Introduction to Bioprocessing

Stay up to date on the latest science with Brush Up Summaries. 

What Is Bioprocessing?

Bioprocessing is the manipulation of naturally occurring living organisms and systems by bioengineers to achieve research and industrial goals.¹ Bioprocesses harness a diverse array of biological components including microbial, animal, plant, and fungal cells, as well as enzymes to act as catalysts or source materials in chemical production.^2,3 

Upstream and Downstream Bioprocessing

Bioprocesses encompass a sequence of activities that facilitate biochemical changes, with upstream processing  steps that prepare biomass and substrates for catalytic reactions, followed by downstream processing to handle the resulting materials.¹  To change the phase or composition of raw materials, most systems employ a series of methods called unit operations.² Scientists tailor and optimize the order of these unit operations for specific biological catalysts and industrial production. 

Unit operations commonly employed in bioprocessing include the following:²  

• Absorption
• Centrifugation
• Chromatography
• Crystallization
• Dialysis
• Distillation
• Drying
• Evaporation
• Filtration (e.g., microfiltration and ultrafiltration)
• Flocculation
• Flotation
• Homogenization
• Humidification
• Milling
• Precipitation
• Sedimentation
• Solvent extraction

What is upstream processing?

The first phase of bioprocessing is known as upstream processing.¹ Bioengineers first identify a biological catalyst or system that can be reengineered for industrial purposes.¹ Then they design an industrial environment to support the desired metabolic events.³

Once a researcher selects the ideal biological system, genetic engineering equips host organisms with the traits essential for industrial production.² The researchers then create a kinetic analysis of how the product will be manufactured. This analysis uses mathematical models designed to describe the various features of the biological system such as metabolic rates, substrate utilization, and product formation.^2,4,5

A project’s economic viability hinges on the cost of obtaining necessary biomass and substrate, as well as the parameters essential for catalysis support.² Engineers run small scale experiments and perform comparative analysis between different experimental conditions to make informed decisions on the order of unit operations and manufacturing methods crucial for financial feasibility of a given process.^2,5

Bioreactors, also known as fermenters, serve as the heart of upstream bioprocessing, facilitating major biochemical transformations of substrate and biomass.^1,6 These containers optimize conditions for biocatalysts such as enzymes or whole cells to convert biochemicals into desired products while minimizing manufacturing costs.^2,3 

Bioreactors are versatile instruments with applications across diverse areas of production, including the following:³

• Cell growth
• Enzyme production
• Food production
• Tissue generation
• Algae production
• Protein synthesis
• Anaerobic digestion

Product yields from a bioreactor depend on the instrument’s ability to do the following:⁷

• Maintain high cell concentrations and metabolic activities
• Achieve and preserve sterile conditions
• Provide adequate agitation to achieve uniformity of the microenvironment

What is downstream processing?

Downstream processing recovers the final product once catalyzation is complete.^2,3 The series of unit operations used in downstream recovery depend on the product’s location in the source material and its format, such as extracellular, intracellular, or whole cell biologics.³ 

Table 1: Different product types and associated downstream unit operations³

Filtration, purification, and other product collection techniques that succeed in small scale laboratory workflows might be difficult to implement on a larger scale.² In many bioprocesses, final product retrieval poses the biggest challenge and incurs significant costs.³ For example, in the case of specific recombinant DNA-derived products, the extensive process necessary for purification may constitute 80 to 90 percent of the total processing expenses.² Methodological advancements in downstream processing can significantly decrease processing time and costs while offering higher yields.³

Major considerations in bioprocessing workflows

In bioprocessing, maintaining efficacy while upscaling from laboratory operations to industrial-scale bioreactors requires careful management of biological components, including biomass, gas, and liquid constituents of a bioprocess.²

Instruments such as meters and sensors collect data throughout the bioprocess system. Most bioprocessing occurs in a liquid medium, which makes it vital to monitor the system’s fluid dynamics, such as viscosity, density, and concentration, and maintain mixers and tubing connectors.² Other parameters subject to routine data collection include UV exposure, conductivity, pH, temperature, air, and pressure.²

Additionally, products must meet final purity standards before they are released on the market.^2,3 Instrument and environment sterilization are essential for cultivating only the desired cells or products; scientists often use stainless steel equipment, which is heat or chemically treated between batches.³ Purification techniques such as filtration, chromatography, and precipitation remove impurities and optimize productivity.³

Bioprocessing Methods and Technologies

Advancements in research technologies, such as recombinant DNA, gene probes, cell fusion, and tissue culture continually expand the horizons of bioprocessing, enabling scientists to refine methods and develop new products.^8,9

Bioprocessing culture types

The cellular cultures used in bioprocessing encompass a diverse array of organisms, including bacterial, algal, fungal, and mammalian systems.¹ Each organism’s proliferation is regulated differently, leading to variations in the time required to complete cell cycles or enzymatic actions, even within the same species or cell lines.⁵ Recent developments in cell culture media, feeding techniques, and bioreactor controls help scientists create highly capable systems.⁵

Human and nonhuman eukaryotic cell cultures can either adhere to surfaces or float freely, with recent advancements enabling the creation of continuous cell lines through transformation processes.⁵

