Fed Batch Fermentation

Fed-batch fermentation types are classified in Table 2. This fermentation method is aimed at efficiently carrying out fermentation and is characterized by a low concentration of components in the initial medium to minimize metabolic regulation. At the time of inoculation the medium promotes initial growth of microbes; subsequent supplies of more raw materials drive the desirable increase in metabolite biosynthesis. Feeding is effected either intermittently or continuously. Industrial fermentation of most amino acids is accomplished with this method. Fed-batch fermentation requires feeding equipment in addition to the equipment required for batch fermentation and therefore leads to higher fixed costs (Fig. 1). However, the process can provide improved productivity as a whole because of the enhanced yield and reduced fermentation time. Actual product cost depends on the cost of the carbon source or specific precursors that are used for feeding. The nitrogen source is supplied generally through pH control with ammonia. This process is of particular importance in industrial operations where the reaction of the microbial catalyst does not last long; hence, continuous fermentation cannot be practiced, unlike in the case of L-glutamic acid fermentation from cane molasses using penicillin, described next.

Table 2. Classification of Fed-Batch Microbial Reaction Processes

Case 1 (nonfeedback regulation)

Constant feeding-rate method Exponential feeding method Optimized feeding method Others (intermittent feeding, etc.)

Case 2 (feedback regulation)

Indirect control Direct control Constant control Program control Others

Fed Batch Fermentation Penicillin

Figure 1. Typical system for fed-batch fermentation. AF, air filter; DF, defoamer; PC, penicillin; FIC, flow indication control; PHIC, pH indication control; TIC, temperature indication control; PIS, pressure indication sum; PIA, pressure indication alarm; HIC, highest indication control; FRCS, flow record control sum.

Figure 1. Typical system for fed-batch fermentation. AF, air filter; DF, defoamer; PC, penicillin; FIC, flow indication control; PHIC, pH indication control; TIC, temperature indication control; PIS, pressure indication sum; PIA, pressure indication alarm; HIC, highest indication control; FRCS, flow record control sum.

Continuous Fermentation

In continuous fermentation, a complete medium is fed to a fermenter after an appropriate period of batch fermentation, and the same quantity of broth is continuously taken from the fermenter to maintain the fermentation broth at a fixed volume. This may be performed either by the chemostat method using a substrate or limiting substance, or by the turbidostat method in which the cell level is adjusted to maintain constant cell mass. Because the continuous fermentation process allows improvement of productivity compared with the ordinary fermenter, the initial investment in equipment is small relative to the production volume, and operation cost is low. However, one drawback is that it is not suitable for small-scale production, and the challenges of sterile operation and equipment maintenance are more necessary than they are for batch and fed-batch fermentation.

This process shifts from batch fermentation to continuous fermentation when productivity per unit time in the former is relatively high. There are many reports analyzing the steady-state condition in continuous fermentation. Most of them relate to cell culture, but a few reports are available specifically on amino acid fermentation (5). One of the reasons may be that studies on amino acid fermentation have been mainly directed to the influence of metabolic regulation, as in the case of the penicillin addition method in glutamic acid fermentation, or because some amino acid processes have a distinct growth phase and production phase, and continuous culture cannot be used. Many of the microbial strains used in amino acid fermentation are released from metabolic regulation to a remarkable extent. This makes it easier to analyze continuous processes and thereby optimize them. It is necessary to study optimum conditions for each process and to optimize their industrial application.

Unlike processes of chemical synthesis, continuous fermentation processes have their own restrictions and duration. This is because microbes undergo spontaneous mutation within the system, and an increase in the fraction of microbes with decreased productivity may lead to rapid reduction in productivity (Fig. 2). Hence, it is necessary to breed a strain with high genetic stability.

Enzymatic Method

Of the amino acid production processes using direct enzymatic biotransformation, those for L-alanine (6), L-aspartic acid (7), L-lysine (8), and L-tryptophan (9,10) have been the most extensively studied, and some of the results have led to standard industrial processes. Although the enzymatic production process of L-lysine from DL-aminocaprolactam did not result in practical application, this technology is interesting because of its use of petrochemical products for fermentation raw materials. The outline of the process is shown in Figure 3.

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