Penicillin was discovered by Alexander Fleming in 1929. However, before 1941 it couldn’t produce on large scales. Between 1929 and 1941 Fleming, Florey and Chain conducted their research about penicillin, they used it as a medicine to cure eye infections and in clinical trials which is conducted with mice (van der Beek & Roels, 1984). However, penicillin became famous during World War II. In World War II, penicillin was used to cure soldiers and became a scale-up production. And in 1945, Fleming, Florey and Chain get the Nobel prize because of penicillin (Gaynes, 2017).

Figure 1: Penicillin G biosynthesis from cysteine, valine, æ-aminoadipic acid (van der Beek & Roels, 1984).

Figure 1: Penicillin G biosynthesis from cysteine, valine, æ-aminoadipic acid (van der Beek & Roels, 1984).

Over time, different types of penicillin started to be produced. In the first stage, scientists came up with penicillin G or V, after strain technology developments scientists achieved penicillin K which is highly productive than penicillin G (van der Beek & Roels, 1984). Also, semisynthetic penicillin showed in the market. These penicillins are produced from the purified penicillin G or V by removing some side chains, such as the phenylacetic acid side chain (van der Beek & Roels, 1984). Also, adding new side chains are another option for creating semisynthetic penicillin (van der Beek & Roels, 1984).

Figure 2: Semisynthetic penicillin (van der Beek & Roels, 1984).

Figure 2: Semisynthetic penicillin (van der Beek & Roels, 1984).

α-aminoadipic acid is a product that is shown in the intermediate phase of lysine synthesis which is come together with cysteine and valine to form tripeptide (figure 1) (van der Beek & Roels, 1984). After is penicillin N formation α-aminoadipyl moiety (α-AAA) is exchanged with phenylacetic acid or phenoxy acetic acid and respectively result in penicillin G or Penicillin V (figure 1) (van der Beek & Roels, 1984). Synthetic penicillins are listed in figure 2 (van der Beek & Roels, 1984). To achieve penicillin exchanging elements are added into the fermentation system after cell growth occurred and they are known as a precursor (Shuler, 2002a).

Penicillin produces by using the fermentation process (Shuler, 2002b). However, there are several problems in the producing such as production volume and purification of the product while penicillin is very fragile. By developing the fields of both industry and genetics these problems are solved by changing the media and the strain. Contamination, heat and supplying oxygen were other problems seen in the manufacturing of penicillin. To overcome this problem bioreactors are designed. So, penicillin production volume has gone from 0,001 g/l to 50 g/l (Shuler, 2002b).

In general, penicillin is a widely used antibiotic for different diseases. It is used for almost 90 years. It is started scale-up production from World War II by Pfizer, Merck, USA, Glaxo, etc (van der Beek & Roels, 1984).

Figure 3: Penicillin production (Shuler, 2002b).

Figure 3: Penicillin production (Shuler, 2002b).

The schematic production of penicillin is shown in figure 3. To produce penicillin on large scale, the fermentation process is used in industry. While the general system is remaining, some additional components are shown due to the used strain of penicillium (Andersen & Frisvad, 1994). For example, Penicillium chrysogenum, P.nalgiovense, P.turbatum and P.cineascens (Andersen & Frisvad, 1994). Penicillium chrysogenum is a widely used cell in the bioprocess of penicillin. For the culture media corn steep liquor is used which contains CaCO3, salts, and lactose as a carbon source. In 1981, Koning et.al used two different stains (P.chrysogenum H613 and H617) to observe penicillin production. For P.chrysogenum H613 raw materials of the system is Lactose monohydrate (5.5%), corn steep liquor (5.0%), (NH4)2HPO4 (0.7%), CuCO2 (1%) and MgSO47H2O (0.3%) also, Sodium phenylacetate (0.05%) is added after 24h each 12h (Knig et al., 1981). For P.chrysogenum H617 raw materials of the system is Lactose monohydrate (10.0%), sucrose (2.0%), pharma media (4.0%), CaCO3 (0.75%), Na2S2O35H2O (0.75%) and potassium phenylacetate (0.6%) (Knig et al., 1981). So, the H613 strain produces penicillin G by using Fed-batch culture and H617 produce penicillin V by using batch culture (Knig et al., 1981). Also, in the research, they used two different reactors respectively Loop reactor and Standard stirrer Biostat 5 (Knig et al., 1981).

