What Role does Fermentation Play in the Pharmaceutical Industry?

By Arzoo PuriReviewed by Lily Ramsey, LLM

Pharmaceutical manufacturing using industrial fermentation techniques is becoming increasingly prevalent. This article discusses the role of fermentation in the pharmaceutical industry.

​​​​​​​Image Credit: Gorodenkoff/Shutterstock.com

Introduction to Fermentation in Pharmaceutical Manufacturing

Fermentation is a method in which microorganisms or mammalian cells produce a variety of biomaterials, drugs, and metabolites in a regulated culture environment.¹

Fermentation adheres to good manufacturing practices (GMP) guidelines for high-quality biopharmaceutical drugs. It involves both downstream and upstream processes.²

It can begin with either genetically engineered or untreated cells such as fungi, bacteria, mammals, or plants. Typically, large-scale fermentation activities are carried out in single-use or stainless steel bioreactors.²

The Process of Fermentation and Its Importance

The fermentation process usually employs bacteria, fungi, or yeast to generate a specific therapeutic compound or intermediate, which is subsequently extracted and refined to make the final pharmaceutical drug. It is a low-cost and efficient approach commonly employed in the pharmaceutical sector.³

The "upstream process" refers to the microbial growth needed for producing pharmaceuticals or other biomolecules. It includes a series of events such as cell line and media selection, growth parameters, and cell growth condition optimization to attain pharmaceutical production.⁴

The primary purpose of the upstream fermentation process is to convert substrates into desirable metabolic products.⁴

Downstream fermentation processing includes purification methods that separate a biological product from cell culture medium by eliminating contaminants such as DNA, host cell proteins, and process-associated pollutants. It consists of three stages: initial recovery, purification, and polishing, which include centrifugation, filtration, and chromatography.⁴

Fermentation is vital in the production of new-generation products such as antiviral medicines, monoclonal antibodies and therapeutic recombinant proteins. ¹

Fermentation techniques can boost productivity and lower production costs by optimizing physicochemical conditions and improving media composition. ⁵

It also provides scalability, allowing for large-scale manufacturing of pharmaceutical drugs with uniform quality.⁶

Applications of Fermentation in Drug Production

Fermentation finds diverse applications in drug production across various therapeutic areas. Examples include anticancer cytotoxic medications and vaccinations, anti-infectious disease antibiotics and hormonal disorder therapy drugs.⁷

Antibiotics: Molds produce the vast majority of commercially available antibiotics. However, gram-positive bacteria secrete certain antibiotic chemicals that have a bacteriostatic impact on gram-negative bacteria. The first marketable antibiotic was 'Penicillin'.¹

Vaisala is a biotech company that commercializes Penicillin, an antibiotic manufactured through fermentation. The Penicillium chrysogenum strain is grown in huge vessels using all of the necessary carbon and energy sources.⁸

Recombinant Proteins: Recombinant proteins are currently widely used to treat a variety of human disorders, including cancer and infertility. For instance, Tumour Necrosis Factor alpha (TNFa) receptor fusion proteins against rheumatoid arthritis and a range of monoclonal antibodies targeting cancer.¹

There are various stages to consider, ranging from fabrication to application. This necessitates a genetically modified organism, effective fermentation processes, and a mode of transport into host cells. E.coli has been widely employed to produce recombinant proteins throughout the last few decades.¹

Antivirals: Antiviral drugs are administered for the treatment of viral infections. Tamiflu, a widely used oral antiviral medication for the treatment and preventive measures against influenza, is produced using complex azide chemistry from shikimic acid, a fermentation product.¹

Shikimic acid can be generated via microbial fermentation, chemical synthesis, and plant extracts. ⁹

Innovations in Fermentation Technology

Fermentation technology advancements have accelerated the pharmaceutical sector's growth, improving process efficiency, output, and quality of the product.

One major advance is the creation of innovative bioreactor models and control systems, which allow for precise management of fermentation variables (parameters) to maximize yield and lower production costs.

