Date of Award


Degree Type


Degree Name

Master of Science in Chemical Engineering (MSChE)


Chemical Engineering

First Advisor

Geoffrey D. Bothun


Since its inception, the biotechnology industry has faced the problem of pH control and CO2 management. This research paper explores the challenges of developing a first principles, unstructured, dynamic, nonlinear mathematical model to maintain pH and control carbon dioxide levels in an aerobic Chinese hamster ovary (CHO) cell culture in a perfusion bioreactor. Perfusion bioreactor is an extremely complex bioreactor to model because the cells grow in a quasi-steady state system. Cell growth, feed, substrate consumption, by-product formation and product formation are all time dependent, equations for which can only be solved through numerical methods. Added complexity comes from presence of stiffness in solving the non-linear equations due to the different time scale of each set of equations. Equations related to pH that involve acid/base ionization have reaction rates on the order of nano- or pico-seconds. CO2 or O2 hydration and bubble dynamics involve the reaction rates on the order of seconds and cell growth equations are on the order of days. This research paper also presents a framework for software development to solve these equations without conducting experiments, except as a final trial before using the results of the model on the manufacturing floor.



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