Mixing, aeration and cell damage, 30+ years later: what we learned, how it affected the cell culture industry and what we would like to know more about

•Animal cell culture producing biopharmaceuticals is a 200 billion dollar industry.•In thirty years, final product concentrations have risen from 50 mg/L to 25 g/L.•These dramatic increases in productivity achieved with fundamental questions remaining.•Model(s) predicting cellular response to hydrodynamic forces is needed.•As productivity continues to increase the need for fundamental understanding will increase.

Greater than $100 billion in sales of human biopharmaceuticals are produced in large scale, animal cell culture in stirred tank bioreactors. Despite initial and continuing concerns of the “shear sensitivity” of animal cells, over the last 30 years, incredible advances have been made in the productivity of suspended animal cells to produce biopharmaceuticals, from mg/L of product to over 5 g/L. In this contribution, a summary of the current state of this “shear sensitivity” concerns will be discussed, demonstrating that it is not in general a problem with current bioprocesses. Examples of what is considered the current limits above which effects of hydrodynamic and interfacial phenomena become a concern and begin to negatively impact the cells and the bioprocess will be presented.