Heparin Contaminate Identified

Ladies and Gentlemen: In this corner, wearing red, white and blue, we have the United States, represented by the FDA, who are defending their claim that tainted heparin, originating in a Chinese factory, has caused numerous deaths and countless adverse reactions. And in the opposite corner, wearing red and yellow, is China, whose officials dispute the allegations and claim the contaminant can’t be the reason behind the allergic reactions. However, the U.S. may have the scientific evidence in hand to land the winning punch and prove their case.

A team of scientists, led by MIT professor Ram Sasisekharan, have confirmed that the contaminant in the heparin is a chemical called oversulphated chondroitin sulphate (OCSC), reinforcing earlier findings by the FDA. Chondroitin sulfate is a naturally occurring compound made from animal cartilage and is often used in supplements to treat joint pain. However, oversulfated chondroitin sulfate does not occur naturally; it is a man-made form of chondroitin sulfate that not only mimics heparin’s qualities, but has a structure very similar to that of heparin. Identification of this chemical requires highly specialized testing, which is why the tests normally used to inspect heparin batches did not identify the contaminant.

According to the researchers, oversulphated chondroitin sulphate causes severe allergic reactions and low blood pressure by activating two inflammatory pathways. People injected with the contaminated drug have experienced reactions such as difficulty in breathing, vomiting, nausea, excessive sweating and rapidly falling blood pressure. “These results provide a potential link between the presence of chemical contaminant in heparin and the clinical symptoms observed in affected patients,” Sasisekharan said.

Baxter International manufactured and distributed the contaminated heparin, but the contaminated material was supplied by Changzhou SPL, a Chinese subsidiary of Scientific Protein Laboratories. According to a Congressional investigator, oversulfated chondroitin sulfate costs a mere $9 per pound compared to $900 a pound for heparin, leading federal drug regulators to believe the contamination was intentional. Up to 50 percent of the content in some heparin batches were contaminants, “and it does strain one’s credulity to suggest that might have been done accidentally,” said Janet Woodstock, Director of the FDA's Center for Drug Evaluation and Research.

David G. Strunce, chief executive of Scientific Protein Laboratories, described the contamination as “an insidious act” that “seems to us an intentional act upstream in the supply chain,” and says that when his company tried to find the original source of the contamination, they were stopped by Chinese authorities. Robert Parkinson, Baxter International’s Chief Executive, said the company was “alarmed that one of our products was used in what appears to have been a deliberate scheme to adulterate a life-saving medication.” Both Baxter and Scientific Protein Laboratories have recalled the tainted heparin, and as of March 2008, imports from the Chinese supplier had been blocked “until they could be scrupulously tested.”

U.S. officials believe the contamination may have occurred as early as 2006, with the illnesses and deaths only recently being linked. So far, the tainted heparin has been responsible for 81 of the 131 deaths reported in the U.S., but no word on fatalities from 12 other countries who, according to the FDA, also received contaminated batches.

Chinese officials have acknowledged the presence of the contaminant, but say it is not responsible for the allergic reactions or deaths. China claims that no countries other than the U.S. have experienced problems with the drug, contending that the contamination could have occurred in the U.S. and insisting they have access to the facility that made the heparin vials. FDA officials admit they failed to conduct an inspection of the Changzhou SPL plant, but say an inspection would not have been able to uncover the contamination. When the agency did inspect the facility in February, they found so many problems that the plant was blocked from exporting to the U.S. Congressional investigator, David Nelson, criticized Baxter International, which bought heparin ingredients from Changzhou SPL from 2004 to present but did not inspect the facility until September of 2007. “The company sent one person who spent one day in the plant. Five months later, the FDA discovered a myriad of problems,” Mr. Nelson said. “It really is impossible for a plant to have fallen that far out of compliance in five months,” he added.

By law, the FDA is not required to inspect foreign drug plants, and according to the agency lacks the resources to do so. It is unclear exactly how many plants ship pharmaceutical ingredients and finished drugs into the U.S., but the number for China alone is estimated at several hundred. Last year the FDA inspected 250 foreign pharmaceutical ingredient manufacturers, 13 in China. Dr. Woodstock says “the FDA of the last century is not constructed” to regulate the present marketplace and notes that “inspection resources have dropped while responsibilities have soared.” The agency will spend $11 million this year on foreign drug inspections, with a fiscal 2009 budget of $13 million.

New data released April 22 by the Government Accountability Office found the 2009 budget inadequate; estimating that between $67 million and $71 million annually would be needed to biennially inspect the 3,249 foreign drug manufacturers currently listed with the FDA. Dr. Woodstock says the FDA would need another $225 million annually to perform adequate inspections.

She says that manufacturers must assume greater responsibility for the quality of their products. Edward M. Kennedy, Senate HELP Chairman, agrees and says manufacturers must use better tests to detect impurities and contaminants in their products. “Even the most up-to-date manufacturing processes won’t ensure safety if manufacturers can’t guarantee the ingredients aren’t contaminated.” Senator Kennedy said.