title: Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration.
abstract: The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.
authors.affiliation: a Biopharmaceutical Product Sciences; GlaxoSmithKline R&D; King of Prussia , PA , USA.
authors.forename: Sorina
authors.initials: S
authors.lastname: Morar-Mitrica
authors.forename: Manasi
authors.initials: M
authors.lastname: Puri
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beumer Sassi
authors.forename: Joshua
authors.initials: J
authors.lastname: Fuller
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: George
authors.initials: G
authors.lastname: Crotts
authors.forename: Douglas
authors.initials: D
authors.lastname: Nesta
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D055550:Protein Stability
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; C550701:otelixizumab
keywords: CD3, cluster of differentiation 3; CMC, critical micelle concentration; Cys, cysteine; DSC, differential scanning calorimetry; EDTA, edetate disodium; Glut, glutathione; HPLC, high performance liquid chromatography; M, methionine residues; MS, mass spectrometry; MTG, monothioglycerol; Met, methionine; PES, polyethersulfone; PO, polyolefin; PS80, polysorbate 80; PVC, polyvinylchloride; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; administration; adsorption; antioxidant; biopharmaceutical; cIEF, capillary isoelectric focusing; dilution; i.v., intravenous; infusion; intravenous; low concentration; low dose; mAb, monoclonal antibody; monoclonal antibody; oxidation; stability; surfactant