Bio 61bd9545d78b6

Research & Reviews in Biotechnology & Biosciences ISSN No: 2321-8681
Website: www.biotechjournal.in Mini-Review

Volume: 8, Issue: 2, Year: 2021 PP: 116-125
DOI: https://doi.org/10.5281/zenodo.5775455 Peer Reviewed Journal
Bioreactor: Design, Functions and Fermentation innovations

Inderjeet Kaur and Arun Dev Sharma
P.G. Department of Biotechnology, Lyallpur Khalsa College,
Email: kaurinder@lkc.ac.in
Article History Abstract

Received: 24/09/2021 Fermentation technology is the field of study which involves
Accepted: 28/10/2021 studying, controlling and optimization of the fermentation
process right up from upstream activities, mid stream and
downstream or post fermentation activities. Fermentation
should not be seen merely as a process that is entirely focused
Article ID: RRBB/111 on the happenings occurring in the fermenter alone.
Fermentation is defined as a process of energy generation by
various organisms especially microorganisms. The
Corresponding Author:
fermentation process showed unique characteristics by which
E-Mail:
it generates energy in the absence of oxygen. The process of
Inderjeetbiotechlkc@gmail
energy generation utilizes the use of substrate Level
.com
Phosphorylation (SLP) which do not involved the use of
electron transport chain and free oxygen as the terminal
electron acceptor (1).
Key words: Bioreactors, Frementation.
1. Introduction
Bioreactors are closed systems in which a fermentation vessels were developed in the
biological process can be carried out under wake of the process developed (during the
controlled, environmental conditions. It is a First World War, 1914-1918) by Weizmann
device in which a substrate of low value is and co-workers of U.K. to produce acetone
utilized by living cells or enzymes to by a deep liquid fermentation using
generate a product of higher value. A Clostridium acetobutylicum. The large-scale
bioreactor system comprises a bioreactor, aerobic fermentation vessels were first used
sensors, control system and software to in Central Europe during 1930s for the
monitor and control the conditions inside production of compressed yeast; these
the bioreactor. Bioreactors are extensively fermenter had large cylindrical tanks in
used for the production of pharmaceuticals, which air was introduced at the base via a
food bio-based materials (such as poly-lactic network of perforated pipes. In later
acid), food processing, fermentation, bio- modifications, mechanical impellers were
fuels and also in waste treatment, etc (2). used to improve mixing of broth and
The first truly large-scale aseptic anaerobic dispersal of air bubbles. Fermenter design
116
©2020 The author(s). Published by National Press Associates. This is an open access article under CC-BY License
(https://creativecommons.org/licenses/by/4.0/),
was considerably improved during 1940s to food cultures, biopolymers, ethanol,
accommodate the requirements of strict isopropanol, flavorings, perfume chemicals
aseptic conditions, and good agitation and and many other organic chemicals.
aeration for penicillin production from
2. A bioreactor should provide the
submerged cultures (3). Until the discovery
following: (i) Agitation (for mixing of cells
of penicillin and its commercialization in
and medium), (ii) Aeration (aerobic
1943, bioprocessing was not performed on
fermenters; for O2 supply), (iii) Baffles (to
an industrial scale with equipment
prevent vortex formation and to improve
resembling that in a chemical processing
aeration efficiency), (iv) Regulation of
plant. Since then, the number of products
factors like temperature, pH, pressure,
made by fermentation has grown, because
aeration, nutrient feeding, liquid level, etc.,
bioprocessing generally uses less energy
(v) Sterilization and maintenance of sterility,
than other routes, usually uses inexpensive
and (vi) withdrawal of cells/medium (for
raw materials and sometimes makes
continuous fermenters) (Fig. 1). Modern
products that cannot be made by any other
fermenters are usually integrated with
way. Modern products include antibiotics,
computers for efficient process monitoring,
amino acids, enzymes, monomers, proteins,
data acquisition, etc.
Fig.1 Design of Large scale Fermentation Unit (Prescott, 1999).

