Industries 1-Lecture 28

Chemical Industries Technologies Ⅰ
Antibiotics
Dr. Asma Eskhan

Antibiotic production
 Antibiotics are produced by fermentation.
Any large-scale microbial process occurring with or
without air is called Fermentation.
 The process may take a few days to obtain an
extractable amount of product.

 Antibiotic production is done by the batch process.
Properties of the Microorganism
Properties of useful industrial microbe include:
 Grow rapidly on large scale in inexpensive medium.
 Produce desired product quickly.
 Should be Non-pathogenic.
 Amenable to genetic Modification.

Products produced by Microorganisms
 Microbial cells
 Enzymes
 Antibodies
 Steroids
 Alkaloids
 Food additives
 Ethanol, citric acid etc
Primary Metabolites
 Metabolites: Metabolites are the intermediates and
products of metabolism.
 Primary Metabolites: The metabolites which are
required for the growth and maintenance of cellular
functions are called primary metabolites.
 Primary metabolites are formed during the growth
phase.
 Examples are amino acids, vitamins, carbohydrates,
lipids, nucleic acids and enzymes.
Secondary Metabolites
 Secondary Metabolites: The metabolites which are
not required for the growth and maintenance of
cellular functions and are the end products of
primary metabolites are called secondary
metabolites.
 Secondary metabolites are formed near the
stationary phase of growth.
 Drugs, toxins, steroids and polymeric substances like
rubber are some of the examples of secondary
metabolites.
Production of Antibiotics
 The mass production of antibiotics began during
World War II with streptomycin
and penicillin.
• Now most antibiotics are
produced by staged fermentations
in which strains of microorganisms
producing high yields are grown under optimum
conditions .
 Production of antibiotics can be done by 3 methods.
 1. Natural microbial production using
Fermentation technology.
Example: Penicillin
 2. Semi synthetic production (post production
modification of natural antibiotics).
 Example: Ampicillin
 3. Synthetic production of antibiotics made
synthetically in the lab.
 Example: Quinoline
Fermentation Technology
 The source microorganism is grown in large
containers (100,000–150,000 liters or more)
containing a liquid growth medium.
 Oxygen concentration,
temperature, pH and nutrient levels must be
optimum.
 As antibiotics are secondary metabolites, the
population size must be controlled very carefully to
ensure that maximum yield is obtained before the
cells die.
The fermentation process requires the
following
1. A pure culture of the chosen organism, in sufficient quantity.
2. Sterilized, carefully composed medium for growth of the organism
3. A seed fermenter, a mini-model of production fermenter to develop
inoculums to initiate the process in the main fermenter.
4. A production fermenter, the functional large model and
5. Equipment for:
a) Drawing the culture medium in steady state
b) Cell separation
c) Collection of cell free supernatant
d) Product purification and
e) Effluent treatment.
Step 1 to 3 constitutes the upstream and step 5 constitutes the
downstream of the fermentation process.
Strains used for production
 Species are often genetically modified to yield
maximum amounts of antibiotics.
 Mutation is often used -introducing mutagens such as
ultraviolet radiation, x-rays
 Selection and further reproduction of the higher
yielding strains can raise yields by 20-fold or more.
 Another technique used to increase yields is gene
amplification, where copies of genes coding for
enzymes involved in the antibiotic production can be
inserted back into a cell, via vectors such as plasmids.
Raw Materials
 The compounds that make the fermentation broth are the primary
raw materials required for antibiotic production.
• The broth is an aqueous solution made up of all of the ingredients
necessary for the proliferation of the microorganisms.
• Typically, it contains;
 Carbon source: molasses, or soy meal,acetic acid, alcohols, or
hydrocarbons
• These materials are needed as a food source for the organisms.
• Nitrogen Source : Nitrogen is another necessary compound in the
metabolic cycles of the organisms.
ammonia salt is typically used.
Other Elements
 Trace elements needed for proper growth of antibiotic
producing microorganisms such as:
▪ Phosphorus
▪ Sulfur
▪ Magnesium
▪ Zinc.
▪ Anti foaming agents to prevent foaming during
fermentation such as:
▪ Lard oil
▪ Octadecanol
Steps in Production
➢ First the organism that makes the antibiotic must be
identified.
➢ Desired microorganism must then be isolated.
➢ Then the organism must be grown on a scale large
enough to allow the purification and chemical analysis
of the antibiotic.
➢ The antibiotic tested against a wide variety of bacterial
species.
It is important that sterile conditions be maintained
throughout the manufacturing process, because
contamination by foreign microbes will ruin the
fermentation.
A) Starting a Culture
 Before the fermentation process the desired microbe must be
isolated and its number must be increased by many times.
➢ A starter culture from a sample of previously isolated organisms is

created in the lab.
➢ A sample of the organism is transferred to an agar-containing plate.
➢ The initial culture is then transferred to shake flask containing

nutrients necessary for growth.
➢ A suspension is formed which is then transferred to seed tanks for

further growth.
 The seed tanks are steel tanks designed to provide an
ideal environment for growing microorganisms.
 The seed tanks are equipped
with mixers, which mix the
growth medium with
microbes, and a pump to
deliver sterilized, filtered air.
 After about 24-28 hours, the material in the seed tanks
is transferred to the primary fermentation tank.
B) Fermentation
 The fermentation tank is a larger version of the seed tank, which is able to
hold about 30,000 gallons.
 Microorganisms are allowed to grow and multiply.
• During this process, they excrete large quantities of the desired antibiotic.
• The tanks are cooled to keep the temperature between 73-81° F

