At the American Chemical Society national conference last weekend, Rensselaer Polytechnic researcher Dr. Robert Linhart announced that his team may have built the first fully synthetic heparin. Whether or not you believe that the possibility of another contamination crisis of natural raw heparin exists, the potential for a heparin supply independent of the whims and worries of the global supply chain, not to mention the global pig population, is certainly welcome news.
Is synthetic heparin feasible on a large scale? Yes and no, says one of Linhart's collaborators, professor Jian Liu at the University of North Carolina. The science is there to produce synthetic heparin at the milligram level, and almost there to produce it at the kilo level, Liu told me this morning. But a lack of investment and low market incentive may collude to limit the short-term outlook for engineered heparin.
"We need someone who's willing to serve as partner to expedite production," Liu says. Right now, the researchers are talking with several smaller biotech firms about development for clinical trials. They have not yet been approached by larger pharma companies.
Synthesizing heparin involves introducing sulfa groups into polysaccharides derived from E. Coli bacteria, Liu says, in order to produce an key enzyme for heparin production. The cost of this process is 10 to 100 times less than making heparin from human enzyme, Liu says.
There are a couple technical issues to be worked out before synthetic heparin could be produced at greater rates, much less at a rate to satisfy the current market demand of 30 to 40 tons per year. The first, says Liu, would be improving the yield of the starting materials. The second would be scaling up the current lab procedures to an industrial level--an "engineering problem," says Liu.
And there are financial issues. Even though heparin prices have risen this year to more than $5,000 per kilo, the cost is not prohibitive to warrant a major push towards an alternative. The incentive is not there.
Unless another crisis occurred. While Liu and colleagues certainly don't wish for this, the impetus for their research, which began in 2005, was that the heparin supply is vulnerable. Three main factors are involved in control of the supply, Liu notes: the global pig supply, the heparin harvesting and purification process, and the analytical control. While measures by FDA, other regulatory bodies, and heparin suppliers and manufacturers to establish greater control have been "pretty impressive," according to Liu, the current way of making heparin will always be vulnerable to environmental (e.g., porcine disease) and human (e.g., purposeful adulteration) factors.
Liu likens maintaining control of the heparin supply to maintaining antidoping procedures for Olympic athletes. "You have to know what you're looking for," he says. But just as athletes find ways to circumvent drug tests, there may always be heparin contaminants that will fall outside of materials inspection parameters.
Synthetic heparin created in a GMP environment from fermentation to packaging would certainly eliminate these concerns. The best-case scenario, however, is that synthetic heparin could be ready for patient use within 4-5 years, Liu says. But this is only if there are investment dollars for development and production scale-up.
Pharmaceutical Manufacturing, PharmaManufacturing.com, and On Pharma have been covering, and analyzing, the heparin case since it began. In September, we'll take a closer look at the lessons learned from the heparin crisis, and what all manufacturers must do to ensure safe and efficient supply lines.
--Paul Thomas
