ABSTRACT
This chapter covers methods for process intensification in upstream processing of cell culture‐based virus production for manufacturing of viral vaccines and viral vectors. The concept of animal cell cultivation in batch, fed‐batch and perfusion mode is explained, and future needs regarding the development of platform technologies providing high‐cell densities and high virus yields are highlighted. In addition, the integration of upstream and downstream processing is addressed. To establish high cell density processes, cell retention devices are required. Therefore, an overview on membrane‐based retention devices such as tangential flow filtration and alternating tangential flow filtration systems is given. In addition, the use of spin filters, non‐membrane‐based retention devices like centrifuges, inclined settlers, hydrocyclones and acoustic filters is addressed. Key parameters for process evaluation and performance comparison, like cell concentration, virus titers, cell‐specific virus yield, space‐time yield and volumetric virus productivity are introduced and discussed. Critical factors governing virus production at high cell density are presented including metabolic state, time of infection, multiplicity of infection, residence time of cells and virus within a bioreactor or cell retention device, accumulation of defective interfering particles and time of harvest. Finally, the implementation of single‐use bioreactors, including hollow fiber bioreactors and other equipment is discussed.
