Bioreactions

John A. Williams, PhD, P.E.

EPS: Environmental &
Production Solutions, LLC A handful of basic bioreactor
designs is used to produce a

T raditionally, microbiologists have played the

dominant role in bioreaction development,
with assistance from those in multiple disci-
plines, including biochemists, geneticists
and chemical engineers. And while the fermentation
process the precursor to modern bioreactions has
been used since prehistoric days, the major advance-
wide range of products, from
antibiotics to foods to fuels.
Heres how to pick the best
options for your application.
ments of the last half century have had as much to do cal reactors to bear on the issues and opportunities
with technology as with biology. It is our objective to available in bioreactor engineering.
illustrate the relevance of established chemical engi-
neering practices and processes as they apply to todays The distant and recent past
bioreaction engineering, as chemical engineers make Long before anyone understood the concept of
further inroads into a field once thought to be the sole bioreaction, humans were taking advantage of its re-
domain of biology-based scientists. sults. Bread, cheese, wine and beer were all made pos-
This article will discuss the key engineering issues sible through what was traditionally known as fermen-
in bioreactor design and operation, focusing on the tation a little-understood process, successful more
similarities between traditional chemical reactor engi- by chance than design. It was, in fact, the failure and
neering and bioreaction engineering. Our objective is frustration of French vintners who found they were too
not to trivialize the field of biological-based processes; often producing vinegar not wine, that led the famous
it is simply to demonstrate that strong parallels exist French chemist and microbiologist Louis Pasteur to
between the two fields. In fact, we will also discuss the study the fermentation process at their request.
key differences that must be taken into consideration What Pasteur discovered was that fermentation oc-
for successful bioreactions. In so doing, we will pro- curred as a result of the biological activity of a micro-
vide chemical engineers with increased confidence in scopic plant called yeast. When unwanted microbes in-
applying their knowledge and experience with chemi- filtrated the wine and fedon the alcohol produced by

34 www.cepmagazine.org March 2002 CEP

the yeast, the microbes left behind distasteful
and harmful wastes, which ruined the wines
flavor. Pasteurs work laid the foundation for
bioreactors as we know them today, because
once the process was identified and understood,
it could be controlled. And it is the control of
the process that concerns chemical engineers
first and foremost. The scope of bioengineering
has grown from simple wine-bottle microbiolo-
gy to the industrialization of not only beer,
wine, cheese and milk production, but also the
production of biotechnologys newer products
antibiotics, enzymes, steroidal hormones, vi-
tamins, sugars and organic acids.

Bioreactors vs. chemical reactors

By definition, a bioreactor is a system in
which a biological conversion is effected. Al-
though this definition can apply to any conver-
sion involving enzymes, microorganisms, and
animal or plant cells, for the purposes of this ar-
ticle, we will limit the definition. The bioreac-
tors referred to here include only mechanical
vessels in which (a) organisms are cultivated in
a controlled manner and/or (b) materials are
converted or transformed via specific reactions.
Quite similar to conventional chemical reactors,
bioreactors differ in that they are specifically de-
signed to influence metabolic pathways. Tradi-
tional chemical reactor models and designs that
may be used for bioreaction as well include:
continuous stirred-tank reactors, continuous
flow stirred-tank reactors, and plug-flow reac-
tors, singularly or in series; ebullized-bed (i.e., bubbling and Figure 1. Installation of a batch, 765-bbl beer fermenter made of stainless
boiling) reactors; and fluidized-bed reactors. The term steel. (Courtesy of Paul Mueller Co.)
bioreactor is often used synonymously with fermenter;
however, in the strictest definition, a fermenter is a system bioreaction medium, are shear-sensitive to varying degrees.
that provides an anaerobic process for producing alcohol A number of bacteria, yeast and fungi cultures that can be
from sugar. relatively tolerant of high-shear environments exhibit a ro-
Bioreactors differ from conventional chemical reactors bustness in high-energy mixing vessels. Animal, fish, insect
in that they support and control biological entities. As such, and plant cells are delicate and usually require low-shear
bioreactor systems must be designed to provide a higher de- environments for viability. The viscosities of bioreaction
gree of control over process upsets and contaminations, masses may change during growth and production phases,
since the organisms are more sensitive and less stable than and, often, the medium becomes non-Newtonian as a cycle
chemicals. Biological organisms, by their nature, will mu- progressed. Mixing within the bioreactor is integral to effi-
tate, which may alter the biochemistry of the bioreaction or cient heat and mass transfer during the production phases,
the physical properties of the organism. Analogous to het- which places additional constraints on the suitable agitation
erogeneous catalysis, deactivation or mortality occur and mechanism and rheology of the bioreaction medium.
promoters or coenzymes influence the kinetics of the biore- Other key differences between chemical reactors and
action. Although the majority of fundamental bioreactor en- bioreactors are selectivity and rate. In bioreactors, higher
gineering and design issues are similar, maintaining the de- selectivity that is, the measure of the systems capability
sired biological activity and eliminating or minimizing un- for producing the preferred product (over other outcomes)
desired activities often presents a greater challenge than tra- is of primary importance. In fact, selectivity is especial-
ditional chemical reactors typically require. ly important in the production of relatively complex
Organisms, influenced by their morphology and the molecules such as antibiotics, steroids, vitamins, proteins

