Abstract
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 > 80 0 0 feeding strategies to identify a subset of manufacturing conditions that meet constraints on antibody titre and glycan distri- bution 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.