These bioreactors are commonly cylindrical, Key issues in bioreactor design and
ranging in size from litres to cubic metres, operation
and are often made of stainless steel.
117
The goal of an effective bioreactor is to fermentation and Fed-batch fermentation
control, contain and positively influence the are the key modes. In batch fermentation,
biological reaction. To accomplish this, the every material for process of fermentation
chemical engineer must take into including substrate, inoculum and all the
consideration two areas. One is the suitable process parameters are set and filled in a
reactor parameters for the desired biological, fermenter and the process is set on and until
chemical and physical (macrokinetic) the total process comes to an end neither
substrate is added into fermenter nor
System. The macrokinetic system includes
product is taken out of fermenter. It’s a
microbial growth and metabolite
closed system. In continuous fermentation,
production. Microbes can include bacteria,
the substrate is added continuously to the
yeast, fungi, animal, plant, fish and insect
fermenter at a fixed rate which maintains the
cells, as well as other biological materials.
microbes at logarithmic growth phase and
The other area of major importance in
the products that are formed are taken out
bioreactor design involves the bioreaction
simultaneously and here we find growth
parameters, including: controlled
associated products. In fed-batch mode we
temperature, optimum pH, sufficient
find both modes of operations of batch and
substrate (usually a carbon source) such as
continuous modes, where substrate is added
sugars, proteins and fats, water availability,
at fixed time intervals during the
salts for nutrition, vitamins, oxygen (for
fermentation process (5).
aerobic processes), gas evolution and
product and byproduct removal (Fig. 2). In 2. Based on need of supply of aeration: There are
addition to controlling these, the bioreactor aerobic fermentation and anaerobic
must be designed to both promote formation fermentation. Aerobic fermentations: many
of the optimal morphology of the organism large-scale fermentation processes are
and to eliminate or reduce contamination by carried out in presence of aerobic conditions
unwanted organisms or mutation of the where, the contents present in fermenter are
organism (4). agitated with the help of agitator and with
the help of spargers by forcing sterilized air
Types of Fermentations Innovations
into the fermenter. There are several types of
Innovations (new idea, device or process) Microbial cell aerobic bioreactors: CSTR
are the application of better solutions that (suspended cells, mechanically agitated) and
meet new requirements, in articulated needs Airlift fermenter (Suspended cells,
or existing market needs. Fermentation pneumatically agitated). Anaerobic
types are classified into different classes: fermentation: apart from intense need and
1. Based on various aspects like based presence of agitator and sparger to supply
on feeding substrate to fermenter. aeration, rest of the configuration of the
fermenter is as same as aerobic
2. Based on need of supply of aeration fermentation. But the presence of agitator is
3. Based on need of light etc. made compulsion for the even distribution
of temperature, pH, viscosity, nutrients etc.
1. Based on feeding substrate to fermenter: along the medium in the fermenter.
There is Batch fermentation; Continuous Anaerobic bioreactions are used in
118
applications such as ethanol production, used only in low concentrations. There are
winemaking, beer brewing and wastewater other disadvantages to their use, too, such as
treatment. the need to remove the enzyme from the
product once the desired bioreaction has
3. Based on need of light: There are
taken place. Immobilized enzyme
Photofermentation (only photosynthetic
technology is now successfully solving some
bacteria can undergo) and Dark
of these difficulties. With the enzyme
fermentation. Photofermentation is a process
immobilized in a bed or tube, the solution of
of conversion of organic substances to other
substrate for conversion is then passed
utilizable energy compounds following a
through for conversion to product. The
series of biochemical reactions carried out
product is continuously collected as effluent
by a specific group of bacteria named
from the bioreactor. The design and
Photosynthetic bacteria, which only
operation of an immobilized system is
proceeds in the presence of light. Dark
similar to that of processes employing
fermentation in every way it is similar to
heterogeneous catalysis. Heterogeneous
that of photofermentation, but in aspect of
systems enable product recovery at lower
need of light, dark fermentation does not
