Risk Mitigation in Preventing Adventitious Agent Contamination of Mammalian Cell Cultures
Industrial-scale mammalian cell culture processes have been contaminated by viruses during the culturing phase. Although the historical frequency of such events has been quite low, the impact of contamination can be significant for the manufacturing company and for the supply of the product to patients. This chapter discusses sources of adventitious agent contamination risk in a cell culture process, provides a semiquantitative assessment of such risks, and describes potential process barriers that can be used to reduce contamination risk. High-temperature, short-time (HTST) heat treatment is recommended as the process barrier of choice, when compatible with the process. A case study assessing the compatibility of HTST heat treatment with a cell culture medium is presented, and lessons learned are shared from our experiences over many years of developing and implementing virus barriers in mammalian cell culture processes.
KeywordsContamination risk assessment HTST heat treatment Nanofiltration UV radiation Virus barriers Virus contamination
We acknowledge many individuals too numerous to specifically name who, over the course of many years since the initial decision to develop and implement additional virus barriers, have contributed significant time and effort to ensuring success. It has truly taken a village.
- 1.CBER (1997) Points to consider in the manufacture and testing of monoclonal antibody products for human use. J Immunother 20(3):214–243Google Scholar
- 2.Knipe D, Howley P (2013) Fields virology. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
- 4.FDA (1998) International Conference on Harmonisation; guidance on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin (ICH Q5A). Fed Reg 63(185):51074–51084.Google Scholar
- 5.EMEA/CPMP/BWP/268/95/3AB8A (1996) Note for guidance on virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of virusesGoogle Scholar
- 12.Taleb NN (2007) The Black Swan the impact of the highly improbable. Random House, New YorkGoogle Scholar
- 13.Miesegaes G, Lute S, Aranha H, Brorson K (2010) Virus retentive filters. In: Flickinger M (ed) Encyclopedia of industrial biotechnology: bioprocess, bioseparation, and cell technology. Wiley, pp 1–11Google Scholar
- 15.Ge S (2014) Virus aerosol survivability, transmission, and sampling in an environmental chamber. DissertationGoogle Scholar
- 18.Sofer G, Lister D, Boose J (2003) Part 6, inactivation methods grouped by virus. BioPharm Int 6:S37–S42Google Scholar
- 24.Chevrefils G, Caron E, Wright H (2006) UV dose required to achieve incremental log inactivation of bacteria, protozoa, and viruses. IUVA News 8:38–45Google Scholar
- 25.EMA (2012, 05 25) Press release: European Medicines Agency confirms positive benefit-risk balance of MabTheraGoogle Scholar
- 28.Shiratori M, Kiss R, Prashad H, Iverson R, Bourret J, Kim M, Charaniya S (2012) Patent No. US 20130344570 A1. USAGoogle Scholar
- 30.Hauser H, Wagner R (2014) Animal cell biotechnology in biologics production. De Gruyter, BerlinGoogle Scholar