Heparin probe highlights challenges of drug regulation

CHANGZHOU, China - On a dusty lane in east China, a small factory sitting amid strawberry and vegetable fields processes chemicals from pig guts into heparin, a commonly used blood thinner linked to 62 deaths and hundreds of allergic reactions in the U.S. and Germany.

The mysterious problems with heparin from the factory and others like it - China's deadliest product quality scandal since Chinese cough syrup killed 93 people in Central America a year ago - dramatically illustrate the perils of shifting drug production offshore.

With recalls of heparin products now in six countries, it is an issue that regulators are scrambling to address.

In the past month, China's drug safety agency has ordered tighter controls on heparin production. That followed a U.S. Food and Drug Administration order requiring all heparin imports to be tested. The FDA also announced plans to station eight regulators in China and hire five Chinese to work with them.

"This is just the tip of the iceberg in terms of problems with sensitive drugs," said Dr. Bryan Liang, an adviser to the Partnership for Safe Medicines, an American group working to promote drug safety. "The problem is only going to get worse as more materials come from suspect sources."

Heparin is derived from mucous wrung and washed from pig intestines and other animal organs. It has been used for decades to prevent clotting from intravenous procedures, dialysis and heart surgery.

The recent problems were traced to heparin made in China and marketed in the United States; so far, China has reported no allergic reactions to heparin used locally.

The U.S. FDA announced Tuesday that it had found 62 deaths and nearly 800 severe allergic reactions associated with heparin.

The first reports of such deaths were linked to products sold by Deerfield, Ill.-based Baxter International Inc., the biggest heparin seller in the U.S. But the most recent figures also included patients treated with other brands of heparin.

Baxter recalled nearly all its U.S. heparin injections, as have several other companies.

German manufacturer RotexMedica GmbH recalled batches of heparin from China after some 80 reports of allergic reactions, but no deaths.

Danish, French and Italian authorities also recalled batches of potentially contaminated heparin from China as a precaution, the European Medicines Agency said last month.

Three Japanese drug companies and a U.S. manufacturer, B. Braun Medical Inc., also recalled heparin products from Baxter's supplier, Waukanee, Wis.-based Scientific Protein Laboratories, which owns the factory sitting among farm fields outside of Changzhou, a sprawling industrial city west of Shanghai.

The FDA says a contaminant, identified as "oversulfated chondroitin sulfate," accounted for up to half of the active ingredient in some batches of heparin from the factory, known as Changzhou SPL. It has yet to confirm, though, whether the contaminant caused the allergic reactions.

Chondroitin sulfate, usually made of animal or shark cartilage, is used as a food supplement for joint pain. It is more than seven times cheaper than heparin, which might tempt suppliers somewhere along the production chain to substitute it. And its chemical similarity to heparin makes it hard to spot, the FDA said.

Heparin was first made in North America and Europe, but production has shifted to lower-cost developing countries over the past 20 years. The raw chemicals, or active pharmaceutical ingredients, used to make it and many other drugs are now mostly imported from China and India.

"We have an increasingly globalized supply chain," said James Shen, publisher of the industry newsletter Pharma China. "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.

The U.S. FDA inspects only about 7 percent of foreign drug makers each year; it failed to inspect Changzhou SPL because of what it says was a language mistake.

The raw chemicals for the drug are usually made in small, unregulated workshops, using pig guts from slaughterhouses and sausage-casing factories, processed by chemical companies and eventually drug makers before being delivered to hospitals.

"The supply chain that was used to make the materials is impossible to follow," said Liang, of the Partnership for Safe Medicines in Virginia. "Add to that, Chinese manufacturers are not averse to cutting corners, as we've seen in toys, toothpaste, food and drugs."

When FDA experts belatedly inspected Changzhou SPL last month, they found scratched tanks with "unidentified material" sticking to their insides. Records were missing for some of its sources of raw heparin, and testing was incomplete.

"We are a company with high standards. We have nothing more to say to you!" shouted a manager at Changzhou SPL who answered the phone but refused to give his name.

"We have never had chondroitin sulfate on our production list. Just see the official announcements," he said before slamming the phone down.

A Scientific Protein Laboratories statement emphasized that FDA findings suggest the chondroitin sulfate was in the affected heparin before it reached Changzhou SPL.

"The observations made by the FDA during its inspection do not indicate any fundamental or underlying problems with the Changzhou SPL facility," the statement said, quoting industry consultant Robert Rhoades speaking on SPL's behalf.

Importers beware is the principle governing all international trade in drugs and pharmaceutical chemicals, said Shen, of Pharma China.

"For exports, (China) doesn't regulate anything at all. There is no export licensing system in place," he said, noting that such chemicals are generally unregulated. "The U.S. FDA doesn't regulate those exports from the U.S. either."

FDA officials say a U.S.-China agreement on improving cooperation in drug safety, signed in December, has helped the heparin investigation, though heparin was not on the original list of drugs covered by the pact.

Even with inspections, heparin is tricky, said Liu Jian, an expert on the chemical at the University of North Carolina.

"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, its very hard to tell what you have there."

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On the Net:

U.S. Food and Drug Administration: http://www.fda.gov

China State Food and Drug Administration: http://www.sfda.gov.cn