Emerging trends in plasma‐free manufacturing of recombinant protein therapeutics expressed in mammalian cells
Open accessAbstract
Mammalian cells are the expression system of choice for therapeutic proteins, especially those requiring complex post‐translational modifications. Traditionally, these cells are grown in medium supplemented with serum and other animal‐ or human‐derived components to support viability and productivity. Such proteins are also typically added as excipients and stabilizers in the final drug formulation. However, the transmission of hepatitis B in the 1970s and of hepatitis C and HIV in the 1980s through plasma‐derived factor VIII concentrates had catastrophic consequences for hemophilia patients. Thus, due to regulatory concerns about the inherent potential for transmission of infectious agents as well as the heterogeneity and lack of reliability of the serum supply, a trend has emerged to eliminate the use of plasma‐derived additives in the production and formulation of recombinant protein therapeutics. This practice began with products used in the treatment of hemophilia and is progressively expanding throughout the entire industry. The plasma‐free method of producing recombinant therapeutics is accomplished by the use of both cell culture media and final product formulations that do not contain animal‐ or human‐derived additives. A number of recombinant therapeutic proteins for the treatment of several different diseases have been produced by plasma‐free processes, with the objective of improving safety by eliminating blood‐borne pathogens or by reducing immunogenicity. This review describes the factors that drove the development of plasma‐free protein therapeutics and provides examples of advances in manufacturing that have made possible the removal of human and animal‐derived products from all steps of recombinant protein production.
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Current best practice relies on three pillars: selection of appropriate starting and raw materials with a low risk of adventitious virus; testing of cell banks and in-process materials to ensure they are free from detectable viruses; and incorporation of steps to remove and inactivate potential undetected adventitious and endogenous viral contaminants during purification.
“The lessons of the past have led to the current best practice, which relies on three pillars: the selection of appropriate starting and raw materials with a low risk of containing adventitious virus; testing of cell banks and in process materials to ensure they are free from detectable viruses; and finally, the incorporation of steps to remove and inactivate potential undetected adventitious and”
From Viral contamination in biologic manufacture and implications for emerging therapies (2020) · cites this paper as [13]
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Experimental — accuracy not yet measuredAnimal-derived raw materials, especially serum, carry a relatively higher risk of being contaminated with virus and are thus being replaced where possible throughout the industry.
“Animal-derived raw materials (ADRMs), especially serum, carry a relatively higher risk of being contaminated with virus and are thus being replaced where possible throughout the industry 1,9,13 .”
From Viral contamination in biologic manufacture and implications for emerging therapies (2020) · cites this paper as [13]
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Assessment of cell engineering strategies for improved therapeutic protein production in CHO cells
Mohan (2008) · Biotechnology Journal · doi:10.1002/biot.200700249 · Cited by 102 · see citing works
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Viral contamination in biologic manufacture and implications for emerging therapies
Barone, P. W., Wiebe, M. E., Leung, J. C., Hussein, I. T. M., Keumurian, F. J., Bouressa, J., Brussel, A., Chen, D., Chong, M., Dehghani, H., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0507-2 · Cited by 212 · see citing works
Self-citationBerting, A., Farcet, M. R., & Kreil, T. R. (2010) · Biotechnology and Bioengineering · doi:10.1002/bit.22723 · Cited by 88 · see citing works
“Chinese hamster ovary (CHO) cells are one of the main cell lines used in the production of recombinant therapeutics (Wurm, 2004; see Grillberger et al., 2009 for examples of proteins produced in CHO cells).”
BackgroundSelf-citation
- Authors
- Grillberger, L., Kreil, T. R., Nasr, S., & Reiter, M.
- Affiliations
- Baxter (Austria) (AT)
- Corresponding author
- Reiter, Manfred
- ORCID
- Kreil, Thomas R.
- Venue
- Biotechnology Journal
- Publisher
- Wiley
- Published
- 2009-02
- Volume
- 4
- Issue
- 2
- Pages
- 186-201
- ISSN
- 1860-6768 (ISSN-L)
- 1860-7314
- PMC
- PMC2699044
- OpenAlex
- W2128987008
- Cited by
- 144
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 15 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 14 · 2014: 7 · 2013: 17 · 2012: 15
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biotechnology Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Transgenic Plants and Applications
- Keywords
- recombinant therapeutic proteins, mammalian cell expression, blood-borne transmission, hemophilia treatment, immunogenicity reduction, post-translational modification, drug formulation, hepatitis B, HIV, hepatitis C
- MeSH terms
- Animals, Eukaryotic Cells, Humans, Mammals, Recombinant Proteins, Technology, Pharmaceutical, Drug Design, Protein Engineering, Culture Media, Serum-Free
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