CEP March 2002 www.cepmagazine.org 35

Bioreactions

and certain sugars and organic acids. Frequently, the activi- Key issues in bioreactor design and operation
ty and desired selectivity occur in a substantially smaller The goal of an effective bioreactor is to control, contain
range of conditions than are present in conventional chemi- and positively influence the biological reaction. To accom-
cal reactors. Further, deactivation of the biomass often plish this, the chemical engineer must take into considera-
poses more severe consequences than a chemical upset. tion two areas. One is the suitable reactor parameters for
Rate is of secondary importance. For many biological sys- the desired biological, chemical and physical (macrokinet-
tems, an incubation period is needed to prepare a culture used ic) system. The macrokinetic system includes microbial
to inoculate the bioreactor with the producing microbes or growth and metabolite production. Microbes can include
their precursors. Although a bioreaction can be brief, in sys- bacteria, yeast, fungi, and animal, plant, fish and insect
tems where organism or biomass growth is necessary, the cells, as well as other biological materials.
bioreaction can take 1020 d for completion of the batch. Fur- The other area of major importance in bioreactor design
ther, the bioreactor should not be regarded as an isolated unit, involves the bioreaction parameters, including:
but as part of an integrated unit operation with both upstream controlled temperature
(preparation) and downstream (recovery) unit operations. optimum pH
sufficient substrate (usually a carbon source), such as
Products of bioreactions sugars, proteins and fats
Bioreaction products are formed by three basic processes: water availability
1. Processes in which the product is produced by the salts for nutrition
cells is either extracellular, e.g., alcohols or critic acid, or vitamins
intracellular, e.g., a metabolite or enzyme. Production of oxygen (for aerobic processes)
cellular products is divided into two types, based on when gas evolution and
they are produced within a biological cycle. Primary product and byproduct removal.
metabolites are produced during growth and are essential In addition to controlling these, the bioreactor must be
for continuing growth. Secondary metabolites are produced designed to both promote formation of the optimal morphol-
after growth has ceased. Primary metabolites include amino ogy of the organism and to eliminate or reduce contamina-
acids, nucleotides, nucleic acids, proteins, lipids and carbo- tion by unwanted organisms or mutation of the organism.
hydrates. Examples of primary products for industrial use This article will provide a description and overview of a
include ethanol, citric acid, acetone, butanol, lysine, variety of bioreaction systems, including both bioreactors
polysaccharides and vitamins. that are production-oriented and those used for environmen-
Secondary cellular products are formed from the inter- tal control. We will discuss the advantages and disadvan-
mediates and products of primary metabolism, and tend to tages of the various systems, with a brief mention of the
be specific to a species or group of organisms. Not all mi- typical applications for each. It is also worth noting here
croorganisms produce secondary metabolites, but they are that there is a wide variety of bioreaction systems, and any
widespread among the filamentous fungi and plants. Many attempt to categorize them by their various attributes will
secondary products have toxic or antibiotic properties and naturally result in some overlap of system characteristics.
are, as such, the basis of much of the antibiotic industry. We will not include all the various subtopics that may be
Production of enzymes via bioreactions has displaced inef- relevant, since the study of bioreactions is so expansive that
ficient extraction techniques with mutation and genetic ma- it would be impossible to include subtopics here in any de-
nipulation. Industrial enzymes find their home in baking, tail. Those subtopics not covered include: microbiology,
brewing, grain processing, dairy making, and in the pro- sterilization, rheology, mixing, agitator design, fluidization,
duction of detergents, juices, wines and other products. heat transfer, mass transfer, surface phenomena and trans-
2. Processes that produce a cell mass. Bakers yeast, used port enhancements, kinetics, hydrodynamics, scaleup, mod-
in the baking industry, is an example of a produced cell eling, instrumentation and process control. For the most
mass. Others include single-cell proteins for food sources. part, an abundance of literature exists on these conventional
3. Processes that modify a compound that is added to chemical processes, and the treatment is frequently directly
the fermentation process are referred to as biotransforma- applicable to bioreactors with only slight modifications to
tions. Biotransformations occur using the inherent enzy- accommodate for the living organisms involved in the pro-
matic capability of most cells. Cells of all types can be em- cess. For more in-depth reading on these topics, see the sec-
ployed to biocatalyze a transformation of certain com- tion on Further Reading at the end of this article.
pounds via dehydration, oxidation, hydroxylation, amina-
tion or isomerization. Enzymatic conversions frequently Bioreaction/fermentation technologies
exhibit lower activation energies and higher selectivity than Now we will discuss the engineering aspects and applica-
their chemical counterparts. Steroids, antibiotics and tions for a variety of bioreaction/fermentation technologies,
prostaglandins can all be produced via biotransformations. including the challenges of each and the advantages and dis-
advantages of the respective technologies. The various types

