The US FDA has has issued a Guidance for Industry on Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality.

Heparin, a blood-clot prevention drug, is critical ingredient for drugs used during open-heart surgery, bypass surgery, kidney dialysis, and blood transfusions. From India, the companies using heparin are vaccine and biological manufacturers which include Biocon, Panacea Biotech, Serum Institute, to name a few.

The guidance is intended to alert manufacturers of active pharmaceutical ingredients (APIs), pharmaceutical and medical device manufacturers of finished products, re-packers, and others on the potential risk of crude heparin contamination. The industry would need to revert with the comments by April 1.

The manufacturers have been asked to have better control on their use of crude heparin that might contain oversulfated chondroitin sulfate (OSCS) or non-porcine material which are ruminant material contaminants.

The development of methods set forth in the United States Pharmacopoeia (USP) to identify and control the animal origin of crude heparin is critical to monitor and confirm the species origin of heparin. This is consistent with the current USP monograph for Heparin Sodium. The identification of the animal origin of heparin has been studied by physico-chemical, immunological, and polymerase chain reaction (PCR) methods to be used to monitor raw materials used for quality heparin production.

This guidance developed by the Office of Compliance in the Centre for Drug Evaluation and Research (CDER) in cooperation with the Centre for Veterinary Medicine (CVM) and the Centre for Devices and Radiological Health (CDRH) at the FDA outlines the importance of testing for contamination in crude heparin and tests should be performed in addition to the USP monograph tests required for other forms of heparin to detect OSCS.

The term crude heparin refers to unrefined mixture of heterogeneous polysaccharides including various impurities isolated from mammalian tissues that requires further purification and processing before clinical use.

In early 2008, FDA received reports of serious acute hypersensitivity reactions which included  sudden onset of adverse events which suggested the contamination of heparin sodium for injection as a common factor among the cases.

After extensive analysis and screening, FDA identified the contaminant OSCS in heparin API manufactured in China. A large proportion of the heparin supply is imported into the US from foreign facilities. In the past, FDA identified OSCS in the heparin supply, including batches of crude heparin. Apart from US, 10 other countries reported the presence of contaminated heparin within their supply chains. In fact, heparin appeared to be intentionally contaminated with OSCS to reduce the cost of production, according to the regulator.

Now the regulator has called to test and confirm the species origin of crude heparin in each shipment before use in the manufacture of a drug or medical device which contains this drug.

Besides, the regulatory authority has published an assay method to measure  OSCS contamination in crude heparin using Strong Anion Exchange (SAX) high-pressure liquid chromatography (HPLC).

The regulator has asked manufacturers to audit their crude and API heparin suppliers to ensure conformance to CGMP. They should further employ the controls described in ICH Q7 to prevent the use of crude heparin containing OSCS, and to promptly investigate and resolve deviations and failures of quality, identity and purity.