(660e) Dynamics and Control of Oscillatory Bioreactors

As new modalities and continuous operation strategies emerge in the biopharmaceutical industry, the need is growing for deeper biological process understanding and process automation through digital twins and online monitoring technologies [1]. Through a combination of process systems engineering (PSE) tools including mechanistic modelling, controls, and optimization, several such biological systems have been successfully analyzed, continuously processed, and controlled to achieve typical Quality-by-Design and manufacturing objectives at scale [2].

Nearly all biological systems exhibit strongly nonlinear dynamics. Many important biological systems—notably yeast, mammalian cell, and viral systems—are capable of undesirable, sustained oscillatory behavior in their metabolite consumption and production of drug product [3]. Although many methods exist for prediction and control of nonlinear dynamical systems, such as robust nonlinear model predictive control [4], the literature on the optimal control of oscillatory systems has been sparse.

This presentation is an introduction to the numerical simulation, bifurcation/stability analysis, and state feedback control of oscillatory biological systems. Both open- and closed-loop numerical simulations, as well as the optimal control of bioreactor operation for various control objectives, are presented for biological systems described by models that range from ordinary differential equations (ODEs) to coupled systems of ODEs to integropartial differential equations (IPDEs). Stirred-tank batch and perfusion and tubular bioreactor configurations are explored. Results show that the oscillatory dynamics of three case studies—cell budding population asynchrony, substrate inhibition, and infection competition—may be stabilized using simple feedback controls for various bioreactor configurations.

References:

[1] Narayanan et al. (2020). Bioprocessing in the Digital Age: The Role of Process Models. Biotechnology Journal, 15 (1), 1–10.

[2] Feidl et al. (2020). Process-wide Control and Automation of an Integrated Continuous Manufacturing Platform for Antibodies. Biotechnology & Bioengineering, 117 (5), 1367–1380.

[3] Alvarez-Ramirez et al. (2009). On the Existence of Sustained Oscillations in a Class of Bioreactors. Computers & Chemical Engineering, 33 (1), 4–9.

[4] Nagy & Braatz (2003). Robust Nonlinear Model Predictive Control of Batch Processes. AIChE Journal, 49 (7), 1776–1786.