36 www.cepmagazine.org March 2002 CEP

of bioreaction systems covered here include batch, continu- Higher raw material conversion levels, resulting from
ous, semi-continuous, surface/tray, submerged, air-lift loop a controlled growth period.
and trickle-bed setups. As stated before, there are overlapping The disadvantages include:
characteristics in several of the technologies discussed. Lower productivity levels due to time for filling, heat-
ing, sterilizing, cooling, emptying and cleaning the reactor.
Batch bioreactions Increased focus on instrumentation due to frequent
The majority of bioreactions are batch-wise. The first sterilization.
phase of batch bioreaction is commonly sterilization, after Greater expense incurred in preparing several subcul-
which the sterile culture medium is inoculated with microor- tures for inoculation.
ganisms that have been cultivated to achieve a specific result. Higher costs for labor and/or process control for this
During this dynamic reaction period, cells, substrates (includ- non-stationary process.
ing the nutrient salts and vitamins) and concentrations of the Larger industrial hygiene risks due to potential contact
products vary with time. Proper mixing keeps the differences with pathogenic microorganisms or toxins.
in composition and temperature at acceptable levels. Common applications for batch bioreactors include:
To promote aerobic cultivation, the medium is aerated to Products that must be produced with minimal risk of
provide a continuous flow of oxygen. Gaseous byproducts contamination or organism mutation.
formed, such as CO2, are removed, and aeration and gas-re- Operations in which only small amounts of product
moval processes take place semicontinuously. are produced.
Next, an acid or alkali is added if the pH needs to be Processes using one reactor to make various products.
controlled. To keep foaming to acceptable levels, an- Processes in which batch or semicontinuous product
tifoaming agents may be added when indicated by a foam separation is adequate.
sensor. A large, stainless steel batch fermenter for produc-
ing beer is shown in Figure 1. (A batch fermenter is simi- Continuous bioreactions
lar to the bioreactor shown in Figure 3, but without the re- The defining characteristic of continuous bioreaction is
cycle loop.) One of the first types of batch systems is the a perpetual feeding process. A culture medium that is ei-
tray fermenter (Figure 2), used in the early days of com-
mercial aerobic bioreactions for products such as citric
acid and penicillin. In this system, the trays are loaded Exhaust
with the culture medium and the organisms, and the air- Motor Gas
flow produces the bioreaction, during which exhaust gas is
discharged. When the bioreaction is complete, end product
is removed from the trays. Because this method is ineffi-
cient for producing large commercial quantities, it fell
quickly to the wayside with the emergence of submerged
tank systems, which are designed to handle significantly Feed
higher volumes.
Overall, batch bioreaction systems provide a number of
advantages, including:
Reduced risk of contamination or cell mutation, due to
a relatively brief growth period.
Lower capital investment when compared to continu-
ous processes for the same bioreactor volume.
More flexibility with varying product/biological systems.
Gas
Supply Biomass
Recycle

Exhaust
Gas
Value
Gas Product
Pump
Supply
Trays
Separator

Figure 2. A tray bioreactor is loaded with the culture medium and Figure 3. Stirred-tank bioreactor uses baffles and an agitator for optimal
organisms, then airflow is started to initiate the reaction. mixing, and recycles biomass.

