Contaminant In Heparin Is Identified
FDA Investigating Manufacturing Process

By Marc Kaufman
Washington Post Staff Writer
Thursday, March 20, 2008

A modified form of a cheap and widely used dietary supplement sold to relieve joint pain was identified as the contaminant found in tainted and at times lethal heparin produced in China for American patients, Food and Drug Administration officials said yesterday.

Agency officials said they were investigating whether the compound, chemically modified chondroitin sulfate, was intentionally added to cut costs and boost profits or was mixed in by mistake. In either case, they said, it was not part of the prescribed manufacturing process.

"This is a biological compound that is not found in nature," said Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research. "At this point, it's still to be determined if it was introduced intentionally or by accident."

The announcement drew an immediate and worried response from members of Congress and drug experts, who said the tainted heparin is a sign of a much larger problem.

"I have no doubt that there are other contaminated or counterfeit drugs like heparin coming into the country, because there's really no system in place to stop them," said William Hubbard, a top official at the FDA until 2005 and part of a consumer and industry group lobbying -- so far unsuccessfully -- to get more resources for the agency to address the dangers of foreign-made drugs.

A large and growing portion of drugs and drug ingredients for the American market are manufactured abroad, increasingly from lightly regulated nations such as China and India.

Heparin, which has been on the market for six decades, is widely used as a blood thinner in kidney dialysis and surgery.

The contaminant is believed to have caused more than 700 severe allergic reactions in American patients, including a still-undetermined number of deaths. FDA officials said the Chinese contaminant was found in lots of heparin associated with the reactions, but it is not certain whether it caused them.

In a statement, Sen. Edward M. Kennedy (D-Mass.), chairman of the Senate Health, Education, Labor and Pensions Committee, said the FDA's announcement reflects an "unacceptable" situation.

"Whether this contaminant was introduced intentionally or by accident, the full force of the law must be brought to bear to bring those responsible to justice," Kennedy said. "To guard against future abuses, every drug manufacturer needs to inform FDA of where it sources its ingredients and what it is doing to ensure that these ingredients are pure and potent."

Last week, the FDA ordered sophisticated testing of all imported heparin and its active ingredients, either by the manufacturers or the agency. Woodcock said the agency feels "doctors and patients now can be confident that the product on the market has been tested and is safe."

The heparin case is reminiscent of the discovery last year that Chinese suppliers had been putting the compound melamine into gluten used by American pet food manufacturers to make the food appear more nutritious. Thousands of American pets became sick or died as a result.

As in the pet food case, the chondroitin sulfate in the heparin is considerably cheaper to produce than pure heparin.

The tainted drug was distributed by Baxter International, which bought it from a Wisconsin company that gathered and distilled heparin in a plant it built in Changzhou, China. Heparin is made from the intestines of pigs, and chondroitin sulfate can be produced from pig cartilage. Woodcock said the contaminant, over-sulfated chondroitin sulfate, is a chemically modified form of the joint pain supplement that could not be detected by standard quality-control testing.

Baxter's supplier, Scientific Protein Laboratories of Wisconsin, said yesterday in a statement it believed the substance did not come from the Changzhou plant but further upstream in the supply chain, which includes small family farmers and weakly monitored "consolidators."

"Based on what we know, we believe that the contamination identified by the FDA occurred earlier in the supply chain," said Robert Rhoades, an independent consultant with Becker & Associates, who is working with the company.

"Using the very recent tests used by the FDA to detect the contaminant, [the Changzhou plant] tested samples of incoming crude heparin material. The samples showed 'peaks,' indicating that the contaminant was in the material before it reached" the plant, Rhoades said.

Rhoades said a recent increase in allergic reactions to heparin supplied to German patients by a different manufacturer suggests "that the problem is significantly broader than material provided" by the Changzhou plant. The active ingredient for much of the world's heparin comes from China.

Woodcock said because the "over-sulfated" form of the compound detected during testing is not a natural substance, it had to have been deliberately modified. She said some manufacturers have experimented with the over-sulfated form of the supplement, but there have been few clinical trials and there is no approved use for it.

Although the contaminated heparin is the largest and highest-profile instance of tainted prescription drugs made in China, it is not the first. In the late 1990s, a spike in deaths associated with the intravenous antibiotic gentamicin was linked to China-based Long March Pharmaceuticals. Although no definitive link was ever established, tests by German researchers later found a wide range in quality and effectiveness in what were supposed to be uniform dosages of the drug, leading them to write that "it was assumed" the deaths "were related to faulty manufacture."

Hubbard, the former FDA official, said it is not surprising that tainted drugs supplied though agency-approved channels are showing up from abroad. "The history of some of these developing countries in terms of substituting or counterfeiting concerns is a long and well-documented one," he said. "And at this point, the FDA doesn't have the resources or system in place to make sure some of these bad drugs don't get through to the public."