Bioreactor Design

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Chapter: Pharmaceutical Engineering: Bioprocessing

A bioreactor is a device within which biochemical transformations are caused by the action of enzymes or living cells.



A bioreactor is a device within which biochemical transformations are caused by the action of enzymes or living cells. The simple method of shaking cells in a flask to enhance oxygenation through the liquid surface and to aid mass transfer of nutrients without cell damage has to be scaled up for industrial processing.

The use of biotechnology in the manufacture of pharmaceuticals is of increasing interest. Consequently, these techniques require attention in the planning of unit processes.

Bioprocessing can be considered in terms of small-scale bioreactors, or fermenters, and the translation of such processes into large-scale economically viable production operations (Hofmann, 1992; Tatterson, 1994). Bioprocessing is by no means a new field. The topicality of this subject is due to the increasing interest in the use of isolated cells and microorganisms as manufacturing tools. It might well be argued that the technology was developed millennia ago for the purposes of wine and beer production. More recently, the use of attenuated microorganisms or isolated antigenic materials for vaccination resulted in fur-ther developments. In the last decade, interest in genetic engineering and manipulation of the genetic code of certain microorganisms has produced a revolution in pharmaceutical manufacturing.

The major difference between a biotechnological process and other phar-maceutical manufacturing operations is the need for a bioreactor (Fig. 16.2). A bioreactor may be required to produce expressed proteins utilizing bacteria, yeast, insect, or mammalian cells. Table 16.3 illustrates the various processes (Prokop and Bajpai, 1991). It would be difficult to describe the various bioreactor elements and their permutations. Some of the simplest examples of bioreactors are shown in Figure 16.3.

Some important factors in bioreactor design are (i) sterility, (ii) broth rheology, (iii) mass transfer, (iv) mixing, (v) heat transfer, (vi) suspension homogenization, and (vii) shear sensitivity of microorganisms. The importance of these design considerations depends on the nature of the biological systems considered.

FIGURE 16.2 Types of bioreactors.

TABLE 16.3 Biotechnological Processing


The presence of organized structures in the form of mycelial cells or bio-po1ymers tends to induce non-Newtonian properties in broth. The power law of plastic systems (Martin, 1993) may be employed to describe broth rheology. The viscosity and shear rate are related to the concentration of cell mass in the system. These correlations are species specific and depend on the stage of growth in the cell cycle.

FIGURE 16.3 Bioreactors: (A) stirred tank reactor and (B) airlift fermenter.

Mass Transfer

Although all nutrient, waste product, and cell integrity issues in growth may be considered in terms of mass transfer, the most notable of these is oxygen transfer for aerobic growth. A maximum uptake rate of oxygen exists for any system, and the design should be based on an understanding of this limitation. Also the oxygen uptake rate of cells shows a saturation dependence on dissolved oxygen concentration (CL). Assuming a pseudo–steady state of dissolved oxygen con-centration, a design value of gas-liquid mass transfer coefficient, kLα for a biological system can be specified for a specific reactor as

The term “critical” refers to the point in the oxygen uptake rate versus dissolved oxygen concentration plot (CL) at which saturation is achieved and no further oxygen can be dissolved. The gas-liquid mass transfer coefficient often changes during the course of fermentation because of changes in broth rheology or through additives, such as antifoaming agents.


Concentration and temperature are influenced by mixing in bioreactors. Total homogeneity within a system is rarely, if ever, achieved and local variations in mixing within vessels may affect growth, metabolism, or other molecular expression phenomena. Operating conditions influence terminal mixing time (time to reach designated variability associated with complete mixing) and mean circulation time (time to circulate through specific region once). Charac-terization of mixing times and the influence of geometric features of reactors under different operating conditions and scales of operation (bench, pilot, and full scale) are important if efficiency (time and cost) is to be optimized.

Heat Transfer

Heat is dissipated mainly by convection across the walls of the jacket or coils. In aerated systems, metabolic heat production is correlated with oxygen uptake rate. The maximum metabolic load should be considered in design calculations as in gas-liquid oxygen transfer. Handbook values are available for heat transfer on the jacket side, vessel side, and in tubes. In general, heat transfer becomes a problem only in very large scale operations and in dense microbial populations, which are frequent with recombinant cells. In other cases, gas-liquid mass transfer and mixing are the major concerns.


Agitation is required to maintain suspensions of the cells. Agitated bioreactors are designed to maintain complete suspension (no cell mass at the bottom of the reactor) or a homogeneous suspension. These terms imply stable flocculations (aggregates) in suspension or homogeneous cell distribution throughout the suspension.

The mechanism of shear damage to the cells is not clear. Mycelial or protozoan cells exhibit shear rate–limited growth, and cell damage has been monitored by analyzing the concentration of low-molecular-weight nucleotides in the culture broth.

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