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Viral Contamination in Biologic Manufacture and Implications for Emerging Therapies

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Viral Contamination in Biologic Manufacture and Implications for Emerging Therapies PERSPECTIVE https://doi.org/10.1038/s41587-020-0507-2 Viral contamination in biologic manufacture and implications for emerging therapies Paul W. Barone1, Michael E. Wiebe1, James C. Leung1, Islam T. M. Hussein1, Flora J. Keumurian1, James Bouressa2,25, Audrey Brussel3,26, Dayue Chen4,27, Ming Chong5, Houman Dehghani6,28, Lionel Gerentes7, James Gilbert8,29, Dan Gold9, Robert Kiss10,30, Thomas R. Kreil11, René Labatut3, Yuling Li12,31, Jürgen Müllberg13, Laurent Mallet7,32, Christian Menzel14, Mark Moody15,33, Serge Monpoeho16, Marie Murphy4, Mark Plavsic17,34, Nathan J. Roth18, David Roush19, Michael Ruffing20, Richard Schicho21,35, Richard Snyder22, Daniel Stark23, Chun Zhang24,36, Jacqueline Wolfrum1, Anthony J. Sinskey1 and Stacy L. Springs 1 ✉ Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. However, the use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dol- lars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. A consortium of biotech companies, together with the Massachusetts Institute of Technology, has convened to collect data on these events. This industry-wide study provides insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. These results have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise. n the twentieth century, several vaccine products were uninten- human pathogens. The lessons of the past have led to the current tionally contaminated with unwanted viruses during their pro- best practice, which relies on three pillars: the selection of appropri- duction1–3. This included the contamination of poliovirus vaccine ate starting and raw materials with a low risk of containing adventi- I 3 with simian virus 40 (SV40) , for which the health impacts were tious virus; testing of cell banks and in-process materials to ensure not fully known for many decades4. In the early 1980s, unknowingly they are free from detectable viruses; and finally, the incorporation contaminated therapeutic proteins from human plasma caused of steps to remove and inactivate potential undetected adventitious widespread transmission of viruses such as human immunodefi- and endogenous viral contaminants during purification of the prod- ciency virus (HIV) to people with hemophilia who received these uct9,13,14. Because of this approach, these products have been safe for treatments5,6. As a result, public trust in the plasma industry’s abil- over 35 years, and, to our knowledge, there has been no transmis- ity to safely make these therapies declined7,8. To ensure that current sion of a contaminating virus to a patient from a therapeutic protein plasma-derived, vaccine, and recombinant biotherapeutics are safe, produced using recombinant DNA technology. complementary safety strategies to reduce the risk of virus contami- Despite this excellent safety record, viral infection of mam- nation were developed and implemented9–11. malian cell culture is a real risk with severe consequences. Even Since that time, the production of therapeutic proteins has if no contaminated lots are released, patients who require treat- largely shifted to the use of recombinant DNA technology in pro- ment can be affected by drug shortages and public confidence in karyotic and eukaryotic cells12. However, culturing of these cells is the biotech industry can be severely damaged. These events can susceptible to contamination from adventitious agents (primarily cost tens of millions of dollars in investigation, cleanup, correc- bacteria and viruses). Viruses are of particular concern as they are tive actions, lost sales and manufacturing plant downtime15. They often more difficult to detect than other microbial contaminants1 also divert company leadership, encourage the competition, and and in the case of mammlian cell culture can potentially replicate can decrease company value. Finally, they expose the company 1Center for Biomedical Innovation, Massachusetts Institute of Technology, Cambridge, MA, USA. 2Pfizer Inc., Andover, MA, USA. 3Sanofi, Paris, France. 4Eli Lilly, Indianapolis, IN, USA. 5CSL Behring, Melbourne, Victoria, Australia. 6Amgen, Thousand Oaks, CA, USA. 7Sanofi Pasteur, Marcy L’Étoile, France. 8Biogen Inc., Cambridge, MA, USA. 9BioMarin, San Raphael, CA, USA. 10Genentech, South San Francisco, CA, USA. 11Baxter/Baxalta/Shire, now part of Takeda, Vienna, Austria. 12MedImmune, Gaithersburg, MD, USA. 13Bristol-Myers Squibb, Devens, MA, USA. 14Merck Group, Geneva, Switzerland. 