Control of Fermentation Conditions
T Keshavarz, University of Westminster, London, UK
Ó 2014 Elsevier Ltd. All rights reserved.
Introduction
The aim of an industrial fermentation process is to produce
the desired bioproduct as early as possible with the highest
possible rate and yield in a consistent manner, in the simplest
and cheapest possible way. In practice, compromises have to
be made to provide the optimal conditions for high
productivity.
The physiology of the microorganisms and the relevant
metabolic pathways must be well understood, and the nutrient
(and air in the case of aerobic cultures) requirements of the
microorganism must be satisfied. These needs often change
as the microbial biomass increases in concentration and
the environmental conditions (e.g., nutrient composition,
temperature, pH) are altered. For example, the need for carbon
and molecular O2 sources is different at different stages of
batch fermentation. Most industrial fermentation processes are
fed-batch processes, in which nutrients are added to the
fermenter, either intermittently or continuously in a variety
of ways. To ensure that the requirements of the culture are met
as the fermentation progresses, the environmental conditions,
including the concentration of nutrients, must be controlled.
Continuous manual control is not feasible in practice – it
would be expensive, impractical, and at best inefficient. To
maintain the optimal conditions for fermentation, there is
a need for robust automatic control.
Control Systems
Control systems for bioprocesses normally include the
following elements:
l Monitoring and measuring devices
l Controllers
l Operators
The bioprocess itself is considered to be a part of the control
system that often is called a ‘control loop’ (Figure 1).
An automatic control loop deals with the environmental
conditions and all other aspects of a culture external to the
microorganisms. Controlling the environment (i.e., the
fermentation conditions) elicits the best response from
a microorganism in terms of the desired products.
Set
point Error (ε)
Controller
– +
Measured variable
Figure 1 Conventional feedback control loop.
762 Encyclopedia of Food Microbiology, Volume 1
Measuring Equipment
The role of a sensor (measuring element) is to recognize
a process variable and in response to produce a signal, which is
sent to a controller. Examples of variables (properties) are
temperature, pH, and dissolved oxygen tension (DOT), and to
control as many fermentation variables as possible, a wide
range of sensors is needed. Some of the fermentation param-
eters that can be measured by sensors at present are as follows:
1. Physical: temperature; pressure; gas flow rate; liquid inlet
and outlet flow rates; culture level; culture volume; culture
weight; culture viscosity; color; agitation power; agitation
speed; foaming; gas hold-up.
2. Chemical: dissolved O2; dissolved CO2; redox potential;
general gas analysis; pH; nutrients; intermediates; products;
conductivity; ionic strength.
3. Biochemical: carbohydrates; total proteins; vitamins;
nucleic acids; Adenosine Triphosphate, Adenosine Diphos-
phate, and Adenosine Monophosphate; Nicotinamide
Adenine Dinucleotide/Nicotinamide Adenine Dinucleo-
tide; enzymes; amino acids; cell mass composition.
4. Biological: total cell count; viable cell count; biomass
concentration; morphology; cell size and age; doubling
time; contamination.
Some sensors (e.g., temperature and pH probes) have been
available for a long time, but there has been considerable
progress in the design and construction of novel sensors over
recent years.
Measuring and analytical equipment may be classified in
different ways. In relation to fermenters, they may be categorized
as ‘online,’ ‘at-line,’ or ‘offline.’ In relation to the characteristics
of the culture, they may be categorized in terms of their use
for physical, chemical, biochemical, or biological measure-
ments. Fast-response sensors are needed to facilitate the efficient
control of a bioprocess: The time taken to measure a variable
should be compatible with the time taken for it to change.
