Washington, DCPatients with recently-implanted heart stents, vascular stents or grafts are wondering if they are going to be affected by the tainted heparin scare, after the US Food and Drug Administration last week alerted medical device manufacturers that they should review their sources of heparin. Some medical devices, including devices used in pulmonary bypass and in-vitro diagnostic procedures, are coated with heparin.
An FDA spokesperson assures that "we're not talking about a large amount" of heparin, in such devices. Still, amidst revelations that as much as 50 percent of the active ingredient of heparin inbound from China has been substituted with a counterfeit ingredient, one has to wonder about the long-term effects to constant exposure.
"A week ago the FDA announced that deaths linked to tainted heparin from China have tripled, from 19 to 62 since January of last year. In contrast, there were just three deaths due to allergic reactions to heparin in all of 2006.
In the last several weeks, the media has been awash in recall reports. First it was Baxter International—one of the largest suppliers of heparin in the US—followed by B Braun Medical Inc., then Covidien on March 28th.
German manufacturer RotexMedica GmbH recalled batches of Chinese-produced heparin after reports of 80 allergic reactions. There have been no deaths reported so far in Germany. In March, the European Medicines Agency reported that health authorities in Denmark, France and Italy have also recalled heparin in their respective jurisdictions, as a precaution. Japan, too.
At the center of the heparin crisis is a newly-identified counterfeit ingredient that has found its way into the heparin sourced from China: oversulfated chondroitin sulfate, a derivative of animal or shark cartilage taken as a food supplement by patients experiencing joint pain. In response to the spike in adverse reactions (800 reports so far) and patient deaths linked to the blood thinner, the FDA utilized more sophisticated testing.
That's when the oversulfated chondroitin sulfate was discovered. Why it was found in heparin is unclear. However, it has been reported that the substance is seven times less expensive than pure heparin, while impersonating heparin so well from a chemical standpoint that it's hard to spot.
One can imagine the motive, given past indiscretions on the part of Chinese suppliers involving pet food, toothpaste, children's toys and cough medicine. The latter was responsible for the deaths of 93 people in Central America, many of them children, a year ago.
Heparin, refined from the mucous membranes of pigs, has been around for decades and is used as a blood thinner for various procedures, including dialysis and some surgeries.
It should be noted that heparin used to be made primarily in the US and Europe. However, over the last two decades production has shifted to low-cost, developing countries.
"We have an increasingly globalized supply chain," said James Shen, publisher of the industry newsletter Pharma China, in an Associated Press news report. "The Chinese are now major suppliers of bulk pharmaceuticals and also supply intermediate chemicals for drugs.
"It is likely we will continue to see the same problems with other drugs," he added.
So far the facility in China at the center of the crisis, Changzhou SPL near Shanghai, has not been shown to be the actual source for the contaminant. In other words, the oversulfated chondroitin sulfate got into the supply chain before it arrived at the American-owned plant.
Finding the source of that contamination will be next to impossible, given the sheer size and breadth of the largely un-regulated industry currently churning out raw heparin, produced mostly in small shops and backrooms as crude and raw as the heparin they produce.
"The supply chain that was used to make the materials is impossible to follow," said Dr. Bryan Liang, an adviser to the Partnership for Safe Medicines, an American group working to promote drug safety, located in Virginia. "Add to that, Chinese manufacturers are not averse to cutting corners, as we've seen in toys, toothpaste, food and drugs.
"This is just the tip of the iceberg in terms of problems with sensitive drugs. The problem is only going to get worse as more materials come from suspect sources."
It is not clear why the FDA failed to inspect the Changzhou SPL plant prior to giving its approval for the facility to start producing heparin in 2004—a violation of its own policy. However, when an inspection was finally done last month, the Associated Press reported that "unidentified material" was found sticking to the insides of scratched tanks. Records were missing for some of its sources of raw heparin, and testing was incomplete.
A statement made on behalf of Scientific Protein Laboratories, majority owner of the Changzhou SPL facility, suggested "the observations made by the FDA during its inspection do not indicate any fundamental or underlying problems with the Changzhou SPL facility."
It has been reported that China has no system in place for regulating exports. A pact signed in December between the US and Chinese governments to improve co-operation in drug safety has aided the investigation. However, heparin is said not to be on the list of drugs covered by the agreement. Even with inspections, heparin is tricky, said Liu Jian, an expert on the chemical at the University of North Carolina, in an Associated Press report.
"In producing heparin, it's very important to control the quality of the raw heparin," Liu said. "Once you have a contaminant that you didn't get rid of in the early stages, it's very hard to tell what you have there."
While all this is sorted out, patients adversely affected by tainted heparin may have no shortage of hosts to which assess and assign blame: manufacturers for increasingly moving production off-shore in an effort to increase profits and lower costs, regulators without the resources to properly police the supply, and the government itself for not equipping its own regulatory authority, thus allowing this issue to reach such a crisis.