Processes of mass cultivation of animal cells

Mass-culture processes for animal cells have made considerable progress over the last 30 years. They have thus become essential to the biotechnology industries for the production of numerous products with therapeutic and diagnostic applications (viral vaccines, cytokines, growth factors, monoclonal antibodies, recombinant proteins, etc.). These products are used to prevent or treat diseases such as cancer, viral infections, hereditary deficiencies and many chronic illnesses. This acceleration means that production capacity has to be increased. There are now more than fifteen installations using stainless steel stirred-tank reactors of the order of 15,000 liters. More specialized production uses smaller but more diversified systems. Recently, there has been a strong interest in single-use reactors, as links in the production chain or for screening operating conditions. As far as investments are concerned, given the long lead-times for installation and validation of an industrial unit, these must be anticipated as early as possible, based on upstream knowledge and high-performance decision-support tools.

The feasibility of industrial production of a bioproduct using animal cells requires the transfer of cell culture to reactor scale, without loss of production performance and quality. The challenge is to use relatively fragile cells under conditions of environmental, biochemical and physical stress, while maintaining their production potential. This calls for an integrated, multi-scale approach that takes into account aspects relating to bioreactors, cell characteristics and product quality. The challenges to be met combine knowledge of cellular processes in relation to the culture medium, adaptation of cells to reactor constraints, formulation of culture media, research into cell and product analysis tools to improve on-line process control, design of new reactors, control of operating conditions and identification of key extrapolation parameters. This necessarily involves an interdisciplinary approach between life sciences and process engineering.

Against this backdrop, this article sets out to present the main specificities of animal cell culture processes. After outlining the characteristics of the most commonly used industrial cell lines, we will discuss the current challenges facing culture media and provide data on the impact of operating factors on cell behavior. Another section will focus on reactor technologies, both conventional and single-use, as well as tools for controlling and operating these processes. Finally, elements relating to hydrodynamics and material transfer encountered in these processes will be presented.