Search

No matter the scale, stirred tank bioreactors are the most commonly used systems in biotechnological production processes. Single-use and reusable systems are supplied by several manufacturers. The type, size, and number of impellers used in these systems have a significant influence on the characteristics and designs of bioreactors. Depending on the desired application, classic shaft-driven systems, bearing-mounted drives, or stirring elements that levitate freely in the vessel may be employed. In systems with drive shafts, process hygiene requirements also affect the type of seal used. For sensitive processes with high hygienic requirements, magnetic-driven stirring systems, which have been the focus of much research in recent years, are recommended. This review provides the reader with an overview of the most common agitation and seal types implemented in stirred bioreactor systems, highlights their advantages and disadvantages, and explains their possible fields of application. Special attention is paid to the development of magnetically driven agitators, which are widely used in reusable systems and are also becoming more and more important in their single-use counterparts.Key Points• Basic design of the most frequently used bioreactor type: the stirred tank bioreactor• Differences in most common seal types in stirred systems and fields of application• Comprehensive overview of commercially available bioreactor seal types• Increased use of magnetically driven agitation systems in single-use bioreactors

The overall behavior of cell cultures is determined by the actions and regulations of all cells and their interaction in a mixed population. However, the dynamics caused by diversity and heterogeneity within cultures is often neglected in the study of cell culture processes. Usually, a bulk behavior is assumed, although heterogeneity prevails in most cases. It is, however, not valid to conclude from the bulk behavior to the single cell behavior. Instead, it is necessary to include the behavior and kinetics of subpopulations and their interactions into models in order to elucidate the dynamic effects occurring in typical cell cultures. Heterogeneity in cell cultures is largely caused by the progress of the cell cycle. Cell cycle-dependent dynamics resulting for example in variable transfection efficiencies or expression bistability have recently attracted attention. In order to elucidate cell cycle-dependent regulations in cell cultures, it is desirable to synchronize a culture with minimal perturbation, which is possible with different yield and quality using physical methods, but not possible for frequently used chemical, or whole-culture methods. Then, the culture is cultivated again under physiological conditions and subpopulation-resolved analysis and modeling approaches are applied. This should allow to account for the variable contributions of subpopulations to the whole behavior and also for obtaining hereto unaccessible dynamic information of cellular regulation. In this short review, we summarize techniques and key issues to be considered for successful synchronization, cultivation, and modeling in order to achieve the goal of better understanding cell culture at a population level.

A bioreactor system for the continuous cultivation of animal cells with a high potential for scale-up is presented. This reactor system consists of radial-flow fixed-bed units coupled with a dialysis module The dialysis membrane enables the supply of low-molecular-weight nutrients and removal of toxic metabolites, while high-molecular-weight nutrients and products (e.g., monoclonal antibodies) are retained and accumulated. This concept was investigated on the laboratory scale in a bioreactor with an integrated dialysis membrane. The efficiency of the reactor system and the reproducibility of the cell activity (hybridoma cells) under certain process conditions could be demonstrated in fermentations up to 77 days. Based on model calculations, an optimized fermentation strategy was formulated and experimentally confirmed. Compared to chemostat cultures with suspended cells, a ten-times higher mAb concentration (383 mg1(-1)) could be obtained. The highest volumetric specific mAb production rate determined was 6.1 mg mAb (1 fixed bed)-1h-1.