(23-27.2 ° C).
• It is constantly agitated, and a continuous stream of sterilized air is pumped
into it.
 Anti- foaming agents are periodically added.
• Since pH control is vital for optimal growth, acids or bases are added to the
tank as necessary.
C) Isolation & Purification
 After 3-5days, the maximum amount of antibiotic
will have been produced.
• The isolation process can begin.
• The isolation depend on the specific antibiotic

produced, the fermentation broth is processed by
various purification methods.
Water soluble Antibiotics
 Antibiotic compounds that are water soluble, an ion-
exchange method is used for purification.
• The compound is first separated from the waste
organic materials in the broth.
• Then sent through equipment, which separates the
other water-soluble compounds from the desired
one.
Oil soluble Antibiotics
 Solvent extraction method is used for the isolation of oil soluble or
organic antibiotics.
 The broth is treated with organic solvents such as butyl acetate or

methyl isobutyl ketone, which can dissolve the antibiotic.
 The dissolved antibiotic is then recovered using various organic

chemical means.
 At the end of this step a purified powdered form of the antibiotic is

obtained which can be further refined into different product types.
Refining/Packaging
 Antibiotic products can take on many different forms. They can be
sold in solutions for intravenous bags or syringes, in pill or gel
capsule form, or powders, which are incorporated into topical
ointments.
 Various refining steps may be taken after the initial isolation.
• For intravenous bags, the crystalline antibiotic can be dissolved in a

solution, put in the bag, which is then hermetically sealed.
• For gel capsules, the powdered antibiotic is physically filled into the
bottom half of a capsule then the top half is mechanically put in
place.
• When used in topical ointments, the antibiotic is mixed into the
ointment
Quality Control
 Quality control is of great importance in the production of antibiotics.
• Since it involves a fermentation process, steps must be taken to ensure that
absolutely no contamination is introduced at any point during antibiotic
production.
 During manufacturing, the quality of all the compounds is checked on a

regular basis.
• Frequent checks of the condition of the microorganism culture during

fermentation.
• Various physical and chemical properties of the finished product are checked
such as pH, melting point, and moisture content.
Industrial production of Penicillin
Penicillin was the first important commercial product
produced by an aerobic, submerged fermentation.
Penicillium Chrysogenum specie is used.
Production
 Penicillin is produced by the fungus Penicillium
chrysogenum which requires lactose, other sugars,
and a source of nitrogen (in this case a yeast
extract) in the medium to grow well.
 Like all antibiotics, penicillin is a secondary
metabolite, so is only produced in the stationary
phase.
 What sort of fermenter does it require?
 A batch Fermentor.
 A fed batch process is normally used of a growth

limiting nutrient to prolong the stationary period
and so increase production.
Purification
 Downstream processing is relatively easy since
penicillin is secreted into the medium.
 So there is no need to break open the fungal cells.
 However, the product needs to be very pure, since
it being used as a therapeutic medical drug.
 It is dissolved and then precipitated by potassium
salt to separate it from other substances in the
medium.
Products
 The resulting penicillin (called penicillin G) can be
chemically and enzymatically modified to make a
variety of penicillin with slightly different
properties.
 These semi-synthetic penicillin include penicillin V,

penicillin O, ampicillin and amoxicillin.

Industries 1-Lecture 28

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Chemical Industries Technologies Ⅰ

Dr. Asma Eskhan

extractable amount of product.

 Grow rapidly on large scale in inexpensive medium.

 Produce desired product quickly.

 Amenable to genetic Modification.

➢ A starter culture from a sample of previously isolated organisms is

➢ A sample of the organism is transferred to an agar-containing plate.

➢ The initial culture is then transferred to shake flask containing

➢ A suspension is formed which is then transferred to seed tanks for

• The tanks are cooled to keep the temperature between 73-81° F

 Anti- foaming agents are periodically added.

• The isolation process can begin.

• The isolation depend on the specific antibiotic

 The broth is treated with organic solvents such as butyl acetate or

 The dissolved antibiotic is then recovered using various organic

 At the end of this step a purified powdered form of the antibiotic is

• For intravenous bags, the crystalline antibiotic can be dissolved in a

 During manufacturing, the quality of all the compounds is checked on a

• Frequent checks of the condition of the microorganism culture during

 A fed batch process is normally used of a growth

 These semi-synthetic penicillin include penicillin V,

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