15Merrimack Pharmaceuticals, Cambridge, MA, USA. 16Regeneron, Rensselaer, NY, USA. 17Sanofi Genzyme, Cambridge, MA, USA. 18CSL Behring, Bern, Switzerland. 19Merck & Co., Inc., Kenilworth, NJ, USA. 20Boehringer Ingelheim, Biberach, Germany. 21Bristol-Myers Squibb, New York, NY, USA. 22Brammer Bio, Alachua, FL, USA. 23Novartis, Basel, Switzerland. 24Shire, Lexington, MA, USA. 25Present address: Retired, Andover, MA, USA. 26Present address: LFB, Les Ulis, France. 27Present address: Genentech, South San Francisco, CA, USA. 28Present address: Allogene Therapeutics, South San Francisco, CA, USA. 29Present address: Independent consultant, Westcliffe, CO, USA. 30Present address: Sutro Biopharma Inc., South San Francisco, CA, USA. 31Present address: Innoforce, Hangzhou, Zhejiang, China. 32Present address: EDQM, Strasbourg, France. 33Present address: Immunova, Cambridge, MA, USA. 34Present address: Lysogene, Cambridge, MA, USA. 35Present address: Shire, Atlanta, GA, USA. 36Present address: Evelo Biosciences, Cambridge, MA, USA. ✉e-mail: [email protected] NatURE BIOtechnOLOgy | VOL 38 | MAY 2020 | 563–572 | www.nature.com/naturebiotechnology 563 PERSPECTIVE NATURE BIOTECHNOLOGY The CAACB virus contamination in biomanufacturing study Table 1 | Virus contaminations of mammalian cell culture To date, the CAACB has collected a comprehensive set of data on to produce proteins and vaccines, segregated by year, both virus contamination experience, as well as controls in place to pre- publicly reported and contained in the CAACB study vent contaminations, from 20 major biopharmaceutical manufac- Year of Contaminations (virus / host cell) Total turers. A 166-question survey of the CAACB members was used to contamination conduct the study (see Supplementary Note). To ensure a manage- 1985–1989 Blue tongue / CHO 2 able dataset for comparable processes, the scope of the project was EHDV / CHO18,19 limited to virus contaminations in mammalian cell culture manu- facturing. The project did not include bacterial or yeast fermen- 1990–1994 Herpesvirus / primary monkey 7 tation, plasma fractionation or egg-based production of vaccines Herpesvirus / Vero and covered manufacturing from the pilot to commercial scales, MVM / CHO (×2)20–22 Parainfluenza 3 / MRC5 including both current Good Manufacturing Practice (cGMP) and Reo3 / MRC5 non-cGMP operations. Unless otherwise noted, all data and discus- Simian adenovirus / primary monkey sion here relates to information reported directly to the CAACB and does not include information from other published reports. 1995–1999 CVV / CHO 3 Nine out of the 20 responding companies (or almost half of the Reovirus / human primary kidney23 Vesivirus 2117 / CHO24 involved industry respondents) reported having one or more adven- titious virus contaminations in mammalian cell culture operations 25 2000–2004 CVV / unknown (×2) 3 since 1985, totaling 18 virus contamination events reported to the 26 Human adenovirus / HEK293 CAACB. All of these reported contamination events occurred at 2005–2010 CVV / CHO 6 manufacturing sites in North America and Europe, but there is MVM / CHO (×2) insufficient data to determine whether one geographic location has Vesivirus 2117 / CHO (×3)27–29 a disproportionately increased risk of contamination over another. 2010–present MVM / CHO30 3 MVM / BHK-2135 Different host cells, different risks. The contaminated cell type, PCV-1 / Vero31,32 contaminating virus and suspected source of contamination for the Unknown MVM / BHK-2133 2 18 events reported to the CAACB are shown in Table 2. In 67% of Reovirus / Unknown34 reported events, the manufacturing platform was Chinese hamster ovary (CHO) cells, whereas the other 33% of events involved human Contaminating virus and host cell line are indicated where known. Note: some contamination events were reported publicly and in more detail to the CAACB. CVV, Cache Valley virus; EHDV, or primate cell lines. This result is not unexpected as CHO cells are epizootic hemorrhagic disease virus; MVM, minute virus of mice; PCV-1, porcine circovirus type 1; the most commonly used host cells by the recombinant-biologic Reo3, reovirus type 3. industry, with published reports indicating that approximately 70% of approved biotech products are manufactured using CHO cells12. The reported virus contaminations occurred at all stages to intense regulatory scrutiny and can result in a delay in the of the product life cycle, with 3 events occurring during preclini- approval of new products or the accelerated approval of a com- cal non-cGMP manufacture, 2 during clinical cGMP manufacture, petitor’s product16,17. and the remaining 13 occurring during commercial manufacture. Despite the above damaging consequences
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