Physical fermentation variables, such as temperature,
foaming, and the flow rate of gases and media (in fed-batch
and continuous fermentations) are measured online (i.e., in
real time). Some chemical variables (e.g., pH and dissolved O2
and CO2) are also measured online. Online measurement is
not available for all variables (e.g., biomass composition and
Disturbances
Actuator Process Variables, e.g., temperature
(e.g., a pump) (fermentation)
Measuring device
(e.g., temperature probe)
http://dx.doi.org/10.1016/B978-0-12-384730-0.00108-7
 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions 763

some ingredients of the broth), but in some cases, analysis can Cross-flow Pump
be made at-line. In these cases, the property is measured using Pump filter unit
analytical equipment linked to the fermenter, without the need
for an operator to remove samples from the fermenter for later
offline analysis. Examples of techniques that can be used at-line
include the following: high-pressure liquid chromatography,
nuclear magnetic resonance, flow cytometry, fluorometry, and Analytical
Fermenter equipment
image analysis. At-line analysis, however, does not reflect real- (e.g., HPLC)
time events in the fermenter.
The offline measurement of fermentation parameters that
cannot be measured online or at-line is routine in laboratories.
A range of chemical and biochemical assays traditionally have
been employed.
Table 1 lists examples of online and at-line measurements
for monitoring fermentations, together with a brief description
of the related equipment. Steam-sterilizable sampling equip-
ment (autosamplers) is needed for the analysis of fermentation
culture broth and cell characteristics at-line. The major prob- Figure 2 Fermentation system involving at-line analysis. HPLC, high-
lems in designing efficient and reliable autosamplers have been pressure liquid chromatography.
the presence of gas bubbles and solid particles; the blockage of
filters (separating cells from the broth); and the clogging of the
connection lines between the fermenter and the sampler over
long periods. A good autosampler should be stable and durable Biomass Concentration
and should have a low dead volume to avoid losing large
volumes of culture through sampling. This is particularly Biomass is one of the most important fermentation variables
important if the total culture volume is small, the duration of that needs to be controlled. It is one of the indicators of the
fermentation is long, and frequent sampling is required. state of the culture; product yield on biomass contributes into
Figure 2 shows a fermentation system incorporating at-line the economic viability assessment of the process. Many
analysis. As the design of autosamplers has improved, it has attempts have been made to design equipment for the real-time
become possible to measure more fermentation culture measurement of biomass. Traditionally, biomass has been
parameters at-line. For example, it is now possible to obtain measured offline: usually, a culture sample is taken and either
automatic at-line assays of glucose, lactose, ammonia, urea, its turbidity (in the case of bacteria) or dry weight (in the case of
phosphate, sulfate, organic compounds, and penicillin. The use fungi) is measured. Offline data, however, cannot contribute
of nonsterilizable biosensors (see Biosensors section) at-line efficiently to fermentation control, and in recent years, in situ
yields additional information about fermentations. methods of biomass estimation have been introduced. These

Table 1 Examples of online and at-line measurements for monitoring fermentations

Online measurement At-line measurement

Fermentation property equipment equipment Brief description of measuring element

Temperature Thermistor – Exhibits a large change in resistance with a small change

pH
Pressure (head space)
Stirrer rotation speed (rpm)
Dissolved O2 tension
Gas-phase O2, CO2, and other
gases and volatiles
Ionic composition
Media and culture ingredients,
biomass, products
Substrates and products
in temperature; stable; cheap
pH probe – Steam-sterilizable combined reference electrode, made
of silver–silver chloride plus potassium chloride
Pressure gauge – For example, a Bourdon gauge
Tachometer – Uses electromagnetic induction, light sensing,
or magnetic force
O2 electrode – Steam-sterilizable polarographic electrode, with silver
anode and platinum or gold cathode; measures partial
pressure of O2
Process mass –
spectrometer
– Range of ion-specific Electrodes are not steam-sterilizable; response time varies
electrodes from 10 s to a few minutes; ions measured include
ammonium, calcium, potassium, magnesium,
phosphate (PO43
), sulfate ion (SO42
)
Optical-fiber sensor – NIR (near infrared) absorbance (460–1200 nm) utilized
for rapid analysis
– Biosensors Non-steam-sterilizable electrodes; enzymes or microbial
cells are immobilized on a membrane, and a change
in pH or Po2 is detected
764 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions
methods may be classified as optical, calorimetric, acoustic,
fluorimetric, or capacitance based.
