GOALI: Leveraging the interconnectedness between mass transfer and cell metabolism for process control of mammalian cell fed-batch and perfusion cultures

Medicines derived from cells, known as biopharmaceuticals, play a crucial role in preventing and treating various diseases, such as diabetes and cancers. The biopharmaceutical industry heavily relies on Chinese hamster ovary (CHO) cells as the primary organisms for manufacturing these medicines. However, the cultivation of CHO cells poses challenges due to limited methods available to gauge the oxygen uptake rate (OUR) which is a critical metric for assessing CHO cell health. This project seeks to enhance the accuracy of OUR estimation and develop tools to differentiate cell metabolism from other physical system changes. Furthermore, the project constructs a comprehensive mathematical model of cell behavior to improve CHO cell productivity. Beyond technological advancements, this project has broader impact that includes several modes of interaction between graduate students and industry collaborators and the development of curriculum modules at Clemson, focused on fed-batch and perfusion operation, that are shared broadly through Amgen’s curriculum outreach program. This project develops a controls-oriented metabolic model for Chinese hamster ovary (CHO) cells that correlates cell responses with on-line process signals, such as the dissolved oxygen, pH, base addition rates, gas mass flow rates, and off-gas compositions. Additionally, a robust volumetric oxygen mass transfer coefficient (kLa) estimator that accounts for filtering and latency effects, is developed. Accounting for these filtering and latency effects enables oxygen uptake rate calculations in real-time without distortion. Furthermore, the control algorithm enables distinguishing between chemical and physical process disturbances (i.e., antifoam additions and sampling) from cellular metabolic responses (i.e., glucose depletion). These modeling and feed control innovations will lead to reduced waste – improved nutrient utilization and more homogeneous critical product quality attributes, a key long-term long-standing vision in the biopharmaceutical industry. This project is jointly funded by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences, and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.