Insights into large-scale cell-culture reactors: I. Liquid mixing and oxygen supply

In the pharmaceutical industry, it is state of the art to produce recombinant proteins and antibodies with animal-cell cultures using bioreactors with volumes of up to 20 m3. Recent guidelines and position papers for the industry by the US FDA and the European Medicines Agency stress the necessity of mechanistic insights into large-scale bioreactors. A detailed mechanistic view of their practically relevant subsystems is required as well as their mutual interactions, i.e., mixing or homogenization of the culture broth and sufficient mass and heat transfer. In large-scale bioreactors for animal-cell cultures, different agitation systems are employed. Here, we discuss details of the flows induced in stirred tank reactors relevant for animal-cell cultures. In addition, solutions of the governing fluid dynamic equations obtained with the so-called computational fluid dynamics are presented. Experimental data obtained with improved measurement techniques are shown. The results are compared to previous studies and it is found that they support current hypotheses or models. Progress in improving insights requires continuous interactions between more accurate measurements and physical models. The paper aims at promoting the basic mechanistic understanding of transport phenomena that are crucial for large-scale animal-cell culture reactors.