Scale‐up is best approached by considering the need to provide the optimum environment for the cell. It is inevitably a compromise and needs appropriate small‐scale data as discussed here. However, arbitrary and inflexible “scale‐up rules” are not useful. The most critical aspects of scale‐up are oxygen and carbon dioxide mass transfer and their concentration in the broth, all of which depend on the air sparge rate and power input from the selected impeller(s). The Rushton turbine is discussed followed by the now‐preferred hollow‐blade and up‐pumping, high solidity ratio hydrofoils. Bulk blending/homogeneity (especially at the high aspect ratios found on the commercial scale), holdup, and foaming and heat transfer in turbulent conditions as found with small‐sized microorganisms are considered, followed by the additional complexity that arises with these parameters when dealing with high viscosity, rheologically complex broths with mycelial and biopolymer fermentations. The impact of scale‐up on two aspects of bioperformance is considered, namely, mechanical stress from agitation and stresses from the inevitable poorer homogeneity. It is concluded that mechanical stresses are only important with mycelial fermentations and the impact depends on the organism. Stresses due to spatial differences in dO
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and in pH batch fermentations, as well as nutrients in fed batch, cause a poorer performance at the commercial scale. Such information is vital for enabling a realistic appreciation beforehand of the likely large‐scale bioperformance, and for guiding design. Finally, with the present understanding of the physical and biological aspects of bioprocesses, computational fluid dynamics (CFD) is unlikely to be able to significantly improve it.