GMI’s winpact fermentator is a commercial example of fermentation technology advancements, featuring modular design for customization, controlled precision over critical parameters, scalability from laboratory to industrial manufacturing, and extensive storage of data for precise documentation and analysis.^10,11

The modular architecture enables biotech companies to create fermenters based on their individual project requirements, enabling flexibility and expansion. Advanced control systems enable ideal fermentation conditions, which are critical for producing high-quality goods at an industrial scale.¹⁰

Another innovative work used fermentation techniques to increase the yield of gentamicin and its analog, gentamicin C1a. Gentamicin concentrations (titers) increased by 11.5% with improved inorganic and organic salt conditions, resulting in a higher C1a ratio.¹²

Label-free proteomics showed that calcium chloride and sodium citrate impacted critical gentamicin production pathways.¹²

This research paves the way for co-producing gentamicin C1a and gentamicin, potentially advancing antibiotic production via fermentation processes.    

The Future of Fermentation in the Pharmaceutical Sector​​​​​​​

Fermentation is utilized commercially to produce drugs needed in the fabrication of diagnostic tests, medical devices and drug delivery vehicles. ¹

Stem cell therapy, which is currently in its early phases, might need fermentation technology in the near future to produce therapeutic cells on a massive scale to replace defective cells following surgical implantation.¹

Another possible field of research is the fermentation of  microspheres or biopolymers to create new medication delivery methods.¹

As pharmaceutical research improve, the need for innovative and adaptive fermentation technologies will only increase.¹¹

References

1. Rahman M. Medical Applications of Fermentation Technology. Adv Mater Res. 2013;810:127-157. doi:10.4028/WWW.SCIENTIFIC.NET/AMR.810.127
2. Fermentation in the Biopharmaceutical Industry | Eran Yona. https://eranyona.com/fermentation-in-the-biopharmaceutical-industry/. Accessed February 26, 2024.
3. Fermentation in the pharmaceutical industry. https://www.susupport.com/knowledge/fermentation/fermentation-pharmaceutical-industry-complete-guide. Accessed February 26, 2024.
4. Jozala AF, Geraldes DC, Tundisi LL, et al. Biopharmaceuticals from microorganisms: from production to purification. Brazilian J Microbiol. 2016;47(Suppl 1):51. doi:10.1016/J.BJM.2016.10.007
5. Carsanba E, Pintado M, Oliveira C. Fermentation Strategies for Production of Pharmaceutical Terpenoids in Engineered Yeast. Pharmaceuticals. 2021;14(4). doi:10.3390/PH14040295
6. Du YH, Wang MY, Yang LH, Tong LL, Guo DS, Ji XJ. Optimization and Scale-Up of Fermentation Processes Driven by Models. Bioengineering. 2022;9(9). doi:10.3390/BIOENGINEERING9090473
7. Production of pharmaceutical compounds through microbial fermentation. https://manufacturingchemist.com/production-of-pharmaceutical-compounds-through-microbial-fermentation-61614. Accessed February 26, 2024.
8. About us | Vaisala. https://www.vaisala.com/en/vaisala-company. Accessed February 26, 2024.
9. Tamiflu® (oseltamivir phosphate) | Prescription Flu Treatment. https://www.tamiflu.com/. Accessed February 26, 2024.
10. Winpact: Advancements and Innovations in Fermentation Technology | GMI - Trusted Laboratory Solutions. https://www.gmi-inc.com/winpact-advancements-and-innovations-in-fermentation-technology/. Accessed February 26, 2024.
11. About GMI | Global Medical Instrumentation, Inc. | Lab Equipment. https://www.gmi-inc.com/about-us/. Accessed February 26, 2024.
12. Yang P, Lin H, Wu X, Yin Y, Li J, Chen D. Proteomic Analysis of the Effect of CaCl2 and Sodium Citrate on Gentamicin Biosynthesis of Micromonospora echinospora SIPI-GM.01. Fermentation. 2023;9(12):997. doi:10.3390/FERMENTATION9120997/S1