Integration of Bioreactors with Downstream Steps

Biological medicines are produced by a bioprocess: a series of steps, from cell culture through purification to final formulation and possibly freeze-drying. Such a bioprocess must be demonstrated to be in control over the lifetime of the medicine. It is now acknowledged that optimizing each individual unit operation may not suffice for overall control of the bioprocess; interactions among or between individual unit operations may also be critical. Such interactions may also be important in determining the global process optimum, which could differ appreciably from the combination of optima for the unit operations taken individually. This chapter reviews the interactions between the bioreactor, or product generation, steps, and the subsequent downstream processing steps. The critical trade-off in the bioreactor balances product titer against product quality. For different elements of product quality, the trade-off may give quite different results. For instance, when the critical product quality parameter is aggregate level or glycoform distribution (e.g., average sialyl content), the process difficulty may be measured by the additional monomer that is lost in purification through reducing the aggregate or low-sialyl product variants to acceptable levels. However, when the critical product quality parameter is an extent of cell disruption (i.e., viable cell density at the end of the reactor run), then the process difficulty may be measured by the additional filtration and centrifugation steps needed to produce a particle-free load into the chromatography steps, in addition to possible product loss. In designing a robust bioprocess, such trade-offs must be weighed in terms of both process flow and economics. Examples of industrial relevance are critically assessed. Integrated process models that capture such trade-offs are discussed.