title: Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events.
abstract: Peginesatide (Omontys(®); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction. Commercialization was initiated with a multiuse vial presentation, which differs in formulation from the single-use vial presentation used in phase 3 studies. Standard physical and chemical testing did not indicate any deviation from product specifications in either formulation. However, an analysis of subvisible particulates using nanoparticle tracking analysis and flow imaging revealed a significantly higher concentration of subvisible particles in the multiuse vial presentation linked to the hypersensitivity cases. Although it is unknown whether the elevated particulate content is causally related to these serious adverse events, this report illustrates the utility of characterizing subvisible particulates not captured by conventional light obscuration.
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kotarek
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Christine
authors.initials: C
authors.lastname: Stuart
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Silvia H
authors.initials: SH
authors.lastname: De Paoli
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Jan
authors.initials: J
authors.lastname: Simak
authors.affiliation: Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Tsai-Lien
authors.initials: TL
authors.lastname: Lin
authors.affiliation: Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ovanesov
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Yideng
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Scott
authors.affiliation: Office of New Drug Quality Assessment, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Janice
authors.initials: J
authors.lastname: Brown
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993. Electronic address: Ewa.Marszal@fda.hhs.gov.
authors.forename: Ewa
authors.initials: E
authors.lastname: Marszal
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993. Electronic address: Jack.Ragheb@fda.hhs.gov.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Ragheb
mesh_terms: D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D017326:Clinical Trials, Phase III as Topic; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects; D052638:Particulate Matter / Q000008:administration & dosage* / Q000009:adverse effects*; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing
chemical_list: D052638:Particulate Matter; D010455:Peptides; D004921:Erythropoietin; C556270:peginesatide
keywords: formulation; particle sizing; peptides; protein aggregation