How Penicillin is Made

The synthesis of penicillin involves a complex process that combines organic chemistry techniques with microbial fermentation. It relies on culture maintenance, fermentation, and extraction/purification procedures that need careful management.

The general overview of the steps involved:-

1. Precursor Chemicals: The synthesis of penicillin starts with the preparation of precursor chemicals, such as 6-aminopenicillanic acid (6-APA). 6-APA is the basic building block for various types of penicillins.
2. Acylation: The precursor chemical, 6-APA, is acylated with different side chains to produce specific types of penicillins. The acylation process involves reacting 6-APA with an appropriate acid chloride or acid anhydride in the presence of a suitable solvent and a catalyst. This step introduces the side chain that determines the characteristics and effectiveness of the penicillin produced.
3. Purification: After the acylation reaction, the mixture is purified to isolate the desired penicillin compound. Purification typically involves techniques such as crystallization, filtration, and chromatography to remove impurities and obtain a highly pure form of penicillin.
4. Fermentation: Once the penicillin compound is purified, it is used as a substrate for microbial fermentation. The antibiotic is naturally produced by certain species of fungi, most notably Penicillium chrysogenum. Large-scale fermentation is carried out in a controlled environment using specially designed fermentation vessels. The penicillin-producing fungi are grown in a nutrient-rich medium, and under suitable conditions of temperature, pH, and oxygen supply, they produce penicillin through metabolic processes.
5. Extraction and Isolation: After the fermentation process, the penicillin produced by the fungi is extracted from the fermentation broth. This is typically done by adding an organic solvent that selectively extracts the penicillin compound. The solvent is then separated from the aqueous phase containing the fungal biomass and other components.
6. Purification and Formulation: The extracted antibiotic is further purified through various techniques like solvent extraction, filtration, and crystallization. This step removes any remaining impurities and isolates the penicillin in its final pure form. The purified penicillin is then formulated into different dosage forms, such as tablets, capsules, or injectables, depending on its intended use.

Costing A Penicillin Process

A number of factors affect the cost of penicillin production. The cost of producing Penicillin G (benzylpenicillin) for example via fermentation can vary significantly based on factors such as production scale, geographic location, raw material costs, and operational efficiencies. Over the years, the capital cost of fermentation has changed because the age of the facility including the fermenter itself changes over time. Many large-scale facilities are over 20 years old now and these fixed charges are reduced significantly unless rebuilding is required (Swartz, 1979). While specific per-kilogram production costs are not readily available in any of the academic sources, we can glean some insights from what data is available.

It’s important to note that the synthesis of penicillin involves several variations and modifications based on the specific type of penicillin being produced. Additionally, advances in biotechnology have allowed for genetic engineering techniques to enhance the production of penicillin by optimizing the fungal strains used in fermentation and improving the overall yield of the process.

Market Pricing and Production Costs

• Market Price: As of late 2024, the price of Penicillin G Sodium in China reached approximately USD 46,000 per metric ton (or USD 46 per kilogram), influenced by supply constraints and increased demand.

Production Costs: While exact figures are not specified, the production cost of Penicillin G is influenced by several factors such as:

• Raw Materials: Costs for substrates like glucose, corn steep liquor, and phenylacetic acid.

• Utilities: Energy consumption for fermentation and downstream processing.

• Labour and Overheads: Operational labour, maintenance, and quality control.

• Capital Expenditures: Investment in fermentation equipment and facility infrastructure.​

Capital Investment Considerations

• Plant Setup Costs: Establishing a Penicillin G production facility with an annual capacity of 625 tonnes may require an investment ranging from USD 5 million to USD 52 million, depending on factors like location, technology, and scale. ​

• Operational Factors: The fermentation process typically spans 120 to 200 hours, with additional time allocated for downstream processing.

Market Dynamics and Challenges

• Pricing Pressures: Historical data indicates that Penicillin G prices have experienced volatility. For instance, in 2004, prices dropped to USD 6 per billion units, leading some manufacturers to reconsider their involvement in the market due to unviable profit margins. ​

• Supply and Demand: Factors such as global demand, raw material availability, and geopolitical events can significantly impact both production costs and market prices.​

While exact production costs per kilogram of Penicillin G are not specified in the available sources, market prices as of late 2024 suggest a selling price of approximately USD 46 per kilogram. Producers must consider various factors, including raw material costs, operational expenses, and capital investments, to determine profitability. Given the complexities and market dynamics, it’s essential for manufacturers to conduct detailed feasibility studies tailored to their specific circumstances.

References

Elander, R. P. (2003). Industrial production of β-lactam antibiotics. Applied Microbiology and Biotechnology, 61(5), pp. 385-392.

Swartz, R. W. (1979). The use of economic analysis of penicillin G manufacturing costs in establishing priorities for fermentation process improvement. In Annual Reports on Fermentation Processes (Vol. 3, pp. 75-110). Elsevier