Composition of OSCS-contaminated heparin occurring in 2008 in batches on the German market

Abstract

In 2008, some 900 cases of adverse events associated with the use of heparin were reported to the Food and Drug Administration of USA and the Federal Institute of Drugs and Medical Devices in Germany. 238 patients died from heparin in the USA. In March 2008, oversulfated chondroitin sulfate (OSCS) was identified to be responsible for these cases. NMR spectroscopic evaluation of heparin samples revealed OSCS, dermatan sulfate (DS), chondroitin sulfate A and C as well as various residual solvents to be present in heparin batches, which could not be identified by means of conventional methods described in various pharmacopoeias at that time. In order to evaluate the situation on the German market, 145 representative samples were collected in 2008 and analyzed by means of 1H NMR spectroscopy, water determination, optical rotation and sheep plasma clotting assay. 66 samples were found to contain pure heparin, 51 samples heparin plus DS, 5 samples heparin plus OSCS, and 23 samples heparin, DS and OSCS, each in varying amounts. In 94 out of 145 batches especially ethanol was found in strongly varying amounts up to about 9.5%. Traces of acetone and formic acid were found with concentrations up to 0.04%, as well as sodium acetate and methanol up to 0.5%. Additionally, in many batches the content of water was found to be relatively high. Whereas the optical rotation was able to identify samples with a high contamination of OCSC, all samples tested fulfilled the requirements of the anticoagulation potency assay of the European Pharmacopoeia 6.0. The presented analysis of a representative set of heparin samples proves the suitability of 1H NMR spectroscopy for the quality control of heparin of both glycosaminoglycans and residual solvents.