US researchers have developed a chemoenzymatic strategy to synthesise the anticoagulant drug heparin and avoid the contaminant that has killed more than 80 people.
The breakthrough was presented at the ACS (American Chemical Society) National Meeting and Exposition in Philadelphia, US, earlier this week and described how Escherichia coli (E. coli) bacteria could be harnessed to synthesise the widely-used anticoagulant that has global annual sales of around $4bn (€2.7bn).
Heparin is produced by extraction from pig intestines and contaminated batches of the drug have been linked by the US FDA (Food and Drug Administration) to more than 80 deaths and hundreds of allergic reactions among patients treated with the drug during heart surgery and kidney dialysis.
The contaminated heparin was traced by the FDA to various batches imported from small, family-run workshops in China which supply about 70 per cent of the world’s supply.
While regulators called for greater cooperation and joint inspections of overseas active pharmaceutical ingredient (API) manufacturing plants, Professor Robert Linhardt of the Rensselaer Polytechnic Institute, US, and Associate Professor Jian Liu of the University of North Carolina, US, to search for an alternative method of production.
Prof. Linhardt was part of the team that identified the suspected contaminant as a structurally similar carbohydrate called oversulfated chondroitin sulfate.
"When we found the contamination, it was another sign that the way we currently manufacture heparin is simply unsafe," said Prof. Linhardt.
Researchers have been trying for years to develop a synthetic production method for the drug, however the first total synthesis described in 2003 by researchers from the Massachusetts Institute of Technology (MIT), US, produced only minute batches at a time and could not be economically scaled-up for commercial production.
The synthesis developed by Prof. Linhardt’s team uses a patented biosynthesis that uses enzymes expressed in E. coli bacteria to replicate the normal biosynthesis of natural heparin.
While the team has only used the technique to create the drug on a laboratory scale, scaling the process up should prove no more difficult than scaling-up the production of any other biological drug.
The group plans to begin the necessary preclinical and clinical trials needed to bring the synthetic heparin to market. If successful, the new heparin could be on the market in two to five years.
"With the problems associated with contaminated heparin produced from pig tissues in China, a non-animal source of this essential drug is gaining importance as a safer version of the drug could result in less adverse effects and fewer deaths," said Prof. Linhardt.
"Unlike the current heparin that is harvested from possibly disease carrying animals in often very poor conditions, our fully synthetic heparin will be created in a pharmaceutical manufacturing environment from fermentation to packaging. This will give drug manufacturers extreme control over the safety and purity of the product."