Baxter tracked the contaminant to SPL, which has a facility in China that manufactures the heparin that companies such as Baxter bought and used in their blood-thinner products. The Chinese facility, known as Changzhou SPL, used a supply chain for the ingredients to make its heparin that the included unregulated labs and farms in rural China. The FDA ultimately traced the poisoned heparin back to 12 Chinese companies that had added OSCS to their products.
Chinese officials initially disputed charges that the contaminants came from their country but have since acquiesced to the FDA's demand that Chinese companies test all ingredients used in U.S. drugs for contamination. The FDA, which says it has developed improved tests for screening heparin for contamination, is also planning to participate in an international summit at an undetermined location next year where international scientists and regulators will discuss ways to improve and enforce drug safety rules. This case—like those involving melamine in baby formula and pet food—illustrates the danger of U.S. dependence on products, including drugs, from other countries where safety standards are lower than those enforced by the FDA.
Searching for a synthetic alternative
Nearly all of the $3-billion worth of heparin sold worldwide annually is derived from swine, but "there aren't enough pigs in this country to treat our own needs," Linhardt says.
Jian Liu, an assistant professor of medicinal chemistry at the University of North Carolina School of Pharmacy at Chapel Hill agrees. "We don't like the way we're getting heparin now," says Liu, who is working with Linhardt to create synthetic heparin. "The process of getting the raw materials for heparin from swine leaves the finished product open to viral contamination."
The threat has given a new sense of urgency to Linhardt's effort to develop a synthetic version of the heparin use in short-term blood thinners, but he still faces some major obstacles. Although it is possible to bioengineer heparin in the lab, the drug's complex structure makes it difficult to mass produce: It takes at least 100 metric tons of heparin to meet the world's needs for a single year. Through trial and error, it took Linhardt and his team a year to make just 100 milligrams of his synthetic version. "The challenge is there are multiple enzymatic steps involved," Liu says. "These enzymes are very sensitive to temperature and not very stable," which means the fermentation process is not always successful.
Even if the enzymes survive the fermentation process and produce heparin, making that much of the drug synthetically (without the use of swine) could require using a 264,172-gallon (one-million-liter) fermenter 100 times. The largest fermenter on RPI's campus has a capacity of 10.6 gallons (40 liters) and would be able to produce only one gram of synthetic heparin at a time with each successful fermentation.