Chinese Drugs are Gross

The Heparin Trail
China's Role In Supply
Of Drug Is Under Fire
By GORDON FAIRCLOUGH and THOMAS M. BURTON
February 21, 2008; Page A1

YUANLOU, China -- In a small, damp factory here, blood-smeared men wring pulp from pig intestines, then heat it in concrete vats.

The activity at Yuan Intestine & Casing Factory is the first step in the poorly regulated process of making raw heparin, the main ingredient in a type of blood-thinning medicine that in recent days has come under suspicion in the deaths of four Americans.

More than half the world's heparin comes from China. The chemical is often extracted from pig entrails in small factories -- many as rudimentary as this one, which also manufactures sausage casings from intestines. The heparin eventually ends up in drugs used world-wide by patients having surgery or who need dialysis.

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Gordon Fairclough
Bare-handed workers at Yuan Intestine & Casing Factory untangle and flush pig intestines that will be used to make heparin.
Heparin goes through extensive processing in its journey from abattoir to IV bag. Nevertheless, because some of it originates in tiny Chinese factories like these, if there's a problem with the final medication, it can be nearly impossible to trace the raw heparin back to the source, the pigs whose tissue was used to make it.

The lack of a well-documented supply chain for medicines such as heparin is a problem that has come under the spotlight with last week's announcement of four deaths and some 350 allergic reactions among patients who received heparin sold in the U.S. by Baxter International Inc. Yesterday the Food and Drug Administration, which is trying to pinpoint the cause of the deaths, inspected a heparin-production facility in China.

David Strunce, the president of Scientific Protein Laboratories, Baxter's main supplier of heparin, says that the Yuan Intestine & Casing Factory isn't in his company's supply chain. He says Scientific Protein can't trace its supplies in China in as much detail as it can in the U.S. "We're all dealing with the China collection system," Mr. Strunce says.

Baxter declined to comment beyond a statement saying that it selects "suppliers that have proven quality track records."

The root causes of the recent deaths and illnesses remain unclear. However, visits to Chinese factories that produce raw heparin, and interviews with industry executives reveal widely varying standards of regulatory oversight.

Furthermore, interviews with regulators and suppliers in both the U.S. and China make it clear there are divergent views about how necessary it is that heparin be traceable to the source pigs.


WSJ's Gordon Fairclough visits a factory in a small village in China where workers are making heparin, an anti-clotting medication, from pig intestines. Such heparin is traded and bought in bulk from pharmaceutical companies.
The growing concern over heparin's safety brings to the forefront the question of whether the raw materials from which it is made -- for that matter, the raw materials for any drug derived from animals -- should be more tightly controlled. The FDA's position is that the purification steps in the drug-making process are sufficient to produce a pure product from pig tissue, and that "companies are responsible for sourcing the materials" and "appropriately processing the material."

Heparin goes through numerous, intensive purification steps before reaching medicine cabinets. However, some doctors and industry executives say it's still essential that even raw materials be consistent, clean and traceable so that if a problem arises it can quickly be contained.

The health of the animals from which heparin is extracted can be important to the safety of the drug. Drug makers in the U.S. and Europe stopped using cows -- a once-common heparin source -- after the discovery of bovine spongiform encephalopathy, or "mad cow" disease, amid concerns that the illness could be passed on.

In China, not all heparin makers answer to drug regulators. That's partly because some are registered as chemical makers, not drug producers. It's a legacy of a regulatory system that focuses on finished drugs, not their ingredients, says Shen Chen, a spokesman for the State Food and Drug Administration in Beijing.

"It's a situation that China and the U.S. have to face together," he says.

Heparin makers in China readily acknowledge the lack of oversight. Yuan Changkun, the owner of the small factory here, says health regulators don't visit his plant. Mr. Yuan doesn't keep records of where he acquires the intestines he uses. Nor is he sure who the end customers are.

"Basically, it goes overseas. It's for foreigners," he says.

Selling to Middlemen

Like many small producers, Mr. Yuan sells his output to middlemen, making it tough to know where in the world it eventually ends up.


Some drug-industry executives say that minimizing heparin contamination -- even at the early stages -- can be crucial. It's "the only way to ensure the necessary product quality and safety," says Li Li, chairman of Shenzhen Hepalink Pharmaceutical Co. The company makes highly refined heparin used by Baxter's main rival in the U.S. heparin market, APP Pharmaceuticals Inc.

In contrast with the FDA's position that the heparin-purification process alone may be sufficient, Patrick Soon-Shiong, APP's chairman, contends that the ability to trace back to individual animals is important. Heparin is extracted from the guts of the animal, he notes, "and lymph nodes in the bowel may harbor contaminants from infections."

Officials from Baxter declined to discuss the question of traceability of raw materials.

China is the world's largest heparin exporter, shipping more than $100 million of the substance a year. China's lack of consistent oversight of its heparin industry highlights a regulatory gap that's opening as drug makers increasingly go shopping globally for ingredients.

The raw heparin made by China's myriad small producers ends up in the hands of about 50 export companies, which sell to customers overseas. In the first half of last year, more than 85% of these heparin exports went to the U.S., Austria, France, Italy and Germany, according to an industry trade group.

Officials from the FDA are now in China to inspect one of Baxter's key heparin suppliers in Changzhou, a city northwest of Shanghai. It remains unclear whether the troubles with Baxter's drug are in any way caused by heparin made in China by its supplier, Wisconsin-based Scientific Protein and that firm's Chinese partner.

