Wheels turning: CHO cell modeling moves into a digital biomanufacturing era: Subtitle: CHO Metabolic Modeling.

Recent advancements in biologics production using CHO cells have been partly driven by improved understanding of how variations in the cell culture environment influence cellular metabolism, productivity, and the attributes of the final product. In-silico models serve a valuable role in mapping the effects of various process parameters and media changes on cellular response. Advances in technologies such as data-driven analysis, self-learning systems, and digital twins are reinforcing progress toward smart manufacturing, enabling the real-time control of production processes. Furthermore, kinetic, and constraint-based mechanistic modeling, combined with omics approaches, are becoming increasingly incorporated into the bioprocess development and manufacturing innovation ecosystem. In this review, we cover CHO central metabolism as a foundation for mechanistic modeling and extend the discussion to include various mechanistic modeling approaches, highlighting the incorporation of glycosylation and secretory pathways. Multi-omics approaches provide a deeper understanding of intracellular processes and the dynamic interactions between product quality and pathways. In parallel, to achieve the Industry 4.0 vision of digitalization and machine learning techniques are finding wider adoption in biopharmaceutical development. We discuss the potential applications of these techniques for predictions, inference, optimization, and control. The role of big data analytics and artificial intelligence methods in reinforcing progress towards smart manufacturing and enabling real-time control of production processes is discussed. Finally, we summarize the application of machine learning and hybrid models to CHO bioprocesses, aiming to develop and manufacture drugs more efficiently and at a lower cost for patients.