title: Characterization of currently marketed heparin products: key tests for quality assurance.
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 (1)H 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.
authors.affiliation: Division of Pharmaceutical Analysis, Food and Drug Administration, CDER, 1114 Market St, St. Louis, MO 63101, USA. David.Keire@fda.hhs.gov
authors.forename: David A
authors.initials: DA
authors.lastname: Keire
authors.forename: Hongping
authors.initials: H
authors.lastname: Ye
authors.forename: Michael L
authors.initials: ML
authors.lastname: Trehy
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kolinski
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Westenberger
authors.forename: Lucinda F
authors.initials: LF
authors.lastname: Buhse
authors.forename: Moheb
authors.initials: M
authors.lastname: Nasr
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Hakim
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000032:analysis; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004340:Drug Contamination; D019075:Electrophoresis, Capillary / Q000379:methods; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011786:Quality Control; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000925:Anticoagulants; D006493:Heparin; D002809:Chondroitin Sulfates