to improvements in process monitoring, control, and optimization, and the development of novel bioreactor designs, are making the transition from the research laboratory to industry standard practice. Clearly, this will lead to a reduction in the cost and complexity of the process of recombination-protein production using mammalian cell lines by placing the technology on a firmer scientific footing.

In order to optimize the viable cell number and protein productivity, a detailed understanding of the factors that lead to cell death in the bioreactor is required. These factors may be classified into three groups:

1. The hydrodynamic environment of the cell

2. The accumulation of toxic metabolites

3. The exhaustion or local limitation of nutrients and oxygen

Although each of these areas has now been investigated to varying degrees, recent studies have demonstrated that at least some of the cell lines used in bioreactors undergo apoptotic death rather than necrosis, indicating that a reassessment of the subject is required. As described later, the greater understanding of the mechanism of cell death in commercial cultures should provide new routes to culture optimization. The resultant enhancement in culture efficiency would be expected to manifest itself in three forms:

1. First, the nutrients and culture time invested in generating a viable cell will be wasted if that cell should die prematurely. If the survival time of the cell can be enhanced, the proportion of culture resources utilized for production of the biopharmaceutical of interest can be increased by eliminating the need for regeneration of cellular biomass.

2. Second, as a cell dies, it releases proteolytic enzymes into the culture medium, which can lead to degradation of the product. Thus, product stability should be enhanced by minimization of cell death.

3. Finally, high levels of cellular debris in the culture medium can complicate the recovery of the target protein. This will add to the cost of downstream processing and lead to a reduction in the efficiency of target protein recovery.

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