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Characterization of currently marketed heparin products: key tests for quality assurance

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Abstract

During the 2007–2008 heparin crisis, it was found that the United States Pharmacopeia (USP) testing monograph for unfractionated heparin sodium (UFH) did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS) in heparin. In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to not only detect the contaminant OSCS but also to improve assurance of quality and purity of the drug product. Additional tests were also developed to monitor the heparin supply chain for other possible economically motivated additives or impurities. In 2009, a new USP monograph was put in place that includes 500 MHz 1H NMR, SAX-HPLC, %galactosamine in total hexosamine, and anticoagulation time assays with purified factor IIa or factor Xa. These tests represent orthogonal approaches for UFH identification, measurement of bioactivity, and for detection of process impurities or contaminants in UFH. The FDA has applied these analytical approaches to the study of UFH active pharmaceutical ingredients in the marketplace. Here, we describe results from a comprehensive survey of UFH collected from seven different sources after the 2009 monograph revision and compare these data with results obtained on other heparin samples collected during the 2007–2008 crisis.

Figure

A plot the 1.90 to 2.30 ppm region of an overlay of the 500 MHz 1H-NMR spectra of 20 mg samples of a heparin sodium API alone or spiked with 1.0%, 5.0% or 10.0% weight percent of OSCS and the same API alone or containing 1.0%, 5.0% or 10.0% of DS. Signals associated with the presence of the spiked OSCS or DS in heparin are denoted.

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Authors and Affiliations

  1. Division of Pharmaceutical Analysis, Food and Drug Administration, CDER, 1114 Market St, St. Louis, MO, 63101, USA

    David A. Keire, Hongping Ye, Michael L. Trehy, Wei Ye, Richard E. Kolinski, Benjamin J. Westenberger & Lucinda F. Buhse

  2. Office of New Drug Quality Assessment, Food and Drug Administration, CDER, Silver Spring, MD, 20993, USA

    Moheb Nasr & Ali Al-Hakim

Authors
  1. David A. Keire
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  2. Hongping Ye
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  3. Michael L. Trehy
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  4. Wei Ye
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  5. Richard E. Kolinski
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  6. Benjamin J. Westenberger
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  7. Lucinda F. Buhse
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  8. Moheb Nasr
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  9. Ali Al-Hakim
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Correspondence to David A. Keire.

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The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.

Published in the special issue on Heparin Characterization with Guest Editor Cynthia K. Larive.

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Keire, D.A., Ye, H., Trehy, M.L. et al. Characterization of currently marketed heparin products: key tests for quality assurance. Anal Bioanal Chem 399, 581–591 (2011). https://doi.org/10.1007/s00216-010-4023-y

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  • DOI: https://doi.org/10.1007/s00216-010-4023-y

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