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The US regulatory and pharmacopeia response to the global heparin contamination crisis

Nature Biotechnology volume 34, pages 625–630 (2016)Cite this article

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Abstract

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

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Figure 1: Heparin crisis and resolution timeline.
Figure 2: Structures of disaccharide-repeating units of glycosaminoglycans.
Figure 3: Orthogonal analysis of heparin.

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Acknowledgements

The authors appreciate the financial and logistical support provided by USP; the contributions of USP volunteers, the scientific community, and the collaborating laboratories; the public comments; and the collaboration of the FDA, including helpful review and discussion.

Author information

Authors and Affiliations

  1. Biologics and Biotechnology Department, US Pharmacopeia, Rockville, Maryland, USA

    Anita Y Szajek & Tina Morris

  2. Structure Elucidation/Technology Resources, Baxter Healthcare Corporation, Round Lake, Illinois, USA

    Edward Chess

  3. Sjølundsparken, Hellebæk, Denmark

    Kristian Johansen

  4. Boehringer Ingelheim, Ben Venue Laboratories, Inc., Bedford, Ohio, USA

    Gyöngyi Gratzl

  5. National Institute for Biological Standards and Control, South Mimms, Potters Bar, UK

    Elaine Gray & Barbara Mulloy

  6. US Food and Drug Administration/Division of Pharmaceutical Analysis, St. Louis, Missouri, USA

    David Keire

  7. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA

    Robert J Linhardt

  8. Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

    Jian Liu

  9. Institute of Pharmaceutical Science King's College London, Franklin Wilkins Building, Waterloo Campus, London, UK

    Barbara Mulloy

  10. R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA

    Moheb Nasr

  11. Department of Biological Engineering, Harvard-MIT Division of Health Sciences & Technology, Koch institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Zachary Shriver

  12. Product Development - Analytical Innovation and Development, Fresenius Kabi USA, Skokie, Illinois, USA

    Pearle Torralba

  13. Sanofi, Vitry sur Seine, France

    Christian Viskov

  14. US Pharmacopeia, Rockville, Maryland, USA

    Roger Williams

  15. Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

    Janet Woodcock & Ali Al-Hakim

  16. Pfizer Quality Operations Biotech, Chesterfield, Missouri, USA

    Wesley Workman

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Corresponding author

Correspondence to Ali Al-Hakim.

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Competing interests

A.Y.S., K.J., G.G., E.G., T.M., B.M., M.N., R.W., J.W., D.K. and A. A.-H. declare no competing financial interests. R.J.L. declares competing interest in the form of funding derived from the NIH in the form of research grants in the area of heparin analysis and regularly consults on heparin analysis. J.L. declares competing interest in the form of funding derived from the NIH and FDA in the form of research grants in the area of heparin. J.L. is a founder of Glycan Therapeutics, LLC. C.V. is an employee of Sanofi and has financial interest in the company. E.K.C. was a stockholder and employee of Baxter Healthcare Corporation during the completion of this work. W.E.W. is an employee of Pfizer and has financial interest in the company.

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Szajek, A., Chess, E., Johansen, K. et al. The US regulatory and pharmacopeia response to the global heparin contamination crisis. Nat Biotechnol 34, 625–630 (2016). https://doi.org/10.1038/nbt.3606

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