CEP March 2002 www.cepmagazine.org 37

Bioreactions

ther sterile or comprised of microorganisms is continuous- ism usually outgrows another. Chemostats are continuous-
ly fed into the bioreactor to maintain the steady state. Of flow stirred-tank bioreactors (CFSTRs) in an idealized
course, the product is also drawn continuously from the re- steady-state, i.e., the feed- and outlet-stream compositions
actor. The reaction variables and control parameters remain and flows are constant, and perfect mixing occurs within
consistent, establishing a time-constant state within the re- the CFSTR vessel. In chemostats, the outlet stream compo-
actor. The result is continuous productivity and output. sition is considered to be the same as within the bioreactor.
These systems provide a number of advantages, including: Bioreactors operated as chemostats can be used to enhance
Increased potential for automating the process. the selectivity for thermophiles, osmotolerant strains, or
Reduced labor expense, due to automation. mutant organisms with high growth rates. Also, the medi-
Less non-productive time expended in emptying, fill- um composition can be optimized for biomass and product
ing and sterilizing the reactor. formation, using a pulse-and-shift method that injects nu-
Consistent product quality due to invariable operat- trients directly into the chemostat. As changes are ob-
ing parameters. served, the nutrient is added to the medium supply reser-
Decreased toxicity risks to staff, due to automation. voir and a new steady state is established.
Reduced stress on instruments due to sterilization. A third advantage is the quality of the product. Because of
The disadvantages of continuous bioreactors include: the steady-state of continuous bioreaction, the results are not
Minimal flexibility, since only slight variations in the only more reliable, but also more easily reproducible. This
process are possible (throughput, medium composition, process also results in higher productivity per unit volume,
oxygen concentration and temperature). because time-consuming tasks, such as cleaning and steriliza-
Mandatory uniformity of raw material quality is nec- tion, are unnecessary. The ability to automate the process also
essary to ensure that the process remains continuous. renders it less labor-intensive, and, therefore, more cost-effi-
Higher investment costs in control and automation cient and less sensitive to the impact of human error.
equipment, and increased expenses for continuous steril- Along with the strengths of continuous bioreaction,
ization of the medium. there are inherent disadvantages that may make this pro-
Greater processing costs with continuous replenish- cess unsuitable for some types of bioreaction. For exam-
ment of non-soluble, solid substrates such as straw. ple, one challenge lies in controlling the production of
Higher risk of contamination and cell mutation, due to some non-growth-related products. For this reason, the
the relatively brief cultivation period. continuous process often requires feed-batch culturing,
Continuous bioreaction is frequently used for processes and a continuous nutrient supply. Wall growth and cell ag-
with high-volume production; for processes using gas, liquid gregation can also cause wash-out or prevent optimum
or soluble solid substrates; and for processes involving mi- steady-state growth.
croorganisms with high mutation-stability. Typical end prod- Another problem is that the original product strain can
ucts include vinegar, bakers yeast and treated wastewater. be lost over time, if it is overtaken by a faster-growing one.
The viscosity and heterogenous nature of the mixture can
Continuous vs. batch also make it difficult to maintain filamentous organisms.
There are several major advantages to using continuous Long growth periods not only increase the risk of contami-
bioreactions as opposed to the batch mode. First, continu- nation, but also dictate that the bioreactor must be extreme-
ous reactions offer increased opportunities for system in- ly reliable and consistent, incurring a potentially larger ini-
vestigation and analysis. Because the variables remain un- tial expenditure in higher-quality equipment.
changed, a benchmark can be determined for the process
results, and then the effects of even minor changes to phys- Semicontinuous bioreactions
ical or chemical variables can be evaluated. Also, by This hybrid of batch and continuous operations is found
changing the growth-limiting nutrient, changes in cell in many types of processes. One of the more frequently
composition and metabolic activity can be tracked. The used is initiating the bioreaction in the batch mode, until
constancy of continuous bioreaction also provides a more the growth-limiting substrate has been consumed. Then,
accurate picture of kinetic constants, maintenance energy the substrate is fed to the reactor as specified (batch) or is
and true growth yields. maintained by an extended culture period (continuous). For
Secondly, continuous bioreaction provides a higher de- secondary metabolite production, in which cell growth and
gree of control than does batch. Growth rates can be regu- product formation often occur in separate phases, the sub-
lated and maintained for extended periods. By varying the strate is typically added at a specified rate. Like batch reac-
dilution rate, biomass concentration can be controlled. Sec- tors, semicontinuous reactors are non-stationary. These
ondary metabolite production can be sustained simultane- systems provide a number of advantages, including:
ously along with growth. In steady-state continuous biore- Higher yield, resulting from a well-defined cultivation
action, mixed cultures can be maintained using chemostat period during which no cells are added or removed.
cultures unlike in batch bioreaction, where one organ- Increased opportunity for optimizing environmental

