Use of mathematical models to determine the effect of various raw materials on mammalian cell culture performance at commercial-scale

BIOT 116

Siddhartha Jain1, Bernhard Schilling1, Abhinav A. Shukla, abhinav.shukla@bms.com2, and Steven Lee, steven.lee@bms.com3. (1) Biotechnology Development, Bristol-Myers Squibb Company, P.O. Box 4755, Syracuse, NY 13221-4755, (2) Bristol-Myers Squibb, 6000 Thompson Road, East Syracuse, NY 13057, (3) Biotechnology Development & Operations, Bristol-Myers Squibb Co, PO Box 4755, Syracuse, NY 13221-4755
Commercial-scale manufacturing of various therapeutic recombinant proteins involve mammalian cells cultured in bioreactors using a combination of chemically-defined serum-free components and complex medium components. Mammalian cells are sensitive to their hydrodynamic and chemical environment, and a variability in raw materials can significantly impact protein production by the cells. During commercial production of the recombinant proteins, it is often difficult to identify the effects of individual raw materials on cell culture performance due to interactions between components of different raw materials and use of multiple lots of the same raw material during production. We developed and used mathematical models in combination with various statistical tools to simulate the observed titers of a recombinant protein manufactured at different manufacturing facilities. Results from the simulations were used to predict the contribution of individual raw materials and of specific raw material lots, and helped us identify the critical raw material in our manufacturing process. We propose that mathematical tools such as the one presented in this work can be used to identify the critical raw materials and increase understanding of the recombinant protein manufacturing process.