Computational Life Sciences

# Breakdown of the History and Recent Rapid Development of Biomanufacturing

The future of biomanufacturing is bright. Read here to learn about history and recent developments in this emerging domestic industry.

Alexander Titus, PhD

December 9, 2022

Biomanufacturing is undergoing a true paradigm shift as the industry is fast moving from time-consuming, one-off manufacturing to streamlined and automated production with manufacturability designed into the process from the start.

While it is still early days, this development fundamentally changes the dynamics in a number of industries. Instead of asking “can this be done at all”, the question will now be “how can we best design a product early on to make it easily manufacturable in a biological at scale?”1

In this blog we’ll take you on a tour of biomanufacturing, what it is, how it developed and how companies need to adjust and foster new skills to succeed in this rapidly developing industry.

## What is Biomanufacturing?

The CDC defines biomanufacturing as “the use of biological systems that have been engineered, or that are used outside their natural context, to produce a product.” 2

These “biological systems” are generally microorganisms and cell cultures, including plant or animal cells, traditionally Chinese hamster ovary (CHO) cells.3,4 Typically, these cells have been genetically engineered to produce the molecule of interest at large quantities as the goal of biomanufacturing is not to produce small quantities sufficient for experimental purposes but to make commercially important products at scale.

In essence, biomanufacturing uses living cells as mini factories.

Companies use biomanufacturing for many different applications and industries. Here we highlight four industries that benefit significantly from biomanufacturing:

### Pharmaceutical Industry

The last decade has brought a shift to the type of products pharmaceutical companies develop. While small molecule drugs that can be chemically synthesized were the norm before, now large molecule drugs which are produced in living cells, such as therapeutic antibodies, recombinant proteins or recombinant nucleic acids, make up an increasing percentage of newly approved drugs.

The trend towards precision medicine, especially in the treatment of cancer, has also led to a boom of large molecule drugs, or biologics. An example are targeted therapies like trastuzumab (Herceptin) that find and kill cancer cells by homing in on specific molecular changes seen primarily in those cells. More recently immunotherapy, e.g. immune checkpoint inhibitors or adoptive cell therapy, utilize the patient’s immune system to fight cancer. 5, 6

### Examples of biomanufactured drugs

Here are some interesting examples of drugs made with biomanufacturing rather than chemical synthesis:

• First drug manufactured in a living system: Insulin, manufactured in E. Coli cells. The first recombinant insulin was approved in 1982
• First biologic manufactured in mammalian cells: Activase, a human tissue plasminogen activator, manufactured using Chinese hamster ovary (CHO) cells. Approved in 1986.
• Commercially most successful biologic: Humira (adalimumab), anti-inflammatory used to treat rheumatoid arthritis, plaque psoriasis and other diseases. Approved in 2002
• Drug manufactured in plant cells: Elelyso (taliglucerase alfa) for Gaucher disease, manufactured using carrot cells in culture. Approved in 2012

### Food & Agriculture

Biomanufacturing is used to produce amino acids, enzymes and protein supplements for the food and beverage industries. Enzymes such as amylase and lipase are critical for breadmaking where they break down complex sugars (amylase) or in the processing of fats and oils (lipase) 7,8.A new development is the use of biomanufacturing methods to grow cultured meat that can replace animal-derived products. 9

### Energy & Fuels

Microorganisms can be used to generate renewable fuels from a number of different biological substrates, e.g. they can easily transform carbohydrates into ethanol which can be used as fuel. 10

### Consumer products

Living cells, esp. bacteria have been used since the 1980s to manufacture enzymes that are utilized in everyday products such as laundry detergents, personal care and paper products, fabrics and many others.

## ‍A Short History of Biomanufacturing

Biomanufacturing has an interesting and very long history. Humans have used microorganisms for thousands of years to raise bread, make alcohol or cheese and to ferment products to preserve them.

Modern biomanufacturing dates back to the early 20th century when researchers started to use mono-culture microorganisms and large-scale anaerobic liquid fermentation to produce primary metabolites such as ethanol, acetone, butanol, amino acids, and organic acids.

The next advance in biomanufacturing came in the 1940s with the production of penicillin. The innovation was the use of microorganisms to generate secondary metabolites that serve as medicines, flavorings, and fragrances. Penicillin is the most well-known example. While it was discovered in 1928 large scale, more affordable manufacturing using aerobic submerged fermentation wasn’t introduced until 1942.

The 1980s saw the next significant improvement: the development of recombinant DNA technology and better cell culture capabilities. These advancements enabled biomanufacturing of large molecules, e.g. insulin and growth factors instead of just metabolites. The modern biopharmaceutical industry was built on these technologies.

These new capabilities also spawned the use of biomanufacturing to generate enzymes for consumer products, biomolecules such as restriction enzymes used in research, and to replace expensive and hazardous chemical synthesis processes.

Around the turn of the millennium, we saw the latest stage of biomanufacturing innovations emerge based on new technologies such as pluripotent stem cells, synthetic and systems biology approaches as well as advanced bioengineering approaches and computational biology advances that are allowing us to manufacture products far more efficiently, at larger-scale and shorter time frames. These innovations will also enable us to manufacture completely new products, e.g. human tissues or cells made by regenerative medicine.