The turbidity of a bacterial culture can be measured using
a steam-sterilizable flow cell linked to a computer. As cell
numbers and the turbidity increase, however, corrections must
be made to the readings. In addition, the wall of the flow cell
must be cleaned frequently to minimize adherent microbial
growth.
A method for noninvasive online monitoring of biomass
has been developed that utilizes an ancillary consisting of an
optical sensor attached to the exterior side of the vessel (over
the glass body or the glass view port). A monitor processes the
reflectance signals and a linear response to changes in biomass
is produced with good performance and a high degree of reli-
ability for bacterial and yeast cultures in fermenters up to 250 l.
An important feature of this system is that unlike other systems
in which the instrument and the culture are in direct contact
(e.g., the probe is immersed in the culture), there is no contact
between the probe and the culture and hence there is no culture
growth on the probe or the instrument (biofilm formation)
and there is no drift due to fouling. Furthermore, it is now
possible to detect much higher biomass concentrations,
a significant improvement to the earlier noninvasive devices in
which monitoring was over a short range due to the long
distance between the source and the detector. Like the previous
method, however, this approach cannot be adopted when
discrete small-size cells are not a feature of the cultures (e.g., in
the case of filamentous fungi).
The calorimetric method of biomass estimation measures
the heat produced by metabolically active cells, but it has not
been used widely. The acoustic method employs the relation-
ship between the resonant frequency of a liquid and its specific
gravity, but it can yield erroneous results due to the presence of
CO2 microbubbles – the amount of CO2 depends on not only
the concentration of the microbial cells but also their metabolic
activity. In addition, the presence of suspended solid particles
affects the results.
The fluorimetric method utilizes the excitation of NADH/
NADPH by ultraviolet light: A detector measures the fluores-
cence. The fluorescent-active ingredients of the medium and
the metabolic state of the cells, however, may interfere with the
results. The combined detection of infrared radiation and
culture fluorescence could provide a measurement of the total
and viable biomass concentration.
The concentration of cells can be measured online using
a laser flow cytometer (although these are expensive) or
a Coulter counter. Recently, a steam-sterilizable in situ probe for
the measurement of culture capacitance has been introduced.
Several reports suggest that the results are reliable when the
probe is used for bacterial or fungal cultures grown in defined
or complex media, with different modes of fermentation and at
different scales. These studies have shown a linear correlation
between offline biomass measurements and online capacitance
values.
Biosensors
The development of biosensors has enabled the provision
of more comprehensive data from fermentation cultures.
Biosensors use a biological sensing device, together with
a transducer, to produce an electrical signal from a biological
change. The operation of a biosensor is shown in Figure 3.
The use of enzymes in biosensors has enabled the selective
monitoring of fermentation cultures. One of the limitations of
biosensors is that they cannot be steam sterilized and lack
durability. Even if steam-sterilizable biosensors were devel-
oped, their repeated sterilization, for use in sequential
fermentations, would shorten their life. Other important
criteria in the design of biosensors are sensitivity, stability,
linearity, and reproducibility of response. Physical and chem-
ical interference from the culture broth can cause problems in
the performance of biosensors.
When it is not possible to use a biosensor in a fermenter for
online measurement, it may be used at-line. Some of the
biosensors used for the monitoring of fermentation variables
at-line are as follows:
1. Glucose: glucose oxidase immobilized on an oxygen elec-
trode in a mixture with bovine serum albumin and glutar-
aldehyde measures glucose concentration in the range 0.2–
2 mmol l
1.
2. Urea: includes a pH electrode and a urease immobilized
membrane; effective life span is around 20 days for detec-
tion of urea in the concentration range of about 17–
170 mmol l
1.
3. Alcohol: immobilized cell membrane of Gluconobacter oxy-
dans in calcium alginate containing pyrrolo-quinoline
quinone coated with a nitrocellulose layer; ethanol
concentrations of up to 20 mg l
1 can be detected.
4. Integrated multibiosensor: a variety is available, using
different enzyme-immobilized membranes – for example,
electrodes for the simultaneous measurement of glucose
and galactose, or of potassium, sodium, and calcium ions.
