title: Bracketed generic inactivation of rodent retroviruses by low pH treatment for monoclonal antibodies and recombinant proteins.
abstract: Viral safety is a predominant concern for monoclonal antibodies (mAbs) and other recombinant proteins (RPs) with pharmaceutical applications. Certain commercial purification modules, such as nanofiltration and low-pH inactivation, have been observed to reliably clear greater than 4 log(10) of large enveloped viruses, including endogenous retrovirus. The concept of "bracketed generic clearance" has been proposed for these steps if it could be prospectively demonstrated that viral log(10) reduction value (LRV) is not impacted by operating parameters that can vary, within a reasonable range, between commercial processes. In the case of low-pH inactivation, a common step in mAb purification processes employed after protein A affinity chromatography, these parameters would include pH, time and temperature of incubation, the content of salts, protein concentration, aggregates, impurities, model protein pI, and buffer composition. In this report, we define bracketed generic clearance conditions, using a prospectively defined bracket/matrix approach, where low-pH inactivation consistently achieves >or=4.6 log(10) clearance of xenotropic murine leukemia virus (X-MLV), a model for rodent endogenous retrovirus. The mechanism of retrovirus inactivation by low-pH treatment was also investigated.
authors.affiliation: Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Brorson
authors.forename: Sherrie
authors.initials: S
authors.lastname: Krejci
authors.forename: Kitty
authors.initials: K
authors.lastname: Lee
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamilton
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stein
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D016466:CHO Cells / Q000378:metabolism / Q000821:virology; D018929:Cell Culture Techniques / Q000379:methods*; D006224:Cricetinae; D006863:Hydrogen-Ion Concentration; D009052:Leukemia Virus, Murine / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D012190:Retroviridae / Q000737:chemistry / Q000502:physiology; D038301:Virus Inactivation
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins