Cell Culture Bioreactors (2005)

Historically, cell cultivation was ﬁrst devised at the beginning of the 20th century (1,2). For many years, it was restricted to simple small-scale propagation systems applied to tissue culture for basic research. Simultaneously, large bioreactors were already in use for the production of commercially interesting secondary metabolites exploiting microbial fermentation. The development of industrial-scale cell culture bioreactors started in the mid-1950s in response to the need for mass cultivation techniques that were suitable for vaccine production as demanded by the massive vaccination programs launched at that time. Previously, roller bottles were used to culture primary cells at relatively limited scale for vaccine production. These initial cell culture bioreactors were speciﬁcally designed for adherent cells, examples are plate propagators and packed beds as reviewed in Refs. (3,4). The ﬁrst commercially interesting suspension cell products [food-and-mouth disease vaccine produced in suspension culture of BHK cells and interferon produced in Namalva cells (5)] stimulated the adaptation of homogeneous bioreactor systems used for microbial culture to the requirements of the mechanically more sensitive animal cells. The advent of the monoclonal antibody era in the 1970s then gave rise to the development of a plethora of different bioreactors and culture systems suitable for suspension cell culture with special emphasis on increasing the product yield per unit volume through improved nutrient supply and waste product removal. These specialized systems include hollow ﬁber, ﬂuidized bed reactors, and other different types of compartmentalized bioreactors based on cell immobilization and perfusion of fresh medium through the cell-containing compartment (6). The basic idea was to overcome the major limitations of cell cultivation, i.e., slow cell growth and low ﬁnal cell densities, by providing an environment that allows the cells to continuously produce the product of interest at high levels. In parallel, a large number of cell retention devices for stirred tanks or airlift bioreactors were developed allowing for continuous exchange of medium in homogeneous systems. Recombinant DNA technology, which is the basis of modern biotechnology today, enabled the production of a series of protein therapeutics in mammalian cells in the 1980s. This novel opportunity had further impact on the development and optimization of bioreactors for suspension as well as anchorage-dependent cells in large scale. In this regard, a severe biomanufacturingbottleneck is forecasted for the coming decade due to the strong product pipeline for fully human monoclonal antibodies and ultra-large scale bioreactors beyond the 20m2 scale are discussed to meet this anticipated demand of several kilograms of protein per year (7). At the same time scaled-down systems are becoming more important to enable multiple parallel experimental approaches to be taken for cell line and process development. Since the mid-1990s, the available knowledge has also been applied to the design of bioreactors used for artiﬁcial organs (8-13) and systems for tissue and stem cell culture (14,15). Other more recent applications are the production of viral vectors for genetic vaccination or gene therapy (16-19).