The US regulatory and pharmacopeia response to the global heparin contamination crisis

Abstract

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

“…However, the reliance on a single animal species coming predominately from one country for the LMWH supply chain and the burden imposed on regulatory agencies for ensuring the safety of structurally heterogeneous LMWH products remain serious concerns. Despite extensive efforts from the FDA and U.S. Pharmacopeia to improve the purity analysis after the heparin crisis in 2007, the animal-sourced heparin is still not 100% risk-free because of the lack of “unequivocal and specific analytical techniques” (9). The U.S. Congressional Committee on Energy and Commerce has also raised concerns over the safety of the heparin supply chain in a letter to the FDA in 2016 (https://energycommerce.house.gov/news-center/press-releases/committee-leaders-express-continued-concern-fda-s-califf-about).…”

Heparin's solution structure determined by small‐angle neutron scattering

“…Heparin was discovered in 1916, and its use as a clinical anticoagulant predates the establishment of the United States Food and Drug Administration . Heparin is required in extracorporeal therapy, in major surgery, and in the treatment of thrombosis, and without its use the practice of modern medicine would be difficult .…”

“…Heparin is required in extracorporeal therapy, in major surgery, and in the treatment of thrombosis, and without its use the practice of modern medicine would be difficult . Worldwide, currently about 100 metric tons of heparin are used annually, making it, after insulin, the second most widely used biopolymeric drug . Despite its critical importance, the full primary sequence and secondary structures of heparin remain unknown.…”

“…Despite its critical importance, the full primary sequence and secondary structures of heparin remain unknown. This lack of understanding of heparin's structure was partially responsible for the heparin contamination crisis of 2008 that led to the injury and death of hundreds of patients when heparin was adulterated with the related toxic, semisynthetic polysaccharide, namely oversulfated chondroitin sulfate …”

Chemoenzymatic synthesis of unmodified heparin oligosaccharides: cleavage of p-nitrophenyl glucuronide by alkaline and Smith degradation

“…The supply chain of pharmaceutical heparin has been poorly regulated and this presented safety concerns. A worldwide distribution of contaminated heparin in 2007, caused by its adulteration with a semi-synthetic oversulfated chondroitin sulfate contaminant, adversely affected the purity and safety of animal-sourced UFH and LMWH, and was associated with over 200 deaths in the US 16, 17 . Another potential threat is that other bioactive entities, such as viruses or prions that might remain associated with the HS chains in animal extracts.…”