Batch culture and Feed Batch culture are like each other. While in batch culture all raw materials are added in the beginning and there is no addition observed after cultivation start, in feed batch culture general raw materials are added in the beginning but precursors and limiting nutrients can be added after cultivation start to control the reaction rate (Srivastava & Gupta, 2011).

In conclusion, used reactors and culture systems can change respectively the used strain and expected result. However, the general system is based on fermentation.

The production cost of penicillin is decreased by the time and developments in the industry. In 1982 it was calculated 19 dollars per kilogram, in 2000 15 dollars per kilogram and in nowadays it is estimated 1.3 cents per 100.000 units (Shuler, 2002a).

Penicillin marketing size will be 2.9 billion dollars in 2025 (IndustryARC, n.d.). Pfizer, Inc., GlaxoSmithKline Plc, Johnson & Johnson, Lonza AG, Novartis Healthcare, Merck & Co, Dr Reddy Laboratories, Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc., Eli Lilly are the main industries that take place in penicillin productions (IndustryARC, n.d.).

Figure 4: Antibiotics market size; penicillin is the second-biggest market in antibiotics (Grandviewresearch, n.d.).

Figure 4: Antibiotics market size; penicillin is the second-biggest market in antibiotics (Grandviewresearch, n.d.).

In the manufacturing scale of production main goal is to lower the cost and higher value of the product while the product is highly purified. In penicillin production, in the beginning, the cost is high while the production size is small. In time, the production cost of penicillin is decreased, and the production size of penicillin is increased by development in the culturing, strains and fermentation bioprocesses. While penicillin is a secondary metabolite and produced in the stationary phase of culturing, fed-batch cultures are more suitable for the higher product size. Also, penicillin is an antibiotic to increase the bioprocess efficiency moulds can be used in downstream processing. In this way, waste products are used, and high efficiency can be obtainable. To decrease the cost, the main step is using the best strain. If the strain is chosen and cultured correctly, the cost-product relation has achieved the highest value. Most competitive strain means, less additional precursor and purification methods are needed. Each precursor to increase production and purification method is to increase the cost of the bioprocess.

References:

  1. Andersen, J., & Frisvad, J. C. (1994). Penicillin production by Penicillium nalgiovense. Letters in Applied Microbiology, 19(6). https://doi.org/10.1111/j.1472-765X.1994.tb00988.
  2. Gaynes, (2017). The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use. Emerging Infectious Diseases, 23(5). https://doi.org/10.3201/eid2305.161556
  3. Grandviewresearch. (n.d.). Retrieved June 27, 2021, from https://www.grandviewresearch.com/industry-analysis/antibiotic-market
  4. IndustryARC. (n.d.). Retrieved June 27, 2021, from https://www.industryarc.com/Report/15050/penicillin-streptomycin-market.html
  5. Knig, , Seewald, Ch., & Schgerl, K. (1981). Process engineering investigations of penicillin production. European Journal of Applied Microbiology and Biotechnology, 12(4). https://doi.org/10.1007/BF00499488
  6. Shuler, L. (2002a). BIOPROCESS ENGINEERING BASIC CONCEPTS (P. Guerrieri & B. Goodwin, Eds.; Second Edition). Prentice-Hall PTR.
  7. Shuler, L. (2002b). BIOPROCESS ENGINEERING BASIC CONCEPTS (B. Goodwin & P. Guerrieri, Eds.; Second Edition). Prentice-Hall PTR.
  8. Srivastava, K., & Gupta, S. (2011). Fed-Batch Fermentation – Design Strategies. In Comprehensive Biotechnology. Elsevier. https://doi.org/10.1016/B978-0-08-088504-9.00112-4
  9. van der Beek, P., & Roels, J. A. (1984). Penicillin production: biotechnology at its best. Antonie van Leeuwenhoek, 50(5–6). https://doi.org/10.1007/BF02386230

Inspector: Eylül ASLAN

No responses yet

Leave a Reply

Your email address will not be published. Required fields are marked *