In this 3-part series, chemistry PhD student and GoBio super-intern Melissa Stewart explains what we mean by biomanufacturing, shows what we’ve learnt in biomanufacturing’s long history, and offers some ideas of how we can capture the opportunities ahead.
Firstly, what are we talking about?
Biomanufacturing is the use of natural or engineered biological systems as a means of making commercial products. This harnessing of living things allows us to benefit from the power and complexity of nature, which every day produces things that often cannot be produced (effectively, or at all) using synthetic, or non-bio, chemical processes.
What jobs link to biomanufacturing?
Much of the interest in biomanufacturing today relates to medical products, which has been undeniably impactful in areas such as regenerative medicine and advanced therapies (1), but the impact of biomanufacturing spreads far wider and further into history. Before the discovery of genetic engineering technologies, the biomanufacturers of the past used natural cultures of microorganisms to produce food products like wines, cheeses and breads. Agriculture and livestock farming are also biomanufacturing at its most fundamental, producing the food, materials, fuels and other feedstocks of society.
Biomanufacturing today is very much an interdisciplinary field, involving elements of chemical and mechanical engineering, robotics, software, biochemistry, and microbiology, and also taking in new and exciting fields such as metabolic engineering, functional genomic and synthetic biology. Taking new techniques to commercial scale calls for industrial design expertise to develop and automate existing processes, allow easy integration into the target industry systems, and provide real-time analysis of manufacturing workflows.
Choosing a system
Before you set up your biomanufacturing process, however, there are many factors to consider. Choosing the best biological system to make your chosen product is one of the most crucial. Each system comes with its own pros and cons in terms of maintenance costs, capital expenditure and time allowance, as well as ease of integration, modification extraction from the organism. Unicellular hosts are available in the form of microbes, cultured mammalian, plant or insect cells, and more recently, in microalgae (2). Alternatively, an approach known as “pharming” uses whole organism systems, such as engineered plants and animals.(3)
Stages in the process
Most types of biomanufacturing involves three main steps: controlled organism growth, the transformation of raw materials into product, and separation of the product from the organism.
Growth will often require the use of a bioreactor in processes using single-cell organisms (in terms of transgenic species, the animal or plant itself can be considered a “living bioreactor”). The function of the bioreactor is to control the active organism’s growth, and in turn the desired metabolic reaction. To maximise yield of these reactions, biochemical engineers must optimise parameters such as pH, temperature, substrate availability such as sugars, proteins and fats, as well as the availability of water, salts, vitamins and oxygen (or lack of, in anaerobic fermentation). Industrial design of mixing, agitator sterilization, product-induced feedback regulation processes and scale-up modelling must also be considered. Several bioreactor production models have allowed for higher yield and efficiency, such as continuous stirred tank, airlift, packed bed, photo- and membrane-based bioreactors all have pros and cons in terms of nutrient input, by-product extraction and cell support. Therefore, the design of the bioreactor will depend heavily on the chosen organism and expression system.(4)
After production has taken place, there is usually a need for extraction, purification and clarification (though this is not always the case: a popular example being the use banana vaccines for which the whole organism is suitable for consumption).
In transgenic organisms, extraction is usually straightforward: popular production methods uses selective expression approaches so the desired product can be found in the milk, urine, blood, or eggs of the organism. In cell-based processes, desired products may remain in the cell or be excreted into the medium they are grown in. Separation in this case often involves a series of filtration, centrifugation, chromatography and sterilization steps to take out used media, bulk contaminants and other byproducts, as well as inactivate any viruses used. Depending on the nature of the product, it is then ready for downstream processing or commercial sale (5).
The wider environment
It should come as no surprise that biomanufacturing processes is heavily regulated globally, due to its use of genetically modified organisms; all work in the EU currently must comply with EU GMO regulations. The process by which products are made are incorporated into decisions for product approval and the acquisition of IP protection. In the face of Brexit, sales and distributions will still have to be compliant, with post-Brexit medical regulations most likely to remain aligned with the European system. Despite these restrictions, increasing pressure to drive down costs, speed up processing and increase efficiency will drive innovation in this rapidly evolving industry.
- L Sherley J. Accelerating Progress in Regenerative Medicine by Advancing Distributed Stem Cell-based Normal Human Cell Biomanufacturing. Pharm Anal Acta [Internet]. 2014;5(2). Available from: https://www.omicsonline.org/open-access/accelerating-progress-in-regenerative-medicine-by-advancing-distributed-stem-cellbased-normal-human-cell-biomanufacturing-2153-2435.1000286.php?aid=23983
- Adrio JL, Demain AL. Recombinant organisms for production of industrial products. Bioeng Bugs. 2010;1(2):116–31.
- Maksimenko OG, Deykin a V, Khodarovich YM, Georgiev PG. Use of transgenic animals in biotechnology: prospects and problems. Acta Naturae [Internet]. 2013;5(1):33–46. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3612824&tool=pmcentrez&rendertype=abstract
- Spier MR, Vandenberghe LPDS, Medeiros ABP, Soccol CR. Application of different types of bioreactors in bioprocesses [Internet]. Bioreactors: Design, Properties and Applications. 2011. 53-87 p. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-84892132755&partnerID=40&md5=5862effd1c5e7b6a71dec75ef24e1b81
- Collaborative NBC&. Downstream Processing. In: introduction to biomanufacturing. 2012. p. 424–58.
Image credits (from top): CC BY 2.0, Connor Lawless; CC BY 2.0, PEO ACWA