Penicillin Production

By , MD, PhD

Penicillin, which remains an important part of our antimicrobial armamentarium, had a significant impact on the second half of the twentieth century. Deep-fermentation methods, which were primarily developed for the production of penicillin during the war, gave rise to the development of antibiotics and contributed to the nascent biotechnology industry which appeared in the 1970s.

Akin to other antimicrobials, penicillin is a secondary metabolite, thus it is only produced in the stationary phase. The industrial production of penicillin was generally classified into two processes – upstream processing and downstream processing.

Upstream processing encompasses any technology that leads to the synthesis of a product and includes the exploration, development and production. The extraction and purification of a biotechnological product from fermentation is referred to as downstream processing.

The fermentation process

Fermentation is the technique used for the commercial production of penicillin. It is a fed-batch process that is carried out aseptically in stainless steel tank reactors with a capacity of 30 to 100 thousand gallons. The fermentation involves two to three initial seed growth phases, followed by a fermentation production phase with a time cycle ranging from 120 to 200 hours.

Various carbon sources have been adopted for this process – including glucose, sucrose and other crude sugars. Approximately 65% of the carbon is used for cellular maintenance, 25% for growth and only 10% for penicillin production. Sugar is also used for the regulation of the pH value during active penicillin production phase.

Mini-harvest protocols are usually employed in penicillin fermentation. They involve the removal of 20-40% of the fermentor contents and its replacement with fresh sterile medium. This procedure can be repeated several times during this process without yield reduction; quite the opposite, it can enhance the total penicillin yield per fermentor.

Penicillin is excreted into the medium and recovered at the end of fermentation. Whole broth extraction is best performed at acidic pH, with a 2-5% improvement in overall extraction efficiency. Solvent extraction of chilled acidified broth is carried out with amyl, butyl or isobutyl acetate.

Present-day penicillin fermentations are highly automated and computerized. All the necessary precursors, ammonia, sugar, carbon dioxide, oxygen are controlled, with thorough monitoring of temperature and pH for optimal antibiotic production. The pH should be between 6.4 and 6.8 during the active production phase.

Pursuit for a better yield

When penicillin was initially made at the end of the Second World War using the fungus Penicillium notatum, the process yielded one milligram per cubic decimeter. Today, with a use of a different species (Penicillium chrysogenum) and improved extraction procedures the yield is 50 grams per cubic decimeter.

The yield of penicillin can be further increased by improving the composition of the medium, isolating aforementioned Penicillium chrysogenum which grows better in huge deep fermentation tank, but also via the development of submerged culture technique for cultivation of mold in large volume of liquid medium through which sterile air is forced.

Still, classical strain improvement has been the mainstay of penicillin production. The amplification of the penicillin biosynthetic gene cluster between tandem repeats represents one of the most important phenomena in high-yielding Penicillium chrysogenum strains. Molecular strategies that differ from those involving an increase in biosynthesis gene doses have also been developed.

Further Reading

Last Updated: Apr 20, 2015

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