Fed-Batch Cultivation - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 663

while at low concentrations of malt, the yeast growth was limited. The sudden change in the
production of ethanol is due to the overflow metabolism of the cells and also known as Crab-
tree effect in Chapters 10 and 12. The problem was then solved by a controlled feeding
regime, so that yeast growth remained high but under substrate-limited conditions.
The fedbatch concept was then extended to the production of other products, such as some
enzymes, antibiotics, growth hormones, microbial cells, vitamins, polyhydroxyalkanoate,
amino acids, and other organic acids. Basically, cells are grown under a batch regime for
some time (seed culture preparation), usually until close to the end of the exponential growth
phase. At this point, the reactor is fed with a solution of substrates, without the removal of
culture fluid. This feed is balanced to keep the growth of the microorganisms at a desired
specific growth rate, while reduces simultaneously the production of undesired by-products
(especially that can be growth or product production inhibitory and make the system less
effective). These by-products may also affect the culture environment in such a way that
might lead to early cell death even though sufficient nutrients are available or are still being
provided. A fed-batch is useful in achieving high concentration of products as a result of high
concentration of cells for a relative large span of time. Two cases can be considered: the
production of a growth-associated product and the production of a non-growth-associated
product. In the first case, it is desirable to extend the growth phase as much as possible, mini-
mizing the changes in the fermentor as far as specific growth rate, production of the product
of interest and avoiding the production of by-products.
For non-growth-associated products, the fed-batch would be having two phases: a growth
phase in which the cells are grown to the required concentration and then a production phase
in which a carbon source and other requirements for production are fed to the fermentor. This
case is also of particular interest for recombinant inducible systems: the cells are grown to
high concentrations and then induced to express the recombinant product.
Also, considering that plasmid stability (Chapter 15) is very often guaranteedby the presence
of anantibioticmarker gene and that the lifetime of this antibiotic in a fermentor canbe limited, it
might be of interest to use the fed-batch concept to feed this same antibiotic continuously so that
the presence of the plasmid in the cells is more of a reliable fact. Fed-batch fermentations can be
the best option for some systems in which the nutrients or any other substrates are only spar-
ingly soluble or are too toxic to add the whole requirement for a batch process at the start.
Finally, in fermentations such as mycelial culture, the increase of viscosity with time can be
compensated by the addition of relatively small quantity of water during the fermentation
time, although the efficacy of this protocol is controversial among researchers. Many factors
are involved in the regulation of a fed-batch reactor. As an example, however, the feed rate
can be varied to control the concentrations of nutrients in the bioreactor.
Fig. 13.1 shows a schematic of fed-batch reactor operation. Fed-batch reactor operation is also
commonly seen when a continuous reactor is being charged (i.e. start-up of chemostat). To
ensure that a favorable steady state is achieved, a well mixed continuous flow reactor
(commonly known as CSTR for chemical transformations and chemostat for biotransforma-
tions)must be run in a semi-batchmode until the desired reaction conditions are reached inside
the reactor before the full continuous operation is implemented. This is a control strategy for
CSTR operation. In other cases, fed-batch operation is an alternative to continuous operations.
This can occur in bioprocess industry where batch operations are common. Batch growth is an
uncontrolled growth. To implement control on cell growth, fed-batch becomes a viable option.