38 www.cepmagazine.org March 2002 CEP

conditions of the microorganisms in regard to the phase of Many types of airlift bioreactors are currently in use today.
growth or production and age of the culture. Air is typically fed through a sparger ring into the bottom
Nearly stationary operation, important with slightly mu- of a central draught tube that controls the circulation of air
tating microorganisms and those at risk for contamination. and the medium (Figure 4). Air flows up the tube, forming
The disadvantages include: bubbles, and exhaust gas disengages at the top of the col-
Lower productivity levels due to time-consuming pro- umn. The degassed liquid then flows downward and the
cedures for filling, heating, sterilizing, cooling, emptying product is drained from the tank. The tube can be designed
and cleaning the reactor. to serve as an internal heat exchanger, or a heat exchanger
Greater expenses in labor and/or dynamic process con- can be added to an internal circulation loop.
trol for the process. Airlift systems provide some advantages vs. more con-
Semicontinuous bioreactors are typically used when ventional bioreactors, such as the standard fermenter:
continuous methods are not feasible, for example, those in Simple design with no moving parts or agitator
which slight mutation or contamination of the microorgan- shaft seals, for less maintenance, less risk of defects and
ism occurs. Such bioreactors are also used when batch easier sterilization.
methods do not offer the desired productivity levels. Lower shear rate, for greater flexibility the system
can be used for growing both plant and animal cells.
Submerged bioreactors stirred tank Efficient gas-phase disengagement.
The most common type of aerobic bioreactor in use Large, specific interfacial contact-area with low-
today is the stirred-tank reactor, which may feature a specif- energy input.
ic internal configuration designed to provide a specific cir- Well-controlled flow and efficient mixing.
culation pattern. Ideal for industrial applications, this unit Well-defined residence time for all phases.
offers manufacturers both low capital and operating costs. Increased mass-transfer due to enhanced oxygen solu-
For laboratory experiments with smaller volumes, the mix- bility achieved in large tanks with greater pressures.
ing vessel is typically made of glass. Stainless steel tank Large-volume tanks possible, increasing the output.
construction is the standard for industrial applications in- Greater heat-removal vs. conventional stirred tanks.
volving larger volumes. The height-to-diameter ratio of the The main disadvantages are:
vessel can vary, depending on heat removal requirements. Higher initial capital investments due to large-
The operating principles of the stirred-tank bioreactor are scale processes.
relatively simple. As shown in Figure 3, the sterile medium and
inoculum are introduced into a sterilized tank, and the air sup-
ply typically enters at the bottom. For optimal mixing, the tank Exhaust Gas
features not only an agitator system but also baffles, which help
prevent a whirlpool effect that could impede proper mixing. In
the early stages of the process, warm water may be circulated
through the baffles to heat up the system; later, cool water may
be circulated inside of them to keep the process from overheat-
ing. The number of baffles typically ranges from four to eight.
As the bioreaction progresses, the bubbles produced by
the air supply are broken up by the agitator as they travel
upward. Many types of agitators are currently used, with
the most common one being the four-bladed disk turbine.
Newer designs featuring 12 or 18 blades, or concave ones,
have also been shown to improve the hydrodynamics. At
the top of the tank, exhaust gas is discharged and the prod-
uct flows back down, where it is drained from the tank.
In a continuous flow stirred-tank reactor, the substrate is
continuously fed into the system and the product is contin-
ually drawn out and separated, with the producing organ-
Gas Supply
ism recycled back into the tank for reuse. As with conven-
tional chemical reactors, bioreactors can be placed in series
or parallel with controlled recycle streams. Valve
Product
Airlift reactor systems
Also known as a tower reactor, an airlift bioreactor can Figure 4. The simple design of a concentric draught-tube bioreactor
be described as a bubble column containing a draught tube. with annular liquid downflow results in less maintenance.