The research community has witnessed significant
improvement in the state of sensor technology with a variety of
areas of application. Of particular interest is the development
of noninvasive probes. In fermentation technology, these
probes provide real-time monitoring of a process without
interfering with the process itself.
Indirect Measurement
If the direct measurement of a fermentation variable is not
feasible, indirect methods may be possible. A remarkable
example is the use of process mass spectrometry for the analysis
of fermentation exhaust gases, volatile materials, and light
Reaction converted to electrical signal
Display
Biosensor tip
(containing biocatalyst)
Medium/culture ingredient
Figure 3 Simplified operation of a biosensor.
 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions
organic acids. The process mass spectrometer measures O2 and
CO2 online and is a sensitive method for the early detection of
contamination, because each culture has its own specific
respiration profile. The O2 uptake rate, CO2 evolution rate, and
respiratory quotient are important physiological parameters
that can be monitored by the process mass spectrometer. Using
this information, it is possible to estimate the volumetric O2
mass transfer coefficient (KLa), the biomass concentration, the
substrate utilization rate, and the specific growth rate. The
online data available through mass spectrometry, together with
that obtained through at-line liquid-phase analysis, facilitates
the use of sophisticated process controls. Mass spectrometry is
being advanced to directly analyze for a number of metabolites
providing real-time measurements of metabolic fluxes and
feedback controls.
Neural Networks
In spite of recent advances in the development of sensors
for the online measurement of process variables, many
fermentation parameters (e.g., metabolite concentrations)
cannot be monitored online. In cases in which some of these
variables may have significant roles in process optimization,
artificial neural networks can be powerful tools in process
control. Neural networks work on the principle of learning
from previous experiments. A neural network includes
nonlinear interconnected processing units. Three layers (input,
hidden, and output) with different connecting weights
(strength) are linked, and the strengths can be adjusted to fit
a particular case and produce the desired output. This process
of adjustment is called ‘training’ of the network. In fermenta-
tion processes, online, at-line, and offline measurements of
environmental and state variables (e.g., temperature, pH, DOT,
concentration of components of the medium) can be used as
input values for a neural network. The output parameters of the
fermentation process (e.g., concentrations of biomass and of
measurable metabolites) can be used to train the network. The
aim is to minimize the difference between the desired output
and the predicted output.
Control Systems
Feedback Control
In a simple control loop with feedback control, the controller
receives a signal from the measuring element, compares it with
a set point (desired value), and then responds with a control
action, calculated according to an internal algorithm. The
controller may be pneumatic, electronic, or computerized
(digital). The use of computers with advanced programs has
introduced the possibility of the efficient control of fermenta-
tion by mimicking proportional, integral, and derivative (PID)
control (see Table 2 Controllers and their charecteristics
section) and by the simultaneous handling of several control
loops. The controller should be robust, should produce fast
and reliable responses, and should match the requirements of
the fermentation system. A conventional feedback control
system is shown in Figure 1.
765
In general, four types of controller can be identified, based
on the control action: on–off or two-position, proportional,
integral, and derivative. A fifth type combines PID control
actions in a single system (Table 2). The on–off controller is the
simplest type, the most complex being the PID controller. The
more complex controllers offer potential for improved control
of fermentation, but care must be taken – a poorly tuned PID
controller can cause fermentation failure.
More complex control systems than feedback systems
include cascade control, feed-forward control, and adaptive
control (see the sections Cascade Control, Feed-Forward
Control, and Adaptive Control).
Cascade Control
When two processes to be controlled are closely linked, it is
conventional to apply feedback control to each. It is possible to
cascade the control loops, as shown in Figure 4. This usually is
done when a fast process, which is subject to disturbances, is
linked to a slower process. An example is the control of the
culture temperature in a jacketed fermenter together with the
control of the water temperature in the fermenter jacket.