separation costs than do corresponding
need any light to initiate the reactions and a
homogeneous systems. Gas-liquid-solid
diversified group of microbes are involved
contacting bioreactors have been
in dark fermentation.
investigated with a number of immobilized
Design of Bioreactor System used in enzyme systems. Enzyme immobilization
Bioprocess Technology can take a variety of different forms and it
Designing a bioreactor system involves has been studied on a range of supports. The
mechanical, electrical and bioprocess method used in a particular application
engineering. The design process should be depends on the characteristics of the
organized in such a way that systems can be enzyme, its system, the substrate and the
used under the strictest of regulations. A bioreactor fluid. Enzymes may be supported
number of new processes are being on a mesh-type or conventional mass-
developed. One involves the use of isolated transfer structure, encapsulated in a film,
enzymes rather than whole cells to carry out supported by gel or silica-derived systems,
a chemical change. The advantage is that on macroporous ion-exchange resins, or on
this process does not require catering to the other polymeric supports. One system that
special requirements of living cells. currently employs this technology is the
However, enzymes, too, can undergo trickle bed bioreactor. Not unlike certain
changes and, therefore, require determining types of biofilters traditionally used for
the optimal conditions to express their emission control, this system features a
catalytic activity. An additional problem is screen onto which the enzyme is adhered
that using isolated enzymes is frequently an and immobilized, and through which the
expensive undertaking for a single use substrate solution is passed for conversion.
application. Consequently, long reaction Membranes and hollow fibers have been
times may be necessary if cost factors tried for immobilized bioreaction systems.
necessitate that expensive enzymes must be An example is hollow fibers with enzymes
119
incorporated into their walls. The diffusion the mixing impeller and liquid additions are
of the substrate through the tube wall allows done from the top of the bioreactor. Stirred
contact with the gelled enzyme and tank bioreactors are available from 0.05 litres
conversion into product. Subsequent up to 100 cubic metres in volume (6).
diffusion of the product provides the
(ii) Bubble Column Bioreactors: These are the
separation necessary for its recovery. Under
simplest type of tower fermenters; they
the influence of the differential pressure
consist of glass or metal tubes into which air
across the tube wall, the product flows
is introduced into the bottom section
through to the inside of the tube, eventually
through perforated pipes, plates or metal
to be collected at a multitube header.
micro porous sparger for mixing and
The different types of bioreactors used in aeration purposes. Fermenter volumes from
bioprocess technology are: (1) Submerged 3L to up to 950 L have been used, and the
Culture Bioreactors. The major types of aspect ratio may be up to 16: 1. These tower
submerged culture bioreactor are: (i) fermenters have been used for citric acid
Continuous Stirred Tank Bioreactors (ii) and tetracycline production, and for a range
Bubble Column Bioreactors (iii) Airlift of other fermentations based on mycelial
Bioreactors (iv) Fluidized Bed Bioreactors (v) fungi.
Trickle Bed bioreactors. (2) Solid State
(iii) Air lift Bioreactors: Similar to bubble
Bioreactors.
column reactors, these differ by the fact that
1. Submerged Culture Bioreactors they contain a draft tube. There are two
types of draft tube: an inner tube (air-lift
(i) Continuous Stirred Tank Bioreactor: The
bioreactor with an internal loop); or an
most common type of aerobic bioreactor in
external tube (air-lift bioreactor with an
use today is the stirred tank reactor, which
external loop). The draft tube improves
may feature a specific internal configuration
circulation and oxygen transfer and
designed to provide a specific circulation
equalizes shear forces in the reactor. Air is
pattern. Most production facilities and FDA
approved production processes for typically fed through a sparger ring into the
biopharmaceuticals are based on the stirred bottom of a central draught tube that
tank bioreactor. Generally, the tank has an controls the circulation of air and the
aspect ratio of between 1:1.5 (for medium. Air flows up the tube, forming
bubbles, and exhaust gas disengages at the
mammalian cell culture) and 1:3 (for
top of the column. The degassed liquid then
microbial fermentations). Baffles (enhance
flows downward and the product is drained
mixing) diameter is typically one tenth of
