The original definition of fermentation is ‘the anaerobic conversion of sugar to carbon dioxide and alcohol by yeast’, and most of us will have had first-hand experience of the fermentation process through its most famous and popular use - the brewing of beer.
The original definition of fermentation is ‘the anaerobic conversion of sugar to carbon dioxide and alcohol by yeast’, and most of us will have had first-hand experience of the fermentation process through its most famous and popular use - the brewing of beer.
The original definition of fermentation is ‘the anaerobic conversion of sugar to carbon dioxide and alcohol by yeast’, and most of us will have had first-hand experience of the fermentation process through its most famous and popular use - the brewing of beer.
Through Microbial Fermentation Silvian Shama, Ph.D., cGMP Fermentation Development Manager
Overview Microbial Fermentation–an Introduction
The original definition of fermentation is ‘the anaerobic Microbial fermentation is the basis for the production conversion of sugar to carbon dioxide and alcohol of a wide range of pharmaceutical products, targeting by yeast’, and most of us will have had first-hand practically any medical indication. Examples range experience of the fermentation process through its from anti cancer cytotoxic drugs and vaccines, most famous and popular use - the brewing of beer. anti infectious disease antibiotics and vaccines, to hormonal disorder therapy and many other indications. This original definition has been expanded over time to ‘the conversion of organic materials into relatively Natural biosynthesis of endogenous molecules simple substances by microorganisms- essentially involves specific multi-step complex routes, some efficient, flexible bio factories.’ During their growth of which can be manipulated for the biosynthesis of and lifespan microorganisms build a wide range of foreign molecules. Microorganisms may be genetically different molecules types required for viability and modified (recombinant technology) or metabolically multiplication; adaptation to changing environment; engineered by substantial alteration of their stressful conditions and defence against hostile, endogenous routes. competitive microbial threats. The key elements of fermentation development are Microorganisms that are typically used within the strain selection and optimization, media and process pharmaceutical industry include: prokaryotes such development, and finally, scale-up to maximize as Bacteria (e.g. Escherichia coli, Staphylococcus productivity. Downstream processing utilizes various aureus) and Streptomycetes (e.g. Streptomyces spp, technologies for extracting, concentrating and purifying Actinomyces spp), eukaryotes such as Filamentous the product from a dilute fermentation broth. Fungi (e.g., Nigrospora spp, Aspergillus spp,) and Yeast (e.g. Saccharomyces cereviciae, Pichia pastoris). Fermentation derived product diversity- the recovery and selective purification of the specific desired The molecules that are of primary interest to the product out of the whole molecular repertoire- pharmaceutical industry are small molecules such makes fermentation technology a multi- disciplinary as short peptides and low molecular weight organic methodology encompassing microbiology, organic molecules, larger molecules including proteins and chemistry, biochemistry and molecular biology. nucleic acids (DNA, RNA) and macromolecules such as lipids and carbohydrate polymers, plus When fermenting volumes larger than 10L, necessary various combinations of product types, for example biosafety measures are taken, especially when Risk lipopolysaccharides, lipopeptides, peptidoglycan. Group 2 (RG2) pathogens are used. These include Biosafety Level 2 Large Scale (BSL2-LS) containment Any of these product types could potentially serve as facility design and special operational procedures. a drug’s Active Pharmaceutical Ingredient (API). As these products can be toxic and hazardous, their recovery and purification require adequate chemical/ biochemical facilities and equipment including isolators for handling High-Potent APIs (HPAPIs).
Under cGMP fermentation procedures, quality is
built into the entire process ensuring that regulatory agencies requirements are met in terms of safety, product identity, quality and purity.
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Why Choose Microbial Fermentation?
Fermentation is the only route to chemical APIs that A further approach is to reduce the protein expressed relies solely on microorganisms with no equivalent in to the minimal effective domain (Nanobodies/ other processes. Examples of its applications include Peptibodies in the case of antibodies). The principal mammalian cells, antibiotics/secondary metabolites advantages of fermentation over the mammalian made in fungi serving as anti cancer or anti infectious system, as illustrated in the table below, are time and agents, or lipid A made in gram negative bacteria yield which ultimately translate to cost. serving as adjuvants. Microbial Mammalian These organic molecules can be obtained through Fermentation Culture multi-step synthesis from their building blocks. Generation 20 minutes-hours hours-days However, organic molecules are very complex in time nature, potentially encompassing structures such Growth length 1-4 days 10-14 days as chiral centers, large stereospecific rings or unique Proteins conjugated double bond systems. Going down Secondary metabolites Proteins Product types the synthetic route not only requires significant Cell wall components development but is time consuming and entails DNA
higher costs than the fermentation option. Crude protein
1-15g/L 1-5g/L titer The semi-synthetic approach draws upon the Media cost low high advantages of fermentation in the generation of new Growth low high drugs. Natural molecules are produced through sensitivity fermentation then modified synthetically, reducing Post Some available toxicity, increasing potency and selectivity, and translational Yes in yeast overcoming bacterial resistance to traditional modifications antibiotics. Therapeutic proteins requiring modification, for Fermentation might also be the sole source for example glycosilation of antibodies were, until recently, natural therapeutic proteins exclusively expressed in expressed in mammalian cell cultures. Driven by microbial systems. Proteins are complex molecules cost considerations, scientists looked to express of mid to high molecular weight. Their functionality glycosilated therapeutic proteins in microbial systems, and stability largely depend upon their secondary and resulting in a novel approach – Glycoengineering- tertiary structure, as well as various post-translational whereby the endogenous glycosilation pathway in high modifications, mainly glycosilation. The synthetic yield expression recombinant yeast was modified. The option is limited to very short peptides. modified pathway reproduced the human pathway therefore allowing the expression of humanized Recombinant technology enables the expression antibody fragments. of foreign gene encoding for therapeutic proteins in microbial systems, including those from human Conclusion source. Using microbial fermentation is advantageous Although not a new technology, microbial fermentation for expression of proteins that do not require continues to evolve and is now frequently the preferred post-translational modifications as microbial systems, production method for chemical compounds and such as E. coli, lack post-translational mechanics. therapeutic proteins, offering an optimal economic route, which allows pharmaceutical companies to shorten production processes and time to market.
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