Bioreactor Operation Modes

The following operation modes for cell culture bioreactors have been described in the literature; batch, fed-batch, continuous culture without cell retention (chemostat or cytostat), and continuous culture with cell retention (perfusion). During perfusion culture sometimes a cell bleed is applied or obtained due to noncomplete cell retention. The kinetics that is observed during this type of continuous culture is a combination of the two types of continuous mode, i.e., perfusion and chemostat. The different modes are discussed in more detail in this chapter. For a quick overview, the typical operation schemes and associated kinetics are shown in Fig. 11; the mass balance equations for ideal systems (i.e., excluding cell death, cell lysis, accumulation of product, product degradation, or nutrient degradation) are given in Table 6. Common for the different operation modes is that the temperature, the oxygen partial pressure, and the pH of the culture are controlled. This means continuous supply of oxygen and removal of carbon dioxide. A comparison of the different culture modes is attempted in Table 7.

Batch and Repeated Batch Cultures

In batch culture the bioreactor is charged with cells and medium, no further medium is added or withdrawn during the process and at the end of the culture the whole reactor content is harvested at once. The cells grow exponentially while nutrients are consumed and metabolic waste products are accumulated until the maximum cell density for the given medium is reached due to nutrient limitation or waste product inhibition (see Fig. 11). Historically, ammonium, lactate, and CO2 have been considered as inhibitory metabolic waste products (82,83,266,329). However, there are reports in the literature on small inhibitory proteins (330,331) suggesting a key role in growth control (99). The length of

Figure 11 Operation principle (A) and kinetics (B) of cell growth, nutrient consumption, and product formation during batch, fed-batch, perfusion, and continuous operations. Shown are the concentrations of nutrients, product, and viable cells versus process time.
Table 6 Mass Balance Equations for Ideal Systems (No Cell Death, Cell Lysis, Accumulation of Product, Product Degradation)
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