A Multiscale Metabolic Model for Fed Batch Culture Process Control

This project will develop a mechanistic model of cell metabolism that can be integrated with a multiscale cell growth model to predict of metabolic behavior in fed-batch culture.

Industry Need

Cells in culture have a high flux of glucose consumption and convert a large portion of the consumed glucose to lactate. In the late stage of fed-batch culture, the high flux metabolism may switch to low flux. The occurrence, or the lack thereof, of metabolic shift in fed-batch cultures affects the productivity and quality of therapeutic proteins.

Approach

This project will integrate a mechanistic model of cell metabolism with a multiscale cell growth model to predict of metabolic behavior in fed-batch culture.

Impacts

Availability of a mechanistic model for cell metabolism integrated with a multiscale cell growth model to predict of metabolic behavior in fed-batch culture including productivity and quality of therapeutic proteins.

Value Statement/Outcomes

By implementing a mechanistic metabolic modeling approach for fed-batch CHO cell culture, an organization could reduce process variability and metabolite-related inefficiencies by optimizing glycolytic flux and growth rate balance, enabling robust biomanufacturing processes that improve product quality and scalability.

Outputs/Deliverables

The team developed and validated a metabolic shift prediction model linked to glycan synthesis using three cell lines.

Publications

O'Brien, C. M., Zhang, Q., Daoutidis, P., & Hu, W. (2021). A hybrid mechanistic-empirical model for in silico mammalian cell bioprocess simulation. Metabolic Engineering, 66, 31-40. https://doi.org/10.1016/j.ymben.2021.03.016

Presentations

A multiscale metabolic model for fed batch culture process control (PC2.1-042), NIIMBL Member Forum, Virtual, May 27, 2021.

Lu, Y., Hu, W., McCann, M., & Zhang, Q., Systematic construction of cell-line specific kinetic models of mammalian cell metabolism, American Chemical Society (ACS) Spring 2022 Meeting, San Diego, CA, March 20, 2022.