Biomanufacturing is a manufacturing process that uses biological systems such as living microorganisms, cultured cells, tissues, enzymes, or in vitro synthetic systems to produce biomolecules used in agriculture, food, material, energy, and pharmaceutical industries. Products of biomanufacturing are isolated from sources such as blood, microbes, animal cells, and plant cells grown using specialized equipment or environments. Genetic engineering, metabolic engineering, synthetic biology, and protein engineering methods may be used to modify cells or enzymes to enhance either the production process or the final product.
While primary metabolites are essential for growth, development, or reproduction of an organism, secondary metabolites often play a role in defense against other organisms and are produced by modification of primary metabolite synthases. Secondary metabolites are produced during the end or near the stationary phase of growth. Examples of primary metabolites include ethanol, lactic acid, certain amino acids and citric acid, an ingredient commonly used in food production, pharmaceuticals, and cosmetics. The antibiotic penicillin is a secondary metabolite produced by the fungus Penicillum.
Enzymes are a type of protein used in biocatalysis, a chemical process where enzymes perform reactions or speed up reactions between organic components. Such enzymes are used in the food, textile, and detergent industries. Examples include subtilisin in detergent and alpha-amylase for starch hydrolysis. Biocatalysis was initially based on natural enzymes; since the 1980s, protein engineering technologies have also been used to expand the substrate range of enzymes or modify them in other ways.
Recombinant DNA technology enabled the biomanufacturing of large-size proteins such as protein-based drugs and enzymes used in biocatalysis since around the 1980s. Recombinant proteins such as insulin are produced in E. coli bacteria or yeast. Certain mammalian proteins need to be produced in mammalian cell culture because organisms can differ in their modifications to proteins, such as the addition of carbohydrates, known as glycosylation.
Rather than producing substances in live whole-cells, another approach is to use in vitro or cell-free reactions with isolated cellular components and machinery. Cell-free biology, as of 2020, is an emerging technology that has applications in research and point-of-care manufacturing of macromolecular and small molecule products. In the research setting, cell-free protein synthesis has been used for in vitro protein transcription and translation since the 1950s. Cell-free systems include crude cell lysates and systems reconstituted with factors essential for protein synthesis. Cell-free protein synthesis (CFPS) has been used for post-translational modification to proteins and for production of other specialized proteins, such as non-natural amino acids. An example of point-of-care manufacturing of a therapeutic protein is cecropin B, an antimicrobial peptide produced at a clinically-relevant dose in a few hours with a microfluidic device.
The bioprocesses used in biomanufacturing are divided into upstream and downstream parts. For a therapeutic protein, the downstream processes include removal of host cells, debris, and impurities to isolate the protein of interest. Critical process parameters (CPPs) and critical quality attributes (CQAs) will be assessed at multiple stages. A successful downstream process depends on the consistency of the upstream material from which the therapeutic protein is harvested. The upstream process may involve raw materials, product titers, cell concentration, and cell viability.
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June 16, 2020
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