Microbial systems offer advantages such as fast, predictable growth rates and high product output with low-cost growth media.³ Microbial bioprocessing is particularly suitable for less complex biotherapeutics that do not require extensive post-translational modifications.⁵

Microalgae are a renewable bioprocessing resource with substantial economic potential, capable of producing biofuels and various bioactive compounds.^3,6    

Fungi abundantly generate enzymes and small molecules, and are well established bioprocessing systems for drug discovery and pharmaceutical applications.^6,10

Single-use bioprocessing

Single-use technologies are increasingly common in industrial settings, offering advantages such as eliminating the need for cleaning or sterilization, thereby minimizing risks of contamination.¹¹ Scientists adopt single-use systems to reduce investment and operational costs while enhancing process flexibility.¹¹ Although single-use systems for commercial manufacturing are projected to become more popular in the coming years, they will likely remain second to stainless steel equipment.¹¹

Applications 

Bioprocessing offers diverse applications in sustainability, economic production, and medical discovery.¹

Bioprocessing in food science

Bioprocessing is commonly found in everyday food production. Depriving anaerobic bacteria of oxygen leads to the metabolic process of fermentation, which people have employed for centuries to enhance and preserve various plant-based components, yielding food staples such as sake, bread, beer, soy sauce, and rice vinegar.⁶

Outside the common kitchen, the food industry is a major buyer on the billion dollar enzyme market.⁹ Conventional enzymes utilized in food processing boast biodegradability and minimal environmental impact.³ Advancements in enzyme-related techniques offer enhanced preservation and novel food components, including flavors, colorants, and phytochemicals.^9,12 

Bioprocessing in the pharmaceutical industry

In 1928, penicillin emerged as a groundbreaking fungal metabolite, marking the inception of biologically-sourced pharmaceuticals.⁶ Now, bioprocessing is the primary source of many drugs and biologics necessary for medical treatments and scientific research.¹

Pharmaceuticals derived from living organisms include recombinant proteins, tissues, cells, genes, allergens, blood components, and vaccines.^1,3,8

For example, cell therapy treats various diseases by introducing cellular material into a patient’s body through injection, grafting, or implantation.¹³ Additionally, scientists and clinicians use human mesenchymal stem cells to secrete bioactive factors for regenerative medicine.¹⁴ Optimizing the bioprocessing techniques involved in these and other therapeutics holds immense potential for enhancing human health.¹

Bioprocessing to produce biofuels

Bioengineers convert various organic materials such as forestry waste, agricultural residues, and algal biomass into oil-based plastics and biofuels.¹⁵ These bioprocessing applications offer solutions to energy demands and reduce reliance on fossil fuels.¹⁶

Scientists generate bioethanol, a popular liquid biofuel, through microbial anaerobic fermentation of plants such as corn.¹⁵ Alternatively, utilizing marine vegetation such as algae as a biofuel source addresses challenges in renewable energy and land use allocation.⁶ Despite obstacles in algal biofuel production, such as high energy cost and complicated product harvesting, technological advancements are steadily enhancing its feasibility.¹⁵

References

1. Liu S. Bioprocess Engineering: Kinetics, Sustainability, and Reactor Design. Third ed: Elsevier; 2020.

2. Doran PM. Bioprocess Engineering Principles. Second ed: London: Academic Press; 2013:1-919.

3. Moo-Young M. Comprehensive Biotechnology. Second ed: Elsevier Science; 2011.

4.  Koutinas M, et al. Bioprocess systems engineering: Transferring traditional process engineering principles to industrial biotechnology. Comput Struct Biotechnol J. 2012;3(4):e201210022.

5. Jagschies G, et al. Biopharmaceutical Processing. Elsevier; 2018.

6. Dunford NT. Food and Industrial Bioproducts and Bioprocessing. John Wiley & Sons; 2012.

7. Zydney AL. Perspectives on integrated continuous bioprocessing—opportunities and challenges. Curr Opin Chem Eng. 2015;10:8-13.

8. Tripathi NK, Shrivastava A. Recent developments in bioprocessing of recombinant proteins: expression hosts and process development. Front Bioeng Biotechnol. 2019;7:420.

9. Zhang Y, et al. Enzymes in food bioprocessing—novel food enzymes, applications, and related techniques. Curr Opin Food Sci. 2018;19:30-35.

10. El Enshasy HA. Fungal morphology: a challenge in bioprocess engineering industries for product development. Curr Opin Cheml Eng. 2022;35:100729.

11. Eibl R, Eibl D. Single-Use technology in biopharmaceutical manufacture. In: Wiley eBooks; 2019. 

12. Srivastava PS. Plant Biotechnology and Molecular Markers. Springer; 2005.

13. Kirouac DC, Zandstra PW. The systematic production of cells for cell therapies. Cell Stem Cell. 2008;3(4):369-381.

14. Panchalingam KM, et al. Bioprocessing strategies for the large-scale production of human mesenchymal stem cells: A review. Stem Cell Res Ther. 2015;6:1-10.

15. Yusup S, Rashidi NA. Value-Chain of Biofuels. Elsevier; 2022.

16. Argin-Soysal S, et al. Bioprocessing for Value-Added Products from Renewable Resources. Amsterdam: Elsevier; 2007.