CEP March 2002 www.cepmagazine.org 39

Bioreactions

Greater air throughput and higher pressures needed,

Exhaust Gas
particularly for large-scale operation.
Low friction with an optimal hydraulic diameter for
the riser and downcomer.
Lower efficiency of gas compression.
Inherently impossible to maintain consistent levels of
substrate, nutrients and oxygen with the organisms circu-
lating through the bioreactor and conditions changing.
Inefficient gas/liquid separation when foaming occurs.
However, these disadvantages can and must be mini-
mized in designing airlift systems. For example, if only one
location serves as the feed source, the organism would expe-
rience continuous cycles of high growth, followed by starva-
tion, resulting in the production of undesirable byproducts,
low yields and high mortality rates. A design with multiple
feed points eliminates this risk, especially for large-scale op-
erations. The same risks are inherent in a single entry point
for oxygen, which must be delivered at various places within
Gas Supply
the vessel, with the majority of the air entering at the bottom
to circulate the fluid through the reactor.
Valve
Airlift external-loop reactors
Product
Another type of airlift system is the airlift external-loop
reactor system (AELR; Figure 5), used primarily for batch
Figure 5. An airlift external-loop reactor has induced circulation that operation. Figure 5 shows a cut-away view, that is, the ves-
directs air/liquid throughout vessel. sel and downcomer are actually taller than shown for the
particular diameter drawn. A variation of the airlift system,
the AELR uses induced circulation to direct air and liquid
Exhaust throughout the vessel. This system consists of a riser and
Gas an external downcomer, which are connected at the bottom
and the top, respectively. As the injected air at the bottom
of the riser creates gas bubbles that begin to rise through
the main tank, exhaust gas disengages at the top and the re-
sulting heavier solution descends through the downcomer.
The AELR has some advantages over standard airlifts:
Feed Effective heat-transfer and efficient temperature control.
Low friction with an optimal hydraulic diameter for
both the riser and downcomer.
Well-defined residence time in the individual section
of the AELR.
Increased opportunity for measurement and control in
the riser and the downcomer.
Independent control of the gas input-rate and liquid ve-
locity by a throttling device between riser and downcomer.

Anaerobic bioreactions
Anaerobic bioreactions are used in applications such as
ethanol production, winemaking, beer brewing and
wastewater treatment. Technologies are well established in
Gas Product wine, ethanol and beer production, with improvements re-
Supply Pump sulting from product improvements and manufacturing cost
reductions. Continuous bioreactors for beer have been
commercialized, however, batch fermenters continue to re-
Figure 6. A trickle-bed employs adhered, immobilized enzymes to
accomplish a reaction. ceive capital investments. Waste treatment is a field largely
considered to have matured with fully functional technolo-

