Bioreactor Design and Operation - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 919

is no “back-mixing” of the reactant streamwith product stream. Reactants are loaded initially
and the products are unloaded at the end of the reaction. A batch reactor is characterized by
no input into or output from the reactor during the course of the reaction, eliminating the
potential of external contamination. The substrate concentration remains highest inside the
reactor, while the product concentration remains the lowest possible in the reactor. The reactor
operation is terminated when reaction is completed as desired. A CSTR is characterized by
a steady feed of substrate(s) into and effluent out of the reactor. The substrate concentration
can be controlled to a given value and is the lowest in the reactor. The product concentration
in the reactor is the highest. The reactor operation is not to be terminated frequently (by
design). A fed-batch reactor is a mode between batch and CSTR operation. It can be designed
to capture the qualities of a CSTR operation (and more), while maintaining the flexibility of
a batch reactor operation.
The primary form of continuous culture is a steady-state CSTR or chemostat. A chemostat
ensures a time-invariant chemical environment for the cell cultivation. The net-specific
growth rate is equal to the dilution rate, which is determined by the flow rate to the chemo-
stat. Thus, the growth rate can be manipulated by the investigator. This is a typical method of
controlling the cell growth (and/or production formation rate). A constant dilution rate gives
rise to a constant specific growth rate, which is equivalent to a fixed exponential growth rate.
Another benefit is the control of substrate concentration in the reactor at a given value, which
can promote a desired product formation. A cytostat (or turbidostat) adjusts flow rate to main-
tain a constant cell density (via turbidity). Cell density control via adjusting flow rate is not
effective except at high flow rates. A turbidostat operates well at high flow rates (near the
washout point) and is useful in selecting cellular subpopulations that have adapted to
a particular stress.
Continuous culturing is more productive than batch culturing. The productivity of che-
mostat increases with increasing dilution rate to a maximum before sharply decreases
near the washout limit. There is a maximum cell biomass concentration near the washout
limit.
The growth and/or product formation patterns can be different between batch and contin-
uous cultivations. In a batch system, lag phase is commonly observed which is absent in
a continuous system. On the other hand, Crabtree effect can be observed with changing
flow rates in a continuous system, which is absent in a batch cultivation curve since the
change occurs when the substrate is nearly completely consumed.
Bioreactors using suspended cells can be operated in many modes intermediate between
a batch reactor and a single-stage chemostat. Although a chemostat has potential produc-
tivity advantages for primary products, considerations of genetic instability, process flexi-
bility, low quantities of product demand, and process reliability (such as biocontamination
and biostability) have greatly limited the use of chemostat units. The use of cell recycle
with a CSTR increases volumetric productivity and has found use in large-volume, consistent
production demand and low-product value processes (e.g. waste treatment and fuel-grade
ethanol production).
Multistage continuous systems improve the potential usefulness of continuous
processes for the production of secondary metabolites and for the use of genetically
unstable cells. The perfusion system is another option that is particularly attractive
for animal cells.