title: Characterization of currently marketed heparin products: key tests for LMWH quality assurance.
abstract: During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). 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 detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz (1)H NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor Xa. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied.
authors.affiliation: Food and Drug Administration, CDER, Division of Pharmaceutical Analysis, St. Louis, MO 63101, USA.
authors.forename: Hongping
authors.initials: H
authors.lastname: Ye
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Toby
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Sommers
authors.forename: Houman
authors.initials: H
authors.lastname: Ghasriani
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: Lucinda F
authors.initials: LF
authors.lastname: Buhse
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Hakim
authors.forename: David A
authors.initials: DA
authors.lastname: Keire
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D019075:Electrophoresis, Capillary; D017984:Enoxaparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000032:analysis* / Q000494:pharmacology / Q000592:standards; D009682:Magnetic Resonance Spectroscopy
chemical_list: D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight
keywords: CE; Factor-II(a); Heparin; LMWH; NMR; SAX-HPLC