40 www.cepmagazine.org March 2002 CEP

gy in place, therefore, not as much attention has been paid Gas-liquid-solid contacting bioreactors have been inves-
to developing newer wastewater treatment processes. tigated with a number of immobilized enzyme systems. En-
zyme immobilization can take a variety of different forms
Technologies under development and it has been studied on a range of supports. The method
A number of new processes are being developed. One used in a particular application depends on the characteris-
involves the use of isolated enzymes rather than whole tics of the enzyme, its system, the substrate and the bioreac-
cells to carry out a chemical change. The advantage is that tor fluid. Enzymes may be supported on a mesh-type or
this process does not require catering to the special require- conventional mass-transfer structure, encapsulated in a film,
ments of living cells. However, enzymes, too, can undergo supported by gel or silica-derived systems, on macroporous
changes and, therefore, require determining the optimal con- ion-exchange resins, or on other polymeric supports.
ditions to express their catalytic activity. An additional prob- One system that currently employs this technology is
lem is that using isolated enzymes is frequently an expensive the trickle bed bioreactor (Figure 6). Not unlike certain
undertaking for a single use application. types of biofilters traditionally used for emission control,
Consequently, long reaction times may be necessary if this system features a screen onto which the enzyme is ad-
cost factors necessitate that expensive enzymes must be used hered and immobilized, and through which the substrate
only in low concentrations. There are other disadvantages to solution is passed for conversion.
their use, too, such as the need to remove the enzyme from Membranes and hollow fibers have been tried for immo-
the product once the desired bioreaction has taken place. bilized bioreaction systems. An example is hollow fibers
Immobilized enzyme technology is now successfully with enzymes incorporated into their walls. The diffusion of
solving some of these difficulties. With the enzyme im- the substrate through the tube wall allows contact with the
mobilized in a bed or tube, the solution of substrate for gelled enzyme and conversion into product. Subsequent dif-
conversion is then passed through for conversion to prod- fusion of the product provides the separation necessary for
uct. The product is continuously collected as effluent its recovery. Under the influence of the differential pressure
from the bioreactor. The design and operation of an im- across the tube wall, the product flows through to the inside
mobilized system is similar to that of processes employ- of the tube, eventually to be collected at a multitube header.
ing heterogeneous catalysis. Heterogeneous systems en- Ethanol production has been achieved in the laboratory with
able product recovery at lower separation costs than do immobilized enzymes in fixed-bed and membrane reactors.
corresponding homogeneous systems. Enzymes have already been successfully tested for sugar
conversion to ethanol.
Glucose isomerization to fructose is a well-estab-
Further Reading lished, high-volume commercial process for the produc-
tion of high-fructose corn syrup (HFCS). Technologies
Carberry, James J., Chemical and Catalytic Reaction Engineering, using immobilized glucose isomerase in fixed-bed and
McGraw-Hill, New York (1976).
Chisti, M. Y., Airlift Bioreactors, Elsevier Science, Essex, U.K.
fluidized bioreactor continue to be developed.
(1989).
Crabbe, M. James, editor, Enzyme Biotechnology: Protein Engineer- Summary
ing, Structure Prediction and Fermentation, Ellis Horwood, West Bioreactors will be integral to the development of many
Sussex, U.K. (1990). new high-value products and the replacement of existing
Ghose, Tarun K., editor, Bioprocess Engineering: The First Genera- chemical-based commodity processes. The proper selec-
tion, Ellis Harwood, West Sussex, U.K. (1989). tion and design of the bioreactor will determine the optimal
Jackson, A. T., Process Engineering in Biotechnology, Prentice Hall, commercial bioprocess and the corresponding capital in-
Englewood Cliffs, NJ (1991).
Leigh, J. R., editor, Modeling and Control of Fermentation Process-
vestment. The bioreactor should not be regarded as an iso-
es, Peter Peregrinus, London (1987). lated unit, but as part of an integrated unit operation with
Mijnbeek, G., et al., Bioreactor Design and Product Yield, project of both upstream (preparation) and downstream (separations)
Open Universiteit and Thames Polytechnic, Butterworth-Heinemann, unit operations. CEP

Oxford U.K. (1992).

Sikdar, Subhas K, et al., editors, Frontiers in Bioprocessing, CRC
Press, Boca Raton, FL (1990).
Sinclair, C. G., and B. Kristiansen, Fermentation Kinetics and Mod- JOHN A. WILLIAMS is general manager of EPS: Environmental & Production
eling, Taylor and Francis, New York (1987). Solutions, LLC (17455 Douglas Road, South Bend, IN 46635; Phone: (574)
Underkofler, Leland A., and Richard J. Hickey, eds., Industrial Fermen- 247-6000; Fax: (574) 277-3775; E-mail: jwilliams.eps@att.net). He received a
BS from the Univ. of Delaware in chemistry, and MS and PhD degrees from the
tations, Chemical Publishing, New York (1954).
Univ. of Utah in chemical and fuels engineering. He also holds an MBA in
vant Reit, Klaas, and Johannes Tramper, Basic Bioreactor Design,
finance from the Univ. of Chicago. A registered professional engineer, he is an
Marcel Dekker, New York (1991). AIChE lecturer on the economic evaluation and development of engineering
Wang, Daniel I. C., et al., Fermentation and Enzyme Technology, projects. He is a member of AIChE, ACS, ASHRAE. ASME and ISA.
John Wiley, New York (1979).

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