from the tank. Airlift bioreactors are
the tank diameter. The impeller can either be
available from laboratory scale up to full
marine impeller for axial mixing of the cell
production scale (7).
culture – having a diameter of between one
third and one half of the tank diameter or (iv) Bioreactors with immobilized enzymes and
multiple Rushton turbines for gad bubble cells: In this category, there are Fluidized bed
breaking and axial mixing in microbial bioreactors and Packed bed bioreactors.
cultures. Gas is typically introduced below Fluidized bed bioreactor is comparable to
bubble column bioreactor except the top
120
position is expanded to reduce the velocity packed bed bioreactors do not allow
of the fluid. The design of the fluidized accumulation of the products to any
bioreactors (expanded top and narrow significant extent.
reaction column) is such that the solids are
(v) Trickle Bed Fermenter: These consist of a
retained in the reactor while the liquid flows
cylindrical vessel packed with support
out. These bioreactors are suitable for use to
material (e.g. woodchips, rocks or plastic
carry out reactions involving fluid
structures). The support has large open
suspended biocatalysts such as immobilized
spaces, for the flow of liquid and gas and the
enzymes, immobilized cells, and microbial
growth of microorganisms on the solid
flocs. For an efficient operation of fluidized
support. A liquid nutrient broth is sprayed
beds, gas is spared to create a suitable gas-
onto the top of the support material and
liquid-solid fluid bed. It is also necessary to
trickles down the bed. Air may flow up the
ensure that the suspended solid particles are
bed, countercurrent to the liquid flow. These
not too light or too dense (too light ones
fermenters are used in vinegar production,
may float whereas to dense ones may settle
as well as in other processes. They are
at the bottom), and they are in a good
suitable for liquids with low viscosity and
suspended state. Recycling of the liquid is
few suspended solids.
important to maintain continuous contact
between the reaction contents and 2) Solid State Bioreactors
biocatalysts. This enables good efficiency of These are used for processes where
bioprocessing. In case of Packed Bed microorganisms are grown on moist, solid
Bioreactors, A bed of solid particles, with particles. The spaces between the particles
biocatalysts on or within the matrix of contain a continuous gas phase and a
solids, packed in a column constitutes a minimal amount of water. SSF devices vary
packed bed bioreactor. The solids used may in technical sophistication, from very
be porous or non-porous gels, and they may primitive banana leaf wrap pings, bamboo
be compressible or rigid in nature. A baskets and substrate heaps to the highly
nutrient broth flows continuously over the automated machines used mainly in Japan.
immobilized biocatalyst. The products The majority of Solid State Fermentation
obtained in the packed bed bioreactor are (SSF) processes involve filamentous fungi,
released into the fluid and removed. While although some also involve bacteria or
the flow of the fluid can be upward or yeasts. SSF is mainly used in food processes
downward, down flow under gravity is (8). The use of pressure vessels is not the
preferred concentration of the nutrients (and norm for solid state fermentation. The
therefore the products formed) can be commonly used devices are: Tray
increased by increasing the flow rate of the fermenters, Static bed fermenter, Tunnel
nutrient broth. Because of poor mixing, it is fermenter, Rotary disc fermenter, Rotary
rather difficult to control the pH of packed drum fermenter, Agitated tank fermenter
bed bioreactors by the addition of acid or and Continuous screw fermenter (9).
alkali. However, these bioreactors are
preferred for bioprocessing technology Other Bioreactor designs
involving product-inhibited reactions. The
121
3) Photo Bioreactors: These are the receivers by methods such as using
bioreactors specialized for fermentation that centrifugal pumps or airlift pumps. It is
can be carried out either by exposing to essential that the cells are in continuous
sunlight or artificial illumination. Since circulation without forming sediments.
artificial illumination is expensive, only the Further adequate penetration of sunlight
outdoor photo-bioreactors are preferred. should be maintained. The tubes should also
They are generally used for the cultivation be cooled to prevent rise in temperature.
of photosynthesizing organism (plants, Photo-bioreactors are usually operated in a
algae and bacteria). Industrial scale photo continuous mode at a temperature in the
bioreactors can also be open pond systems; range of 25-40°C. Microalgae and
