Batch versus Fed Batch and Perfusion Culture

Since many early animal cell culture practitioners had transitioned from bacterial fermentation experience, it was logical that early bioproduction protocols mimicked bacterial batch fermentation processes (Kadouri & Spier 1997). The batch production process facilitates materials handling and regulatory definition of what constitutes a 'batch' of product, since all of the raw materials including cells are placed into a single bioreactor and the target product is harvested following an appropriate cultivation period and processed as a single unit. To achieve production-scale capacity, biopharmaceutical manufacturers frequently require multiple production suites containing stainless steel bioreactors of 10-12 000 litre capacity and dedicated purification trains. Given the capital investment of early adopters of these batch processes, and given the preferred compatibility of certain biomedical products to batch processes, batch bioproduction processes are likely to remain highly useful for an extended period.

An ideal production environment would have a relatively small bioreactor that could sustain cells at high viability and productivity for an extended period of time. The continuous delivery of nutrients and removal of waste substances would be highly efficient, and the harvested effluent would be highly concentrated with stable product. Perfusion culture accomplishes some, although not all, of these objectives (Vogel et al. 2001). Clearly, the bioreactor scales are downsized by an order of magnitude from stirred tank systems. Many systems have successfully maintained cells at relatively higher viability and productivity for campaign periods lasting for over 100 days, as compared with a batch bioreactor campaign that is typically limited to less than 2 weeks. The efficiency of nutrient utilization, however, varies widely with the user application and the extent of control over bioreactor processes. Consequently, some processes exhibit relatively efficient nutrient consumption and isolate relatively concentrated product from the harvested effluent, while other processes pump excessive volumes of nutrient medium through the bioreactor and require effective capture steps to concentrate dilute product from high harvest volumes. Given the relative complexity of perfusion bioreactor systems, they tend to require a higher level of manual surveillance by trained professionals than might be expected for a batch culture bioreactor. This observation notwithstanding, perfusion bioreactors offer significant capital advantages in terms of the upstream facility footprint and space-time utilization efficiency.

Somewhat intermediate between these two processes is fed-batch culture, which means slightly different things to different people, but basically consists of supplementing a batch bio-reactor with nutrient feeds to replenish consumed materials, and may include multiple product harvests. Optimization of nutrients to be included within the basal medium and as part of the feed stream represents a novel, emerging derivative of the field of medium development (Fike et al. 1993).

Perhaps you were asking yourself why the author is venturing into the area of bioreactor production protocols in a chapter nominally devoted to medium optimization? There exist significant qualitative and quantitative differences in the optimal medium for cultivating a particular cell type in a batch production environment compared with a fed batch or perfusion culture environment. Virtually all of the nutrient media developed for animal cell culture over the past several decades were designed for batch culture applications. To begin to optimize basal formulations and nutrient feeding regimens for perfusion and for fed batch applications may well involve reexamination of fundamental postulates, and reinvention of approaches for investigating and optimizing nutritional requirements of cell culture bioreactors operating in extended modes. Preliminary efforts for selected cultivation systems have demonstrated that productive lifespan may be extended and specific product yield may be increased significantly with a programmed delivery of a simple, optimized nutrient feed stream (Gorfien et al. 2003).

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