Experimental Validation of a Cascade Control Strategy for Continuously Perfused Animal Cell Cultures

Thomas Abbate,Laurent Dewasme,Alain Vande Wouwer,Mihaela Sbarciog

doi:10.3390/pr8040413

Abstract

This paper is dedicated to the experimental validation of a cascade control strategy for simultaneously regulating the glucose and biomass levels in continuously perfused HEK-293 cell cultures. The inner loop consists of a partial feedback linearization, which requires the estimation of the biomass specific growth rate and glucose uptake rate. This latter task is achieved by sliding mode observers, which do not require a priori process knowledge in the form of a process model. The linearized process is then regulated by the outer loop, including two classical PI controllers with autotuning. The four manipulated variables are a feed flow rate with low glucose concentration, another feed flow with a higher glucose content, a bleed flow, and a perfusion stream. The experimental results demonstrate the ability of the control strategy to reach and regulate the prescribed setpoints. The main advantage of the strategy is that it can be applied in a plug and play manner and shows satisfactory robustness. To the best of our knowledge, this is the first time that such a multivariable control strategy, together with sliding mode observers, is applied at the lab scale to an industrial process in the pharmaceutical sector.

Highlights

Mammalian cell cultures have been widely studied over the last few decades [1]
The distinctive feature of our control strategy [19] is to allow controlling independently biomass and glucose at specific setpoints during the course of the culture, the underlying idea being that cell density is related to the productivity objective, whereas glucose concentration is linked to the consumption of the culture medium
The volume of the bioreactor is kept constant during the whole culture, such that the flow entering the vessel (Fin ) must be equal to the one exiting the reactor (Fout ), i.e., Fin = Fout = F = Fb + Fper f

Summary

Introduction

Mammalian cell cultures have been widely studied over the last few decades [1]. Currently, this technology is commonly used in order to synthesize various products of interest such as monoclonal antibodies (Mabs), proteins, vaccines, etc. [2,3]. Mammalian cell cultures have been widely studied over the last few decades [1] This technology is commonly used in order to synthesize various products of interest such as monoclonal antibodies (Mabs), proteins, vaccines, etc. The control of cell cultures usually requires on-line probes, as well as a priori process knowledge under the form of mathematical models [9]. Since a complete bioreactor instrumentation and the knowledge of reliable dynamic models are difficult to achieve in practice, the successful implementation of control strategies highly depends on the possibility to infer on-line information using robust software sensors and to control the process without explicitly requiring a detailed model and the delicate identification of its (possibly numerous) parameters

Methods

Results

Conclusion