Raw Materials

The compounds that make the fermentation broth are the primary raw materials
required for antibiotic production. This broth is an aqueous solution made up of all
of the ingredients necessary for the proliferation of the microorganisms. Typically, it
contains a carbon source like molasses, or soy meal, both of which are made up of
lactose and glucose sugars. These materials are needed as a food source for the
organisms. Nitrogen is another necessary compound in the metabolic cycles of the
organisms. For this reason, an ammonia salt is typically used. Additionally, trace
elements needed for the proper growth of the antibiotic-producing organisms are
included. These are components such as phosphorus, sulfur, magnesium, zinc, iron,
and copper introduced through water soluble salts. To prevent foaming during
fermentation, anti-foaming agents such as lard oil, octadecanol, and silicones are
used.
materials used in bioprocess system includes:

pH 6.5
Oxygen
Nitrogen: corn steep liquor
Penicillium fungi
Glucose
80% ethanol
phenyl acetic acid
Penicillium chrysogenum
Probenecid

Manufacturing Process of Penicillin

Unit Operation - Process
Medium Preparation
Medium preparation is necessary in
bioprocesses which as it generally
involve the use of microorganism to
achieve their products. In the case of
the Penicillium fungus, the medium
usually contain its carbon source which
is found in corn steep liquor and
glucose. Medium also consist of salts
such
as
Magnesium
sulphate,
Potassium
phosphate
and Sodium nitrates. They provide the
essential ions required for the fungus
metabolic activity.

Equipment

Media Preparation Tanks

Heat Sterilization
Medium is sterilized at high heat and
high pressure usually through a holding
tube or sterilize together with the
fermenter. The pressurized steam is
usually used and the medium is heated
to 120C at 30psi or twice of
atmospheric
pressure.
High
temperature short time conditions are
used to minimize degradation of
certain components of the media.
Sterilization Machine
Fermentation
Fermentation for penicillin is usually
done in the fed-batch mode as glucose
must not be added in high amounts at
the beginning of growth which will
result in low yield of penicillin
production as excessive glucose inhibit
penicillin production. In addition to that,
penicillin is a secondary metabolite of
the fungus, therefore, the fed-batch
mode is ideal for such products as it
allows the high production of penicillin.
The typical fermentation conditions for
the Penicllium mold, usually requires
temperatures at 20-24C while pH
conditions are kept in between 6.0 to
6.5. The pressure in the bioreactor is
usually
much
higher
than
the
atmospheric pressure(1.02atm) this is
to
prevent
contamination
from
occurring as it prevents external
contaminants from entering. Sparging
of air bubbles is necessary to provide
sufficient oxygen the viability of the
fungus.

Fermenters

Broth Filtration
The main objective is to remove any
microbial cells and any large solid
particles
such
as, cell
fragments,
soluble
and
insoluble
medium
components, other metabolic products,
Intact micro-organisms. During the
filtration
the micro-organisms
are
captured in a concentrated cake, which
looks like sand, sludge or paste. The
filter drum, partially submerged in the
trough of broth, rotates slowly. Filtrate
and washings are kept separate by the
segments in the drum. The liquid is
drawn through the filter and a cake of
solids builds up on the outer surface.
Inside the drum, the filtrate is moves
from the end of the cylindrical drum
onto a storage tank.

Rotary Vacuum Filter

Cooling
From filtration, the penicillin rich
solution is cooled at 5C. This helps
reduce
enzyme
and
chemical
degradation
during
the
solvent
extraction.

Cooling Machine
Filtration
More filtration is done with the rotary
filtration method

Rotary Vacuum Filter

Solvent Extraction
This method is carried out under the
basis that the extraction agent and the
liquid in which the extract is dissolved
cannot be mixed. Solvent extraction
is suitable for the recovery of penicillin
because of its operation at low
temperatures, greater selectivity and is
less expensive compared to distillation,
evaporation and membrane technology.

Podbielniak Centrifugal Contractor

Carbon Treatment
The penicillin rich solution is then
treated with 0.25-5% activated carbon
to remove pigments and impurities.

Carbon Filtering Machine

Solvent Recovery
The penicillin solvent is usually
recovered by distillation. First the
solvent is vaporized from the solution,
then
the
low
boiling
volatile
components are separated from the
less volatile components in a column,
and finally condensation is used to
recover the volatile solvent fraction.

Distillation Tank

Crystallization
Crystallization is essentially a polishing
step that yields a highly pure product
and is done through phase separation
from a liquid to a solid. To begin the
process a supersaturated solution,
where there are more dissolved solids
in the solvent than can ordinarily be
accommodated at that temperature,
must be obtained through cooling,
drowning, solvent evaporation, or by
chemical reaction. Batch crystallization
is the most the most used method for
polishing
penicillin
G.
Batch
crystallizers simply consist of tanks with
stirrers and are sometimes baffled.
They are slowly cooled to produce
supersaturation.
Seeding
causes
nucleation and growth is encouraged by
further cooling until the desired crystals
are obtained.
Crystal Washing
Even though the penicillin crystals are
pure in nature, adsorption and capillary
attraction can cause impurities from its
mother liquor on their surfaces and
within the voids of the particulate mass.
Thus the crystals must be washed and
pre-dried in a liquid in which they are
relatively insoluble. For this purpose
anhydrous l-propanol, n-butanol or
another volatile solvent is used.

Crystallizer

Industrial Washing Machine

Drying
Drying
stabilizes
heat
sensitive
products like penicillin. The drying of
penicillin must be carried out with
extreme care to maintain its chemical
and biochemical activity, and ensure
that it retains a high level of activity
after drying. The 3 most used methods
for drying would be: Lyophilization,
Spray Dryers, Vacuum Band Dryers
Vacuum Band Dryer

Storing and Packaging

Penicillin salt is stored in containers and
kept in a dried environment. It will then
be polished and package into various
types of products such as liquid
penicillin or penicillin in pills. Dosage of
the particular penicillin is determined
by clinical trials that are done on this
drug.
Packaging Machine
Plant Layout