title: Recognition and identification of UV-absorbing leachables in EPREX pre-filled syringes: an unexpected occurrence at a formulation-component interface.
abstract: During the period of 1998 to 2002, there was an increase in the incidence of antibody-positive pure red cell aplasia (PRCA) in patients receiving subcutaneous administration of EPREX (epoetinum alfa). As part of the investigation of this event, the aqueous formulation containing polysorbate 80, introduced in 1998, facilitated the leaching of small-molecule, aromatic compounds from the uncoated rubber syringe stoppers. The leachables were identified using Liquid Chromatography-Mass Spectroscopy, Electrospray Ionisation-MS/MS, Dithiothreitol reduction, and Hydrogen/Deuterium exchange. The major leachable was identified as a dialkylphenol disulfide, and the majority of the remaining peaks were identified as structural variants containing different numbers of sulfur atoms in the sulfide bridge. In this report, we describe the strategies and experimental designs that were used to overcome the analytical challenges and that led to successful structural identification of the leachables in EPREX pre-filled syringes with uncoated syringe stoppers.
authors.affiliation: Global Analytical Services, Global Biologics Supply Chain, LLC, 1000 Route 202 South, Raritan, NJ 08869, USA.
authors.forename: James
authors.initials: J
authors.lastname: Pang
authors.forename: Tim
authors.initials: T
authors.lastname: Blanc
authors.forename: John
authors.initials: J
authors.lastname: Brown
authors.forename: Steven
authors.initials: S
authors.lastname: Labrenz
authors.forename: Annabelle
authors.initials: A
authors.lastname: Villalobos
authors.forename: Anneli
authors.initials: A
authors.lastname: Depaolis
authors.forename: Srinivas
authors.initials: S
authors.lastname: Gunturi
authors.forename: Steve
authors.initials: S
authors.lastname: Grossman
authors.forename: Peter
authors.initials: P
authors.lastname: Lisi
authors.forename: George A
authors.initials: GA
authors.lastname: Heavner
mesh_terms: D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D004349:Drug Packaging; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000009:adverse effects* / Q000032:analysis* / Q000528:radiation effects; D008401:Gas Chromatography-Mass Spectrometry; D006397:Hematinics / Q000009:adverse effects* / Q000032:analysis* / Q000528:radiation effects; D010969:Plastics; D011994:Recombinant Proteins; D012010:Red-Cell Aplasia, Pure / Q000139:chemically induced*; D013594:Syringes; D014466:Ultraviolet Rays
chemical_list: D006397:Hematinics; D010969:Plastics; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa