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Fed-batch Culture- Definition, Principle, Process, Types,

Applications, Limitations
September 14, 2021 by Sanjogta Thapa Magar

Edited By: Sagar Aryal

Table of Contents
Fed-batch culture Definition
Principle of Fed-batch culture
Process of Fed-batch culture
Types of Fed-batch culture
1. Fixed-Volume Fed-Bat ch Cult ure
2. Variable-Volume Fed-Bat ch Cult ure
3. Repeat ed or cyclic fed-bat ch cult ure
4. Single fed-bat ch process
Application of fed-batch culture
Limitations of Fed-batch culture
References

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Fed-batch culture Definition

In simple words, fed-batch culture is a modification to batch fermentation. In fed-

batch cultivation, nutrients are added aseptically; it is a semi-open system, and the
volume of liquid culture in the bioreactor increases as the culture is systematically
added. A fed-batch culture is more productive, yields better with controlled sequential
additions of nutrients, enables higher cell densities, and prolongs product synthesis.

The main advantages of fed-batch over batch culture are:

1. Long-term synthesis of products, 

2. By increasing the number of cells and thereby increasing the amount of product,
which is proportional to the concentration of the biomass, greater efficiencies can
be achieved in the process, 
3. Increasing yield and productivity with controlled sequential additions of nutrients, 
4. It allows the bioreactor to be used production for non-profitable periods when it
would normally be prepared for the next batch.

In a fed-batch process, the broth does not generally need to be removed during the
entire fermentation process, but the amount of limiting nutrients added determines
the rate of reaction.
Figure: Fed-batch reactor symbol and The graph shows the principle of a substrate
limited fed-batch cultivation with an initial batch phase. After consumption of the
initial substrate, a continuous and constant feed of the substrate is started. Image
Source: Wikipedia.

Fed-batch culture has the following mention advantages:

1. Catabolite repression and Crabtree effects can be managed by limiting the

substrate concentration.
2. The high cell density of the cells could be achieved
3. It is possible to increase the production of non-growth-related metabolites.
4. When necessary, the broth viscosity can be reduced.
5. It allows the replacement of water loss, by evaporation.
 This Low-Carbon Plastic is Made Fro…

Principle of Fed-batch culture

The initial process is similar to batch culture, all of the substrates are added at the
beginning of the fermentation.
The culture broth is harvested usually only at the end of the operational period,
either fully or partially (the remainder serving as the inoculum for the next repeated
run)
In the fed-batch culture, a substrate is added in increments as the fermentation
progresses.
These substrates are added in small concentrations during the production phase.
In the course of operation, there are one or more feed streams but no effluent.
To control the feeding process, many indirect parameters that are related to the
metabolism of a substrate are measured since it is not possible to measure the
substrate concentration directly and continuously. 
Therefore, the culture volume increases during the course of operation until the
volume is full.
Process of Fed-batch culture

The process will be initiated with batch fermentation and consume substrate,
nutrients, and/or inducers. 
Fresh medium will be added through a variety of feed streams.
The microorganisms are inoculated and grown using a batch process for a set
period, then nutrients are added to the fermenter in increments throughout the rest
of the fermentation.
By manipulating the feed rates during the run, carbon, nitrogen, phosphates,
nutrients, precursors, or inducers are added intermittently or continuously to the
culture.
The common feeding strategies are:
discontinuous feeding, achieved by regular or irregular pulses of substrates and
regular continuous feeding of nutrients designed according to pre-calculated data or
based on the feedback control of online measured variables associated with cell
growth and metabolism
As a result of the addition of fresh nutrients, extensive biomass accumulation
normally occurs during exponential growth.
Fed-batch fermentation is therefore very useful for bioprocesses that aim for high
biomass density or high product yield when the desired product is positively
correlated with microbial growth.
 The growth rate can be controlled by the substrate concentration to avoid
catabolite repression.
The products are harvested only at the end of the run. 
The culture volume increases during the course of operation until the volume is full. 
Thereafter, a batch mode of operation is used to attain the final results.

Figure: Characteristic plot for typical substrate-limited fed-batch fermentation. Image Source:
Srivastava, A. K. (2011). 2.38 – Fed-Batch Fermentation – Design Strategies. Comprehens ive
Biotechnology, 1, 515–526. https://doi.org/10.1016/B978-0-08-088504-9.00112-4.

