A worker cleaned pig intestines in Xinwangzhuang, a Chinese village. Lining from the intestines is processed into crude heparin.
THE NEW YORK TIMES - By DAVID BARBOZA and WALT BOGDANICH
Published: February 28, 2008
RUGAO, China — With reports of more than 400 patients in the United States suffering serious complications after receiving the blood-thinner heparin, American investigators are trying to determine whether the raw material for the drug, made from pig intestines, became contaminated on the journey that begins in the slaughterhouses of China.
The investigators are examining the records of a factory an hour from here that supplies much of the active ingredient in heparin for Baxter International, which earlier this month halted sales of multidose vials of heparin after reports of injuries and four deaths.
The owner of the factory, which is known as Changzhou SPL, says its supply chain is safe. It buys raw material from only two reputable wholesalers, it says, and audits their 10 to 12 suppliers.
“We have a collection chain in place, and we stick with that,” said David Strunce, the president of Scientific Protein Laboratories, an American company that owns a majority of Changzhou SPL. He declined repeated requests from The New York Times to identify those smaller suppliers, saying it was proprietary information.
But interviews with dozens of heparin producers and traders in several Chinese provinces, as well as a visit to a village near here dominated by tiny family workshops that process crude heparin from pig intestines, show the difficulties confronting investigators as they seek to trace the supply chain. The picture that emerges is of a chain more complex, and less orderly, than the one Mr. Strunce laid out.
The Chinese heparin market has become increasingly unsettled over the last year, as pig disease has swept through the country, depleting stocks, leading some farmers to sell sick pigs into the market and forcing heparin producers to scramble for new sources of raw material. Traders and industry experts say even big companies have been turning more often to the small village workshops, which are unregulated and often unsanitary.
One of the wholesalers named by Scientific Protein Laboratories, Ruihua Biochemical in Hangzhou, said it provided a mix of crude heparin that it manufactured and some that it bought “from small factories nearby in several villages.” The owner, Hua Ruihua, said he never inspected the small factories. “We are not the government,” he said in a telephone interview. “We have no right to inspect their pigs or intestines or facilities.”
The owner of one of those workshops, Fan Yinan, said, “I sold to Ruihua several times before, but since last September I have had no intestines.” He confirmed that “no one from Ruihua inspected my pigs or intestines.”
Asked about Ruihua Biochemical, the S.P.L. chief, Mr. Strunce, said, “We have no information to suggest that your information is true.”
This week, a spokeswoman for Baxter said the number of reports of adverse reactions to heparin had surpassed 400. A spokeswoman for the Food and Drug Administration in the United States said the agency was reviewing the new reports and did not yet have a revised count.
The authorities have not determined that problems with the heparin supply chain led to the deaths and adverse reactions, first reported last month in Missouri. Nor have investigators determined that heparin from China was the culprit. Baxter also gets some of its ingredients from a plant in Wisconsin. Neither S.P.L. nor Baxter has been accused of doing anything wrong.
Even so, the problems involving heparin have again focused attention on the quality of products from China and the gaps in regulation by both the Chinese and United States governments. S.P.L.’s plant in Changzhou was certified by American officials to export to the United States even though neither government had inspected it. The plant has been exporting heparin to Baxter since 2004.
Like many chemical companies in China that make pharmaceutical ingredients for export, S.P.L. fell into a regulatory void. A spokesman for China’s State Food and Drug Administration, Shen Chen, said his agency had not inspected the S.P.L. factory because “as far as we know, it is not a drug manufacturer; it is a producer of chemical ingredients.” Mr. Shen said his agency was helping American investigators as part of a recent agreement with American regulators.
The process of making heparin begins with the intestines of slaughtered pigs, from which mucous membrane is collected and cooked, eventually producing a dry substance known as crude heparin. Major heparin producers like S.P.L. take that substance, refine it and sell it to companies like Baxter that make the final product, which is widely used in cardiovascular surgery and dialysis.
China Didn’t Check Drug Supplier, Files Show (February 16, 2008) Some experts say as much as 70 percent of China’s crude heparin — for domestic use and for export — comes from small factories in poor villages. One of the biggest areas for these workshops is here in coastal Jiangsu Province, north of Shanghai, where entire villages have become heparin production centers.
In a village called Xinwangzhuang, nearly every house along a narrow street doubles as a tiny heparin operation, where teams of four to eight women wearing aprons and white boots wash, splice, separate and process pig intestines into sausage casings and crude heparin.
The floors had large puddles and drainage channels; the workshops were dilapidated and unheated; and steam from the production process fogged up the windows and soaked the walls. There were large ovens to cook ingredients and halls lined with barrels to store enzymes, resins, intestines and wastewater.
“This is our family-style workshop,” said Zhu Jinlan, the owner of one heparin operation, who stopped sorting pig intestines and invited visitors to a back room, where she lives with her husband and child. “We’ve been doing this about 10 years.”
Experts say the small, unregulated factories could pose dangers because they do not have the same controls and rules as large slaughterhouses, which also produce crude heparin.
“If you don’t control the incoming source, it’s very hard to get rid of the contaminants,” says Liu Jian, a heparin expert at the University of North Carolina.
Mr. Strunce of S.P.L. says his company never buys directly from the crude-heparin producers, only through its wholesalers, which he called “consolidators” — Changzhou Techpool, its Chinese joint venture partner, and Ruihua. His company, he said, has records documenting all the transactions.
But here in Rugao, producers of crude heparin tell a somewhat different story. A sales manager for a major supplier, Nantong Koulong, said he sells directly to S.P.L. without going through either of the two wholesalers. “We provided crude heparin to Changzhou SPL,” said the sales manager, Chen Jianjun. Some of Koulong’s stock comes from the unregulated workshops, he said.
The owner of one such workshop, Ms. Zhu in Xinwangzhuang, said she sold to S.P.L. two years ago. She also sells to Koulong. “We are really a traditional family-style plant,” she said. “We have no certificate.”
S.P.L. said it never bought directly or indirectly from Koulong.
To the south, in Zhejiang Province, two officials of Zhejiang Willing Animal Byproducts Processing said they, too, sold to S.P.L. “We supply heparin to Changzhou SPL,” said Fang Weicai, the general manager, although he said later that he sold it privately and not under the auspices of his company.
After an outbreak of blue ear pig disease swept through 25 of China’s 31 provinces and regions last year, prices soared, and many drug suppliers had to look to the small workshops. The epidemic, said Cui Huifei, a heparin expert at the Shandong University School of Medicine, “made those biotech companies inevitably purchase from the family-style plants, for cheaper prices.”
A sales manager for another large slaughterhouse in Shandong Province, north of Jiangsu, said he was approached late last year by a buyer for S.P.L. offering what he described as rock-bottom prices for crude heparin.
“It was impossible,” said the sales manager, Wang Shengfu, who works for Shandong Jinluo Group, a major producer of crude heparin. “Only small factory-style farms could accept that low price.”
The deal was never consummated.
Mr. Strunce said S.P.L. responded to the disease outbreak by buying less raw material in China. “We were not out looking for additional heparin because we made do with what we already have,” he said, adding that the company “pays more than many people for heparin over there because we require a higher standard of heparin.”