Contaminants in heparins continue to be unfolded.

September 4, 2008; 1:00 p.m. (EST): Earlier this year several batches of heparins were initially recalled due to the increased prevalence of adverse reactions and deaths. Initially the US FDA recalled specific batches of heparin resulting in a total recall of Baxter’s unfractionated heparin. Since then Baxter has not reintroduced this product despite the fact that it had 50% of the total market for unfractionated heparin in the US. The recall impacted on extensive investigations resulting in inspections and warning letters to different suppliers of heparin. Subsequently, the identification of a heparin-like contaminant resulted in a more widespread global recall of heparin. Because low molecular weight (LMW) heparins are produced from unfractionated heparin, several batches of LMW heparin were also recalled in Europe and Southeast Asia. Subsequently, the main contaminant was identified to be oversulfated chondroitin sulfate (OSCS). However, the presence of other contaminants was also identified. The contaminants vary in heparins and may be partly due to carry over of the manufacturing process. However, the presence of OSCS in significant amounts (5-30%) was apparently intentional. The US FDA eventually required additional analysis to determine the purity of imported heparins. The US Pharmacopeia (USP) also addressed this issue and is in the process of revising the heparin monograph including additional analytical approaches to assure purity of heparin. Despite this progress, the biological impact of the contaminant has been minimally addressed. Very limited information on the influence of the contaminant’s presence in heparin on its anticoagulant and other pharmacological effects have become available. Since the contaminant represents an unnatural hyper-sulfated glycosaminoglycan, and since it has been used in a large number of patients for a span of over one year, its residual and sustained pharmacotoxic effects should be clearly addressed. Moreover, its immunogenic profile should be clearly understood in terms of the type of antibodies and their biological functions. The two major publications appearing in April, 2008, addressed the basic chemical structure of OSCS and one of its biological actions, i.e., contact activation which is commonly seen with almost all of the sulfated glycosaminoglycans.