Fermentation in the pharmaceutical industry

What are fermented drugs?

Fermented drugs, or biopharmaceuticals or biologics, are pharmaceuticals, which are synthesized by fermenting live organisms such as bacteria, yeast, or mammalian cells. The genetic modification of these organisms enables the production of targeted medicinal substances such as proteins, hormones, antibodies, and enzymes. The fermentation method facilitates the mass synthesis of highly intricate molecular compounds, which are frequently unattainable by chemical synthesis.

Fermentation Strategies for Production of Pharmaceutical Terpenoids. (Carsanba E., et al., 2021)

Classification of fermented drugs

Fermentation drugs, also known as biopharmaceuticals or biologics, can be classified based on various criteria, including the type of molecule produced, the therapeutic application, the production organism, and the fermentation process used.

Proteins and Peptides: Insulin, growth hormone, and erythropoietin are examples of peptide hormones. Illustrations: Humulin (insulin) and Genotropin (growth hormone). Utilised in enzyme replacement treatments for metabolic diseases. Particular examples are Alglucosidase alfa for Pompe disease and Pancrelipase for pancreatic insufficiency. Key small proteins involved in cellular signaling, frequently employed in cancer treatment or immunological regulation. Key examples are interferons and interleukins.

Nucleic Acids: Among them are DNA or RNA molecules employed for the treatment of genetic diseases by rectifying faulty genes. Illustration: Onasemnogene abeparvovec (Zolgensma) used to treat spinal muscular atrophy.

Antibiotics: They are synthesized by microorganisms during the process of fermentation. Illustrations: Penicillin, Streptomycin.

Vaccines: Recombinant protein vaccines derived from the fermentation of cells selectively designed to generate viral or bacterial proteins. Illustration: Vaccination against Hepatitis B. The production of live attenuated vaccines involves the fermentation of a weakened version of the pathogen. Example: Vaccination against measles, mumps, and rubella (MMR). Inactivated vaccines are manufactured by fermenting and then rendering the harmful microorganism inactive. Illustration: Inactivated polio vaccine (IPV).

Small molecules: Terpenoids manufacturing has utilized batch, fed-batch, and continuous fermentation processing methods.

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Importance of fermented drugs

Large-scale production: The scaling up of fermentation methods enables the production of substantial volumes of biopharmaceuticals, therefore satisfying the worldwide need for vital medications. Especially crucial for pharmaceuticals used in the treatment of long-term illnesses, such as insulin for diabetes or monoclonal antibodies for cancer. Industrial-scale fermentation decreases the expenses associated with pharmaceutical manufacturing, therefore increasing the availability of sophisticated treatments to patients on a global scale. The ongoing advancements in fermentation technology have significantly improved the efficiency and productivity of these processes, hence further reducing manufacturing costs.

Personalized medicine: Development of new kinds of pharmaceuticals, including monoclonal antibodies, gene therapies, and RNA-based therapeutics, has been made possible via fermentation. Previously untreatable or difficult to manage conditions, such as certain malignancies, genetic abnormalities, and autoimmune diseases, have been revolutionized by these breakthroughs. Technological advancements in fermentation enable the development of customized biologics that are specifically designed for particular patient profiles, therefore enhancing therapeutic results and reducing negative side effects.

Reduced toxicity: Multiple studies have demonstrated that fermentation modification or degradation of the toxic constituents of botanical medications leads to a decrease in their cytotoxicity when compared to non-fermented botanical medications. Toxic macromolecular compounds are frequently included in botanical medicines. Furthermore, once entering an organism, they generate irritants that have the potential to induce poisoning or other adverse reactions. The process of fermentation has the potential to mitigate the negative impacts and toxicity of botanical medicines that include cytotoxic substances, including heavy metals, poisonous glycosides, and toxic proteins. Despite its promise as a preventative and therapeutic agent for several illnesses, aconitine poses the danger of ventricular tachyarrhythmias and cardiac arrest, which can be lethal. Therefore, fermentation with probiotics can efficiently mitigate this issue. Huafeng Dan Yaomu has aconitine as its primary component and is used for the treatment of hemiplegia, epilepsy, and facial paralysis. The manufacturing process of Huafeng Dan Yaomu involves alcohol fermentation. The levels of the poisonous alkaloids aconite, neoaconitine, and hypoaconitine declined progressively during the fermentation process. Simultaneously, the less lethal benzoylneaconitine and benzoyl hypaconitine exhibited lesser toxicity.

