Fed-Batch Cultivation - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 686

Hepatitis B surface antigen (HbsAg) used as a vaccine against type B hepatitis has been
purified from human plasma and expressed in recombinant yeast, being now produced
commercially. Again, the production of the recombinant protein is achieved using fed-batch
culture techniques very similar to that developed for S. cerevisiae . A cyclic method is used due
to reports of superior productivity.
Penicillin production is an example for the use of fed-batch in the production of
a secondary metabolite. The fermentation is divided in two phases: the rapid-growth phase
during which the culture grows at the maximum specific growth rate and the slow-growth
phase in which penicillin is produced. During the rapid-growth phase, an excess of glucose
causes an accumulation of acid and a biomass oxygen demand greater than the aeration
capacity of the fermentor, whereas glucose starvation may result in the organic nitrogen in
the medium being used as a carbon source, resulting in a high pH and inadequate biomass
formation. During the production phase, the feed rates utilized should limit the growth rate
and oxygen consumption such that a high rate of penicillin synthesis is achieved and suffi-
cient dissolved oxygen is available in the medium.
Some other examples are the production of thiostrepton from Streptomyces laurentii and the
production of cellulase by Trichoderma reesei . The production of thiostrepton uses pH
feedback control and the production of cellulase utilizes carbon dioxide production as
a control factor.
13.7. PARAMETERS TO BE CONTROLLED OR MONITORED DURING
FED-BATCH OPERATIONS
The ultimate aim of a fed-batch fermentation is to maximize the growth rate, the flow
through the central carbon metabolism, or to reduce the overflow of carbon source to meta-
bolic by-products. Fed-batch reactor can be controlled by a simple one-step method in which
only one of the parameters is used or it can be by a dual-level control in which two param-
eters are used. For example, some processes require the control of different parameters at
different stages of the fermentation. High-density bacterial fermentation, the production of
baker's yeast and penicillin, is such an example. In these cases, two phases can be distin-
guished: 1) a phase in which the substrate needs to be controlled so as to avoid by-products
formation and 2) a second stage in which, due to the high cell density, oxygen transfer is
limiting and so, dissolved oxygen (DO) is the one to be controlled above a critical value,
under which the cellular metabolism changes. The constraints switch from specific growth
rate to DO content after some critical period of time in the fermentation process. The choice
of each parameter is system dependent and the decision should be based on convenience and
experimental data.
13.7.1. Calorimetry
Calorimetry is an excellent tool for monitoring and controlling microbial fermentations. Its
main advantage is the generality of this parameter, since microbial growth is always accom-
panied by heat production, and the measurements are performed continuously online