Table 2 Controllers and their characteristics
Controller Characteristics
On–off Used with on–off actuators (e.g., a valve or a pump)
There is a delay in response
There is oscillation around the set point
Not suitable for processes with large, abrupt changes
Proportional The controller output is proportional to the error
(the difference between the desired value and
the measured value)
The oscillation dampens quickly
A new equilibrium is created, which is different from
the original one (the difference is called the offset)
The controller may be set at high or low sensitivity
(low or high proportional band)
At high sensitivity, there is high oscillation (similar
to the on–off controller) and small offset
At low sensitivity, the oscillation is reduced but there
is higher offset
Integral The controller output is an integral of the error
Early response is slow
The deviation from the set point is high
The system settles down with no offset
Derivative The controller output is the derivative of the error
Provides the ability to control the extent and rate
of the oscillations of a controlled system
If there is no change in the error, then there will be
no control action
There is a fast damping action against the error
PID Combination of proportional, integral, and derivative
actions
The control action is proportional and is the
derivative of the error
The relative weightings can be adjusted to the
requirements of the process
There is no offset
Care should be taken in tuning of the controller,
otherwise unwanted fluctuations will adversely
affect the process
766 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions

Controller Controller Process Process

2 1 1 2
– + – +

Figure 4 Cascade control loop for the control of the temperature of the water in a fermenter jacket (process 1) and that of the culture in the fermenter
(process 2).

Feed-Forward Control 2. Direct digital control: control of fermentation parameters

(acting as a conventional controller).
If the control element (the actuator) is slow, but the distur-
3. Digital set-point control: computer acts a data logging
bances are large and change rapidly, then the disturbances
system, and also changes the set points when necessary.
should be compensated using feed-forward control. The degree
4. Complex: online data handling and analysis; provision of
of compensation must be calculated or estimated, and
at-line and offline data for comprehensive data accumula-
synchronized with the disturbance.
tion and documentation; calculations for more complex
control algorithms.
Adaptive Control 5. Advanced: use of online measuring equipment only,
together with mathematical models and trained neural
Fermentation is a nonlinear process, which varies with time.
network systems for process optimization.
An efficient controller for such a process should adapt to
the changing process characteristics. When the differences
The simplest type of use of computers in fermentation
between the outcomes of conventional control and the
control is in operating valves, pumps, and so on. Batching of
desired outcomes are significant, an adaptive control system
the medium and the time-dependent addition or removal of
might be beneficial. In such a system, the controller learns
nutrients to or from the culture (in fed-batch or continuous
about the process as it controls the process. Adaptive control
cultures) fall into this category.
is particularly useful for batch fermentations, although its
More complex control involves the use of feedback algo-
successful application to fed-batch fermentations has been
rithms, for the simultaneous control of fermentation variables,
reported. Reliable dynamic process models are needed in
such as temperature and pH. In such control, which often is
advanced applications in which computers control the
called ‘direct digital control,’ a computer replaces the conven-
process. Self-tuning adaptive control is used in some large-
tional analog controller, and sensors are linked to the computer
scale biotechnological applications, such as ethanol produc-
through an interface, which converts the continuous analog
tion. ‘Soft sensors’ based on artificial neural network have
signal from the sensors to a digital signal appropriate for the
proved suitable in the detection of time-varying nonlinear
computer. The interface is usually in the form of an analog-to-
systems.
digital converter. There is a trend toward the provision of
measuring equipment that emits a digital signal: A binary-
Computer Control coded digital signal from a sensor can be used as an input for
the computer. The computer compares the digital signal with
The falling cost of computers has facilitated their use in small-
the set point and generates a digital output signal, which is
and large-scale fermentations. Computers can be linked to
translated into an analog signal to an actuator.
measuring equipment to enhance data acquisition, data anal-
Computers provide fermentation process control with
ysis, and fermentation control and optimization. Computers
a high degree of flexibility and precision. If a computer is used
may also be used to model fermentation processes, as a basis
as the sole controller, however, minor failure may cause serious
for improving process control.
problems, and so appropriate backup is necessary. This diffi-
Data acquisition systems include both hardware and soft-
culty can be avoided by using computers in conjunction with
ware. Online and at-line process data (from the measuring
conventional electrical controllers, the latter providing
equipment), as well as offline data, can be stored in the system
conventional control, while the computer plays a ‘supervisory’
for analysis.