Increased efficacy: Most active ingredients of botanical drugs are contained within the cell walls. These dense and hard cell walls act as barriers, preventing the active ingredients from easily leaching out and being absorbed by the body. Microorganisms play a crucial role in the extraction of active ingredients. They target different cell wall components, secrete various extracellular enzymes, and break down the tight structure of the cell. This process enlarges the gaps between the cells, allowing for better diffusion of substances in and out of the cells. Ultimately, this not only enhances the extraction rate of active ingredients but also improves their absorption and utilization. Traditional Chinese botanical drugs are usually administered orally, which results in low bioavailability of the active ingredients. However, during microbial fermentation, extracellular enzymes such as cellulase and pectinase produced by microorganisms enter the culture medium, causing the botanical cells to rupture and exposing the active ingredients. Additionally, fermentation is known to improve the absorption and bioavailability of botanical extracts by aiding in the production or conversion of active components into metabolites, or by producing low-molecular-weight substances such as aglycones from glycosides. Recent research has shown a direct correlation between the oral administration of probiotics and reduced urinary oxalate excretion in both rats and humans. This indicates that probiotic fermentation could be a promising approach to reduce the antinutritional factors of botanical drugs, making them more suitable for human consumption.

Production of new metabolites: Microbial fermentation of botanical pharmaceuticals is a technique used to alter the content of these medications, therefore enhancing the concentration of active components in MFH or generating novel active metabolites via the metabolic processes of microbes. Probiotic bacteria have the ability to synthesise precursor bioactive compounds derived from the active components of botanical medicines, interact with secondary metabolites of microorganisms to generate new metabolites, and influence the metabolism of probiotic bacteria to produce unique metabolites. Many bioactive compounds are present in minute quantities in plants, making the requirement for substantial amounts of useful botanical medicines quite inconvenient. Fermentation enhances the pharmacological characteristics of botanical medicines primarily by altering naturally extracted compounds such as isoflavones, saponins, phytosterols, and phenols, which have advantageous effects on health and prevention of diseases, in accordance with the principles of oriental medicine. Numerous bacterial and yeast strains are employed in the process of fermenting plant pharmaceuticals. Bacillus subtilis and Saccharomyces cerevisiae are the predominant strains employed. Bacillus subtilis fermentation of Panax notoginseng yields ginsenoside RH4, a novel bioactive compound. Fermentation of A. membranaceus with Bacillus subtilis leads to a significantly elevated polysaccharide concentration and an enhanced immunological impact. Bacterial fermentation has been suggested to not only produce beneficial degradation products of flavonoids but also modify their molecular structure. The aforementioned procedure encompasses the deglycosylation, sulfation, or methylation of flavonoids, therefore exerting an impact on their rate of absorption and hepatic metabolism. Absorption rates and total absorption levels can be enhanced by bacterial fermentation-induced modifications in flavonoid structures. This phenomenon might potentially facilitate an augmentation in the bioactivity and bioavailability of the active components, therefore yielding advantageous outcomes for bone health.

Reutilization of botanical residues: As residual products of extraction using water or ethanol, botanical medication residues retain around 30%–50% of the therapeutically active compounds. Phytochemical drug fermentation not only increases efficacy and detoxification, but also utilises residual medicinal residues as a culture substrate. This method not only tackles any environmental contamination problems of dregs, but also enhances the proteins and sugars included in them, so decreasing manufacturing expenses and maximizing the use of herb resources. Both natural environmental conditions and human activities have led to a decline in the quantity and quality of several widely utilized botanical compounds. To optimize the use of conventional botanical medicinal resources, it is crucial to minimize resource wastage. Determining and using appropriate substitutes for valuable and endangered botanical medicines can contribute to the preservation of herbal resources and the maintenance of ecological equilibrium, therefore facilitating the sustainable use of botanical medicinal resources.

Application advantages of fermented botanical drugs. (Luo X., et al., 2024)

Use of fermentative medicinal products

Fermentative medicinal products, derived from the fermentation process involving microorganisms like bacteria, yeast, and fungi, are widely used in modern medicine. These products have a broad range of applications across various therapeutic areas due to their ability to produce complex, biologically active compounds.

Treatment of chronic diseases: One of the most well-known fermentative medicinal products is recombinant insulin. Produced using genetically engineered bacteria or yeast, this insulin is crucial for managing blood glucose levels in people with diabetes. It has largely replaced animal-derived insulin due to its consistency, purity, and reduced risk of allergic reactions.

For cancers: Using fermentation in mammalian cell cultures, monoclonal antibodies are generated to selectively target cancer cells while sparing healthy cells, therefore enabling the treatment of several types of cancer. Notable examples are Trastuzumab (Herceptin) used to treat breast cancer and Rituximab used to treat non-Hodgkin lymphoma.

Infectious disease control: A multitude of antibiotics are synthesised via fermentation methods. Penicillin, an early member of the antibiotic family, is produced by the process of fermentation of the Penicillium organism. Additional antibiotics, such as Streptomycin and Erythromycin, are synthesised by bacterial fermentation and play a crucial role in the treatment of bacterial infections.

References

1. Carsanba E., et al., Fermentation strategies for production of pharmaceutical terpenoids in engineered yeast, Pharmaceuticals, 2021, 14(4): 295.
2. Luo X., et al., Fermentation: improvement of pharmacological effects and applications of botanical drugs, Frontiers in Pharmacology, 2024, 15: 1430238.