Supply Workshops

Scientific Protein's Mr. Strunce says his company's China venture, Changzhou SPL, gets raw heparin from two wholesalers who gather it from "six to 12" workshops. "You can have better, or less good, workshops," Mr. Strunce says.

He says the factories mentioned in this article aren't part of his firm's supply chain.

An ideal system for tracing heparin back to the barnyard would involve tagging individual pigs, then keeping files detailing each animal's record of vaccination, feed and overall health. That record could follow the animal to the slaughterhouse, providing a paper trail which a drug company or the FDA could later tap into.

APP Pharmaceuticals, Baxter's main rival, says its Chinese supplier, Shenzhen Hepalink, is able to trace refined heparin back to individual pigs. Shenzhen Hepalink also says it requires suppliers of raw heparin to follow rules designed to minimize the chances of contamination.

China Jurisdiction

China's State Food and Drug Administration, which regulates drug makers, says the only heparin makers under its jurisdiction are those registered as pharmaceutical companies.

APP's supplier, Hepalink, is registered as a pharmaceutical maker. Hepalink has been inspected and approved by the FDA.

Many other heparin processors, including Changzhou SPL, the plant that supplies Baxter, are registered as chemical or agricultural-byproducts companies and weren't checked by health authorities.

A spokesman for the Chinese government's main product-safety watchdog, the General Administration of Quality Supervision, says his agency "is not responsible for anything related to drug issues."

That leaves makers of raw heparin with no regular government supervision, many manufacturers say.

Wang Jiewen, who runs a sizable heparin and sausage-casing factory in China's eastern province of Anhui, says inspectors routinely check his sausage-casing production lines, but not his heparin operations. "There's not really much regulation for the heparin," he says.

Consumers in the U.S. and Europe are protected in part by their own regulators. But even the FDA can offer only limited oversight.

The agency did, at most, 21 inspections of Chinese drug-making facilities annually in fiscal years 2002 through 2007, according to the U.S. Government Accountability Office. That represents a fraction of the 714 Chinese facilities that, as of the end of fiscal 2007, the GAO says were involved in making drugs or drug ingredients for the U.S. market. FDA Commissioner Andrew von Eschenbach has said he would like to station inspectors in China.

Extracting medicines from animal entrails is by its nature a grisly business. But it's commonplace. An experimental blood substitute is made from cow's blood, for instance, and a clotting medicine, thrombin, also derives from cattle. Before heparin was made from pig intestines, it came from beef lung.

Purifying Heparin

Heparin itself is a molecule related to sugar that's present in pigs, sheep and other animals. Because it is derived from living tissue, companies that purify raw heparin follow a range of steps -- filtration, heat treatments and other processing -- to reduce the risk that it contains active viruses or bacterial toxins.

Since mid-2006, China's pig herds have suffered serious outbreaks of porcine reproductive and respiratory syndrome, a viral illness commonly known as blue-ear disease. Sick animals are supposed to be rejected by slaughterhouses, but enforcement can be lax. Also, infected animals may be slaughtered before symptoms are recognized.

Some drug makers say it's important to be able to trace back to the pigs that served as raw materials. That way, if patients have adverse reactions to a drug, the root problem can be discovered and other possibly tainted batches can be pulled from the market.

Many Chinese heparin manufacturers say this is a very difficult standard to meet in China's business and agriculture environment. Wang Shengfu, manager of another raw-heparin maker in China's Shandong province, Linyi Meiyuan Seasoning Co., notes that unscrupulous businesspeople and middlemen can easily "provide buyers with fake records."

His firm uses pig intestines only from slaughterhouses owned by its parent company, he says, so it can keep accurate records.

Mr. Yuan, the owner of the heparin and sausage-casing factory in the village of Yuanlou, is a gregarious man who takes pride in the business he has built. Now 57 years old, he has earned enough money from heparin to send his two sons to university. Mr. Yuan himself never graduated from high school because his family was too poor to pay for school.

He launched the original business in the mid-1980s making sausage casings from intestines. Later he added heparin production.

Mr. Yuan's four-room factory, which has a roof made of tile and thatch, is part of the compound in which he also lives. In a central courtyard, raw heparin -- a brown-and-white powder -- air-dries on a table.

Every day, his company collects barrels of pig intestines from slaughterhouses in the region. "They give us a commodity. I give them money. We don't keep records," he says. The intestines of about 3,000 pigs are required to produce a kilogram of heparin.

In his factory, men in thick aprons untangle intestines at a bench, flush them with water and pass them through a wringer. The resulting slurry is dumped into concrete vats, where it gets heated. Because coal is expensive, the factory sometimes burns rubbish -- old shoes and clothing -- to heat the slurry.

The slurry is later mixed with a resin that adheres to heparin. That mix passes through several more steps. Toward the end of the process the raw heparin is stored in old-fashioned, Chinese-style ceramic pots on the floor.

Mr. Yuan produces about six kilograms of the stuff a month, which he sells to middlemen. Recently it has been selling for 6,500 yuan, or about $900, a kilogram.

Not all factories are so primitive. Mr. Wang, the owner of the Anhui plant, recently invested in a larger facility that uses stainless-steel tanks and other more modern equipment. There, workers on three assembly lines process the intestines of 6,000 pigs a day.

Still, it is a simple operation. The company's tiny lab performs just one test: Once a day, a heparin sample is tested to make sure it will prevent clotting in sheep's blood, a rough measure of quality. The plant produces 800 kilograms to 1,000 kilograms of heparin a year.

Mr. Wang says his company keeps records of which slaughterhouses provided the pigs in individual batches of heparin. But he says tracing pigs back to individual farms is impractical, since slaughterhouse records aren't detailed enough.

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