role. The computer logs and stores data from the measuring
The data from various items of measuring equipment can be
equipment and changes the set points when necessary. This
compared, combined, and analyzed using mathematical
type of system usually is called ‘digital set-point control’ or
programs. The indirect measurement of fermentation variables
‘supervisory set-point control.’
is also possible and provides valuable information about the
The use of computers in fermentation control has expanded
growth of a culture.
significantly as they have become increasingly cheap and
Depending on the software, different types of control may
powerful. Advanced control strategies, relying on sophisticated
be applied to a fermentation process. These types may be
programs, can now be applied. The availability of more online
categorized as follows:
and at-line measured data, together with the use of neural
1. Simple: control of valves and pumps, feeding of medium, networks, facilitate improved control and hence optimized
removal of culture, based on a preset time. production (Figure 5).
 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions
Process
mass Air outlet
spectrometer filter
Autosampler
At-line sampling
and measurement pH
sensor
Analytical
equipment
Fermenter
Figure 5 Computer control of fermentation. A/D, analog-to-digital; D/A, digital-to-analog.
Solid-State Fermentations
The control of fermentation is not always easy, one of the
main reasons being that the accurate online measurement of
environmental and state variables is not always possible.
A range of online and at-line measuring equipment is
available for submerged fermentations, but the parameters
associated with solid-state fermentations are less easily
measured. A major problem arises because cell biomass is
grown on a solid medium and remains attached to it. In
addition, until recently the design of bioreactors for solid-
state fermentations tended to be basic. New designs aim to
achieve good mixing and heat transfer and improved
monitoring and control.
Two of the variables that must be controlled are heat
generation and moisture, and online sensors are available
for these parameters. The aeration of a moist solid medium
in an aerobic solid-state fermentation is another important
factor influencing productivity and can be controlled: The
online measurement and monitoring of O2 and CO2 in the
exhaust gases is possible when a process mass spectrometer
is employed and infrared CO2 analyzers and paramagnetic
O2 analyzers carry out delayed monitoring of these gases.
The indirect estimation of biomass and specific growth rate
has become possible through the measurement of the rates
of O2 uptake and CO2 evolution. The monitoring and
control of the pH of solid-state fermentations, however, is
not easy.
Submerged Fermentations
Most industrial fermentations are aerobic. In an aerobic batch
culture, as the cells grow, the overall culture requirement for
O2 increases. Although some variables (e.g., temperature)
are best maintained at a constant value throughout a batch
767
Computer output signal to
actuators, based on signals
from the mass spectrometer
and at-line measuring
equipment
A/D
converter Computer
Interface
Computer
dedicated
display
to the
output
fermenter
D/A
converter
Pump Acid / alkali
nutrients
reservoir
fermentation, other variables, including O2 concentration,
must be controlled at a changing level, if optimal productivity
is desired. In this particular case, the automatic control of the
speed of the stirrer can maintain the %DOT above a desired
value. In some batch fermentations, such as those for the
production of secondary metabolites, a fast initial growth
rate, for biomass production, and slower growth subse-
quently, are needed to optimize the process in terms of
productivity. The environmental variables, as well as the state
variables, can be controlled using online measuring equip-
ment linked to a computer, thus achieving optimized batch
fermentation.
In fed-batch fermentations, extended and improved
productivity can be achieved by the continuous or intermit-
tent addition to the culture of one or more of the ingredients
of the medium, particularly if knowledge-based strategies for
feeding the culture are adopted. Computer control, using
appropriate algorithms, is necessary for the implementation
of an accurate and efficient feeding strategy. For the more
complex fed-batch fermentations, such as ‘feed and bleed’
systems, and for continuous culture, computers can provide
accurate control of the inlet and outlet flows. Time-based
changes to a fermentation, such as the addition of certain
ingredients at particular times and the routine sampling of
the culture for at-line analysis, are made possible by
computerization.
Although continuous real-time monitoring and automatic
control of %DOT, pH, and temperature of the cultures is
a routine matter in fermenter vessels, online monitoring of pH
and %DOT in shaken flasks was not achieved until recently.
