Adverse health events associated with the use of adulterated or counterfeit heparin prompted the Centers for Disease Control and Prevention (CDC) and FDA to begin a nationwide investigation in January 2008 of the commonly used blood-thinning drug. FDA confirmed that serious injuries and deaths had been associated with the use of heparin manufactured with an API sourced from China (1). During this investigation, FDA scientists also identified a previously unknown contaminant, oversulfated chondroitin sulfate (OSCS), in the heparin (2).
Working with FDA, manufacturers, and other stakeholders, the US Pharmacopeial Convention (USP) responded to this public health crisis by embarking on a revision of its public quality standards for heparin to enable the identification of OSCS and related contaminants. USP, a scientific nonprofit organization, develops standards that test for the identity, strength, quality, and purity of medicines, including biologic drugs like heparin. Published in its compendia, US Pharmacopeia and National Formulary (USP–NF), USP's documentary or written standards (i.e., monographs) are developed for individual drugs and their ingredients.
Since 2008, revisions of the heparin standards have taken place in three stages in order to better protect the US supply in a timely manner and help prevent future adulteration (see Table I). To address the immediate public health risk posed in 2008, Stage 1 monograph revisions consisted of validating and implementing proton nuclear magnetic resonance spectroscopy (1H NMR) and capillary electrophoresis (CE) procedures initially developed at FDA to detect OSCS. Stage 2 monograph revisions included new identification, potency, and impurity tests to better control the quality of heparin API (3). The Stage 2 revised heparin monographs became official on October 1, 2009 (4).
Table I: Changes to heparin sodium monograph during Stage 1 through Stage 3 revisions.
Stage 3 revisions focus on further optimization of identification tests and a protein impurities procedure as well as the introduction of brand new molecular weight determination and nucleotidic impurities procedures. To decide on specifications for the new molecular weight determination and impurities tests, USP engaged stakeholders in two round-robin studies. The studies were designed to gather feedback on the proposed procedures prior to their publication in Pharmacopeial Forum—USP's free-access, online publication for posting and receiving public comments on standards in development. Round-robin participants were requested to test their in-house heparin API batches using the proposed procedures. Final acceptance criteria for the tests were based on the batch data received during the studies.
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