Jian Liu, PhD, associate professor at the University of North Carolina School of Pharmacy, is recognized as one of the leading heparin researchers in the U.S. Dr. Liu has served as a scientific resource on the recent crisis, and is one of the pioneers in the production of synthetic heparin, a possible alternative to natural heparin. Pharmaceutical Manufacturing’s Paul Thomas spoke with Liu by phone in August 2008.
PhM: In your mind, what happened last year? What was the root of the heparin crisis?
J.L.: The current theory is purposefully contaminated product, which demonstrates the vulnerability of the supply lines. . . . The problem of the oversulfated chondroitin sulfate contaminant, for example, is because our analytical process did not look for this kind of contamination. It’s just like the antidoping procedures for Olympic athletes. You have to know what you’re looking for.
From the manufacturing point of view, you have to control three things: the pig population, the process including purification and harvesting, and the analysis. If any of these three steps is not controlled, then your overall control is not satisfactory.
PhM: With heparin, are these three things more under control today than they were a year ago?
J.L.: The issues of controlling the process and the analytical tools are gone, but the pig population is still the same. Heparin is isolated from pig intestines, from roughly 400 to 700 million pigs each year, and so the size of the pig population is very large. You have to control the quality of the pig through the entire manufacturing process. That’s almost impossible to do.
The question is: What happens next? The entire process is not like we produce aspirin. It’s so much more complex. Often you don’t know something is a problem until it becomes obvious. There is no foolproof system!
PhM: Do you think the regulatory response to the crisis was satisfactory?
J.L.: The FDA did a pretty good job. It identified the contaminant pretty quickly—it took about two months to ID the issue and complete its study. That’s pretty impressive. They’re also working with the Chinese government, which is the right thing to do.
PhM: Some researchers might say that FDA was too hasty in its conclusions, that their might be other key contaminants beyond OSCS.
J.L.: I think the published data is pretty convincing that it’s mainly OSCS. There may be other factors there, but right now if we eliminate this contaminant, everything looks back to normal right now.
PhM: Tell us a little about your work in synthetic heparin.
J.L.: It started about three years ago with Bob Linhardt [at Rensselaer Polytechnic Institute]. Our assumption was that the current way to make heparin is vulnerable because of environmental factors and human factors. According to an article in the New York Times, you have to use tens of thousands of people to do the work to make heparin. It was easy to anticipate problems with this kind of production.
PhM: What kind of recipe do you use to make heparin?
J.L.: You have to introduce sulfa groups into polysaccharides, which is very difficult. You have to do it very precisely. But you can’t get a lot of enzymes in the commercial method, so we used bacteria and we can make a lot of human enzymes, and use that to make heparin. It’s about 10 to 100 times less expensive than making enzymes from hamster cells. But we can only make the heparin on the 10- to 100-milligram scale.
The major challenge is expansion of production. We are looking for a business partner to invest in the project. For an academic lab to do this at the kilogram scale is expensive.
PhM: Why has it been so difficult to scale up production?
J.L.: It’s really an engineering problem. We need someone who’s willing to serve as a partner to expand production. There are a lot of technical issues to overcome before we could begin to produce the 30 to 40 tons of heparin that are currently needed per year. One is how to improve the yield of the polysaccharide starting material, which comes from beef. The second issue is how we can accommodate our lab procedures into industrial-scale synthesis.
Right now we’re talking with several biotech companies—our focus is on how we can overcome these problems. We have not yet received contact from a large pharma company. Our technology is very promising, but we have to do tweaking and more development to make it possible on a large scale.
Another issue is that heparin is cheap. A year ago it was maybe $2,000 per kilo, and now it’s about $5,000 to $7,000 per kilo. Companies don’t yet have the incentive to do this kind of work [to produce synthetic heparin] unless another crisis happens with raw heparin. We’re hoping to develop [synthetic heparin] for market within four or five years, but we need to get investment. If we do we can produce enough for pre-clinical studies, and then we can expand to kilogram- or 100-kilogram synthesis.