Lack of such online facility for culturing in these vessels was
a significant drawback as a majority of research in microbiology
and biotechnology (e.g., particularly for culture optimization)
is carried out using shaken flasks due to their simplicity, ease
of handling, and the possibility of several simultaneous
repeats, increasing the reliability of experiments. Noninvasive
768 FERMENTATION (INDUSTRIAL) j Control of Fermentation Conditions
integrated dual optical chemical sensors provide simultaneous
measurement of %DOT and pH. The detection by the oxygen
sensor is based on selective sensor luminescence. In the case of
pH sensor, the luminescence is recorded through a dual-signal
process using an added sensor (integrated reference sensor).
Additionally, the partial pressure of CO2 in the culture can
also be monitored continuously by opticochemical noninva-
sive CO2 sensors. The system includes a fiber optic CO2
transmitter, which is used with CO2 sensors.
In recent years, great emphasis has been put on miniaturi-
zation of bioprocesses to improve the efficiency of bioproduct
discovery and productivity through high-throughput screening
and high-throughput process development. Bioreactors of
milliliter/microliter scale have been developed with challenges
in design, reliable running, monitoring, and control. Advances
in the design and construction of noninvasive probes have
notable contribution in the future of these bioreactor systems.
Future Perspectives
Over the past 40 years, significant progress has been made in
different areas of biotechnology; these include discoveries at
cellular level, such as omics (e.g., genomics, transcriptomics,
proteomics, secretomics), systems biology, systems chemistry,
and cell communication, as well as advances at the process
level, such as fermenter design, downstream equipment design,
and the development of noninvasive monitoring systems for
advanced process control. Efforts have been made to imple-
ment integration of (1) metabolic engineering strategies into
the fermentation and recovery processes, and (2) integration of
processes in which upstream and downstream processing is
incorporated into one unit with improved economic and
positive environmental impact. Advances in sensor design and
process control have played a substantial role in the evolution
of bioprocessing. The move toward total engineering of a bio-
logical entity through the use of synthetic biology is allowing
for the design of metabolic pathways (and consequently the
production of specific fermentation products) from first
principles.
See also: Fermentation (Industrial): Basic Considerations;
Fermentation (Industrial): Media for Industrial Fermentations;
Fermentation (Industrial): Recovery of Metabolites.
Further Reading
Atkinson, B., Mavituna, F., 1991. Biochemical Engineering and Biotechnology Hand-
book. Macmillan, New York.
Austin, G.D., Watson, R.W.J., D’Amore, T., 1994. Studies of on-line viable yeast
biomass with a capacitance biomass monitor. Biotechnology and Bioengineering
43, 337–341.
Bucke, C., Chaplin, M.F., 1990. Enzyme Technology. Cambridge University Press,
Cambridge.
Cass, A.E.G. (Ed.), 1990. Biosensors: A Practical Approach. Oxford University Press,
Oxford.
Doran, P.M., 1995. Bioprocess Engineering Principles. Academic Press, London.
Fehrenbach, R., Comberbach, M., Petre, J.O., 1992. On-line biomass monitoring by
capacitance measurement. Journal of Biotechnology 23, 303–344.
Fish, N.M., Fox, R.I., Thornhill, N.F. (Eds.), 1989. Computer Applications in Fermen-
tation Technology: Modelling and Control of Biotechnological Processes. Elsevier
Applied Science, London.
Karube, I., Yokoyama, K., 1991. Biosensors. In: Cheremisinoff, P.N., Ferrante, L.M.
(Eds.), Biotechnology Current Progress. Technomic Publishing, Lancaster, p. 1.
Leigh, J.R., 1983. Essentials of Nonlinear Control Theory. Peter Peregrinus, London.
Leigh, J.R. (Ed.), 1987. Modelling and Control of Fermentation Processes. Peter
Peregrinus, London.
Leigh, J.R., 1987. Applied Control Theory. Peter Peregrinus, London.
Lonsane, B.K., Ghildyal, N.P., Budiatman, S., Ramakrishna, S.V., 1985. Engineering
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