ABSTRACT
Over the last 20 years, there has been a significant increase in the number of largescale animal cell culture processes for commercial, therapeutic products. A number of these processes are conducted in bioreactors on the order of 10,000L; yet, no single universal methodology on how to design, operate , and scale-up bioreactors exists. Conceptually, the optimal scale-up (or scale-down) methodology would provide an optimum, constant ‘‘microenvironment’’ surrounding each cell that is scale independent. This constant ‘‘microenvironment’’ would not only include the concentration of all nutrients and byproducts, but also all hydrodynamic forces acting on the cells. This lack of methodology is the result of the complexity of introducing=removing gas-phase nutrients=byproducts into=from the culture and the turbulent nature of the hydrodynamics. The gas-phase challenges are exacerbated by the low solubility of oxygen in the liquid phase, which requires an active oxygen introduction system (either gas sparging or the use of membranes) in culture sizes typically greater than 100L. Equally challenging is the perceived, and in some cases actual, sensitivity of the cells to hydrodynamic forces generated in bioreactors to facilitate the mixing of nutrients and the suspension of the cells.