Types of Fed-batch culture

1. Fixed-Volume Fed-Batch Culture

 This procedure involves feeding the limiting substrate to the reactor very
concentrated so that there is no notable increase in volume.
To achieve an almost constant culture volume, the growth-limiting substrate must
be fed in a form of concentrated liquid or gas, in purified form by dialysis, or by way of
radiation sterilization.
A constant-volume fed-batch system has been used for hyperthermophilic
Archaebacteria cultivated under aerobic conditions.

2. Variable-Volume Fed-Batch Culture

It is a type of fed-batch fermentation that involves the addition of substrate feed

that changes working volume with the fermentation time.
The volume change can be influenced by process requirements, time availability, and
the objective of the fermentation process.
In the variable-volume fed-batch process, the feeding strategy can be decided
based on options such as the following 
For batch processing, a similar medium composition could be used.
As required, only the limiting substrate, at a concentration similar to that used for
batch processing, may be added as per the need and desire, while the rest of the
medium constituents can then be added at the beginning at the same rate as the
total reactor volume.
The limited substrate, in a concentrated form, could be added at a slow rate to
prevent excessive dilution of the fermentation broth

3. Repeated or cyclic fed-batch culture

During this process, when the fermentation reaches the stationary phase and there
are no significant changes in the growth of the cells (either due to substrate
depletion or product inhibition), a certain amount of spent broth from the fermenter
is removed, followed by the addition of fresh nutrient medium.
With this removal and addition, the substrate concentration increases in the
fermenter, which results in an increased specific growth rate.
 However, the specific growth rate again decreases as the substrate is consumed
and a quasi-steady state is attained.
Repeated fed-batch cultivation was used to optimize conditions for penicillin G
biosynthesis by the use of a phosphorous feeding strategy.

4. Single fed-batch process

In single fed-batch culture, the feeding solution is added during the fermentation
process, but spent broth is not removed.
In contrast, the major disadvantage of this method is that a lot of the fermentation
broth is not utilized until the end of the fed-batch process.
Thus, reactor volume can be a serious limiting factor for the duration of the
fermentation.

Application of fed-batch culture

Various products produced or attempted to be produced by fed-batch techniques

Product  Example

Amino Acids Glutamic Acid, Lysine, Tyrosine, Tryptophan, Alanine

Antibiotics Candidin and candihexin;

 Cephalosporin C, Chlorotetracycline, Griseofulvin, Penicillin,

Streptomycin, Tetracycline, Baker’s yeasts

Cellulase, Galactosidase, Isoamylase, Protease, β–amylase, α–amylase,

Enzymes
β–Galactosidase, β–Glucanase, β–Glucosidase

Solvents Acetone, Butanol, Glycerol, 1,3-Propanediol

Vitamins Riboflavin, Vitamin B12

Microbial Cell Mass

Cellulomonas sp., Ps eudomonas Candida boidinii, Candida utilis , Pic hia

Bacteria
farinos e, S ac c haromyc es c erevis iae
Yeasts

Animal Cell Culture Non-GS NS0 cell line, Hybridoma

Acetic acid, Citric acid, Gibberellic acid, Neutral lipids,

Others Polyhydroxyalkanoate (PHA), Dihydroxyacetone (DHA), Human

interferon-γ, Clavulanic acid, Poly-β-hydroxybutyrate (PHB)

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Limitations of Fed-batch culture

1. The microbe needs to be analyzed before its cultivation to determine its

requirements, its physiology, and its productivity.
2. To set up fermentation and develop the process, considerable operator skill is
required.
3. A cyclic fed-batch culture should be designed with care to ensure that toxins are not
accumulated to inhibitory levels and that nutrients other than those incorporated
into the fed medium are not limited if many cycles are run.
4. Higher costs in labor and/or dynamic process control for the process.
5. The quantities of components to control must be above the detection limits of the
available measuring equipment.

Read Also:

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Bioreactor- Definition, Design, Principle, Parts, Types, Applications, Limitations
Amazing 27 Things Under The Microscope With Diagrams
Batch vs Fed-Batch vs Continuous Culture- 20 Key Differences
Stem Cells- Definition, Properties, Types, Uses, Challenges

References