title: Modern analytics for synthetically derived complex drug substances: NMR, AFFF-MALS, and MS tests for glatiramer acetate.
abstract: Glatiramer acetate (GA) is a mixture of synthetic copolymers consisting of four amino acids (glutamic acid, lysine, alanine, and tyrosine) with a labeled molecular weight range of 5000 to 9000 Da. GA is marketed as Copaxone™ by Teva for the treatment of multiple sclerosis. Here, the agency has evaluated the structure and composition of GA and a commercially available comparator, Copolymer-1. Modern analytical technologies which can characterize these complex mixtures are desirable for analysis of their comparability and structural "sameness." In the studies herein, a molecular fingerprinting approach is taken using mass-accurate mass spectrometry (MS) analysis, nuclear magnetic resonance (NMR) (1D-(1)H-NMR, 1D-(13)C-NMR, and 2D NMR), and asymmetric field flow fractionation (AFFF) coupled with multi-angle light scattering (MALS) for an in-depth characterization of three lots of the marketplace drug and a formulated sample of the comparator. Statistical analyses were applied to the MS and AFFF-MALS data to assess these methods' ability to detect analytical differences in the mixtures. The combination of multiple orthogonal measurements by liquid chromatography coupled with MS (LC-MS), AFFF-MALS, and NMR on the same sample set was found to be fit for the intended purpose of distinguishing analytical differences between these complex mixtures of peptide chains.
authors.affiliation: Division of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, US Food and Drug Administration, 645 S. Newstead Ave., St. Louis, MO, 63110, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rogstad
authors.affiliation: Division of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, US Food and Drug Administration, 645 S. Newstead Ave., St. Louis, MO, 63110, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Pang
authors.affiliation: Division of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, US Food and Drug Administration, 645 S. Newstead Ave., St. Louis, MO, 63110, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sommers
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Division of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, US Food and Drug Administration, 645 S. Newstead Ave., St. Louis, MO, 63110, USA. david.keire@fda.hhs.gov.
authors.forename: David A
authors.initials: DA
authors.lastname: Keire
authors.affiliation: Division of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, US Food and Drug Administration, 645 S. Newstead Ave., St. Louis, MO, 63110, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Boyne
mesh_terms: D031521:Fractionation, Field Flow; D000068717:Glatiramer Acetate / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry
chemical_list: D007166:Immunosuppressive Agents; D000068717:Glatiramer Acetate
keywords: Asymmetric field flow fractionation with multi-angle light scattering; Glatiramer acetate; Mass spectrometry; Nuclear magnetic resonance