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Modern analytics for synthetically derived complex drug substances: NMR, AFFF–MALS, and MS tests for glatiramer acetate

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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-1H-NMR, 1D-13C-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.

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Acknowledgments

Funding and support for this work was provided by the CDER Critical Path Program and is gratefully acknowledged.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. 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

    Sarah Rogstad, Eric Pang, Cynthia Sommers, David A. Keire & Michael T. Boyne II

  2. 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

    Meng Hu & Xiaohui Jiang

Authors
  1. Sarah Rogstad
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  2. Eric Pang
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  3. Cynthia Sommers
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  4. Meng Hu
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  5. Xiaohui Jiang
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  6. David A. Keire
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  7. Michael T. Boyne II
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Corresponding author

Correspondence to David A. Keire.

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This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

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Rogstad, S., Pang, E., Sommers, C. et al. Modern analytics for synthetically derived complex drug substances: NMR, AFFF–MALS, and MS tests for glatiramer acetate. Anal Bioanal Chem 407, 8647–8659 (2015). https://doi.org/10.1007/s00216-015-9057-8

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  • DOI: https://doi.org/10.1007/s00216-015-9057-8

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