on antibody titre and glycan distribution as an attribute of product quality. Our computational findings were then verified experimentally, confirming the applicability of this approach to a challenging production system. We envisage that this methodology can significantly expedite bioprocess development and increase operational flexibility. (C) 2019 Elsevier Ltd. All rights reserved.
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