and so are more sensitive to environmental Cyanobacteria are normally used. The
influences. They are made up of glass or organisms grow during day light while the
more commonly transparent plastic (Fig. 3). products are produced during night. Certain
The array of tubes or flat panels constitutes important compounds are produced by
light receiving systems (solar receivers). The employing photo-bioreactors e.g., p-
culture can be circulated through the solar carotene, asthaxanthin.
ct (Figure 4 to Figure 7)
122
Fig. 2 Bioprocesses: Biotechnological Processes (Source: www.slideshare.net
4) Stem Cell Bioreactors: A recent through the inside of the fiber, while the
development is the stem cell bioreactor. cells are grown on the outside of the fiber.
Stem cells are very appealing for Hollow fibers provide a tremendous amount
regenerative medicine, drug screening and of surface area in a small volume. Cells grow
biomedical applications. These cells have on and around the fibers at densities of
unlimited self renewal capacity and greater than 1 × 108 per ml. Hollow fiber cell
remarkable ability to produce mature cells culture is the only means to culture cells at
with specialized functions, such as blood in vivo like cell densities. Cell culture at
cells, nerve cells or cardiac muscle. high densities can achieve a 10 to 100 time’s
However, the actual number of cells that can higher concentration of secreted product
be obtained from available donors is very compared with classic batch processes (12).
low. One possible solution for the The scalability of the hollow fiber system is
generation of relevant numbers of cells is to limited, however, and so these types of
scale up the culture of these cells in vitro bioreactor are mainly used at the laboratory
(10). Several joint research programmes scale. Smaller hollow fiber bioreactors are
between industry and universities are often used for selection and optimization of
focusing on the development of stem cell cell lines prior to stepping up to larger cell
bioreactor systems. Applikon Biotechnology culturing systems (Gramer and Britton,
has participated in several of these projects 2000). Recently, hollow fiber bioreactors
and has developed a number of successful have been tested as novel platforms for the
designs (11). commercial production of high titer
influenza A virus (13).
5) Hollow Fiber Catridges: Hollow fibers are
small tube-like filters sealed into a cartridge 6) Rocking Bag Bioreactors: This system relies
shell so that cell culture medium pumped on the rocking motion of the bioreactor
through the end of the cartridge will flow holder to mix a liquid volume contained in a
123
plastic bag. This type of bioreactor is mainly SW (eds) Encyclopedia of Bioprocess
used for cell cultivation, due to the low Technology, New York: John Wiley, Vol.
oxygen transfer rates and limited cooling 5, pp. 2446-2459.
capacity of such systems (14). 8. Decker EL and Reski R (2008) Individual
cells exert individual conditions of a
Overall, Bioreactors are the integral part for
treatment. Bioprocess Biosys Eng, 31:3-9.
the development of many new high-value
products and the replacement of existing 9. Gramer MJ and Britton TL (2000)
chemical-based commodity processes. The Selection and isolation of cells for
proper selection and design of the bioreactor optimal growth in hollow fiber
bioreactors. Hybridoma, 19(5): 407-412.
will determine the optimal commercial
bioprocess and the corresponding capital 10. Jagani H, Hebbar K, Gang SS, Raj PV,
investment. The bioreactor should not be Chandrashekhar R and Rao JV (2010) An
regarded as an isolated unit, but as part of overview of fermenter and the design
considerations to enhance its
an integrated unit operation with both
productivity. Pharmacology online, 1: 261-
upstream (preparation) and downstream
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(separations) unit operations.
11. Kana G, Oloke EB, Lateef JK and Kana Z
Funding (2003) Constructional features of a 15
No litre home made bioreactor for fed-batch
fermentations. African J Biotech, 2(8): 233-
Ethical issue 236.
No 12. Liu N, zang R, Yang ST and Li Y (2014)
Stem cell engineering in bioreactors for
Conflict of interest
large scale bioprocessing. Eng. Life Sci.,
no 14(1): 4-15.
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MM and Silva CL (2011) Stem cell
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Research & Reviews in Biotechnology & Biosciences ISSN No: 2321-8681

Website: www.biotechjournal.in Mini-Review

Bioreactor: Design, Functions and Fermentation innovations

Article History Abstract

Fig.1 Design of Large scale Fermentation Unit (Prescott, 1999).

References 13. Rodrigues CAV, Fernanades TG, Diogo

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