## Accelerating Biomanufacturing With Skills & Labor

Advancing biomanufacturing and more broadly the bioeconomy requires a skilled workforce with multidisciplinary training, the ability to problem-solve and a willingness to continue to learn. Importantly, in addition to solid education in STEM disciplines, knowledge of automation and digitalization and an understanding of information technology are crucial for the biomanufacturing workforce of tomorrow.

While highly educated individuals are needed to drive ongoing innovations, it isn’t only PhDs that will drive biomanufacturing, but also a large number of undergraduate and graduate level professionals who have the training and expertise to build advanced biomanufacturing capabilities and keep production running 11. Opportunities will mainly be in disciplines like automation and software engineering, chemical and materials engineering, skilled-labor manufacturing. These jobs are - in required skills and level - akin of the position of a software developer in the IT sector.

Training and education are critical for the development of a skilled biomanufacturing workforce. Specialized programs with a biomanufacturing focus both on the undergraduate and graduate level as well as vocational training programs are needed.

Closer collaboration between educational institutions and industry are required to make sure that students learn the skills they need to be successful in biomanufacturing. Companies looking to focus on biomanufacturing need to provide relevant continuing education and upskilling opportunities to their workforce.

## Recent Investments in Biomanufacturing

Given the potential of biomanufacturing to transform everything from how we treat patients to how sustainable our laundry detergent is and how we manufacture plastics, it is no surprise that biomanufacturing has recently received significant interest – and investments. In the US, President Biden signed an Executive Order on September 12, 2022, that launched the National Biotechnology and Biomanufacturing Initiative with the goal to grow domestic biomanufacturing capacity, expand market opportunities for bio-based products, drive R&D and train a skilled workforce, among others. 12 Moreover, on December 8, 2022, the Presidents Council of Advisors on Science and Technology (PCAST) released a report outlining actionable steps that agencies can take to support this initiative16.

Initiatives supporting the development of biomanufacturing capabilities can be found around the world, e.g. Canada has developed a Biomanufacturing and Life Sciences Strategy to grow a strong biomanufacturing industry, the Horizon Europe Programme includes funding for biomanufacturing and the UK’s Engineering and Physical Sciences Research Council is investing manufacturing hubs that support a range of sectors, including biomanufacturing. 13, 14

Given these initiatives along with private funding that flows into the sector it’s no surprise that forecasters estimate robust annual growth rates and a total market size of over $43 billion by 2030 for the biomanufacturing sector. 15 ## Are you interested in modernizing your biomanufacturing computational abilities? #### References 1. Design for Manufacturing: A New Paradigm for Computational Life Sciences, Form Bio: Published September 27. 2022. Accessed October 11, 2022. 2. Biomanufacturing and Synthetic Biology, Centers for Disease Control Accessed and Prevention: Last reviewed August 7, 2019. Accessed October 11, 2022. 3. Plant-based Biomanufacturing A Growing Trend, Genetic Engineering News: Published July 14, 2021. Accessed October 11, 2022. 4. CHO in biomanufacturing: Past, present and future. European Pharmaceutical Manufacturer: Published June 1, 2021. Accessed October 11, 2022. 5. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Institutes of Health: Updated March 10, 2022. Accessed October 11, 2022. 6. Aijaz A. et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng. 2(6): 362-376. (2018) 7. Chandra P. et al Microbial lipases and their industrial applications: a comprehensive review. Microb Cell Fact 19 (169). (2020) 8. Trabelsi S. et al. The optimized production, purification, characterization, and application in the bread making industry of three acid‐stable alpha‐amylases isoforms from a new isolated Bacillus subtilis strain US586. J Food Biochem 43(5). (2019) 9. Accelerating the Biomanufacturing Revolution. World Economic Forum: Published February 2022. Accessed October 11, 2022. 10. Ramamurty P.C. et al. Microbial biotechnological approaches: renewable bioprocessing for the future energy systems. Microb Cell Fact 20, 55 (2021). 11. PhD not required. Published June 2020. Accessed Oct 26, 2022. 12. FACT SHEET: President Biden to Launch a National Biotechnology and Biomanufacturing Initiative. The White House: Published September 12, 2022. Accessed October 11, 2022. 13. Overview of Canada’s Biomanufacturing and Life Sciences Strategy. Government of Canada: Modified May 6. 2022. Accessed October 11, 2022. 14. A platform for future UK prosperity – By contributing to a healthy, connected, resilient, productive nation. UK Manufacturing Outlook: Published July 4, 2022. Accessed October 11, 2022. 15. Next-Generation Biomanufacturing Market worth$43.16 Billion by 2030. PR Newswire: Published June 14, 2022. Accessed October 11, 2022.
16. PCAST Releases Report on Strengthening Biomanufacturing to Advance the Bioeconomy. Published Dec 8, 2022. Accessed Dec 9, 2022.