血液凝固防止 ヘパリン製剤を自主回収 メーカー３社 透析２７万人に影響も
February 29, 2008 New York Times
Blood Thinner Might Be Tied to More Deaths
Amid indications that more people may have died or been harmed after being given a brand of the blood thinner 血液の抗凝結薬 heparin, federal drug regulators said Thursday that they had found "potential deficiencies" at a Chinese plant that supplied much of the active ingredient for the drug.
Baxter International, which makes the brand of heparin associated with the problems, and buys supplies from the Chinese plant, announced that it was expanding a recall to include virtually all its heparin products. Though Baxter produces much of the heparin used in the United States, regulators said the other major supplier would be able to meet the demand.
The Food and Drug Administration said the number of deaths possibly associated with the drug, made from pig intestines, had risen to 21 from 4. But it cautioned that many of those patients were already seriously ill and that the drug might not have caused their deaths.
The F.D.A. emphasized that it had yet to identify the root cause of the problem, and that it had not concluded that the Chinese plant was responsible. The agency also said it was investigating two Chinese wholesalers - also called consolidators - that supplied crude heparin to the Chinese plant, Changzhou SPL, as well as those that sold raw ingredients to the consolidators.
The New York Times reported Thursday that at least one of the consolidators received supplies from small, unregulated family workshops that scraped mucous membrane 粘膜 from pig intestines and cooked it, eventually producing a dry substance known as crude heparin.
The F.D.A. admitted this month that it had violated its own policy by failing to inspect SPL, located west of Shanghai, before the factory began shipping the heparin ingredient to Baxter in 2004. China's drug agency also did not inspect the plant.
Last week, the F.D.A. sent inspectors to the plant. Among the potential problems they found was a failure to properly follow the steps for identifying impurities and deficiencies related to manufacturing equipment. According to a redacted inspection report released by the agency, the SPL plant appeared to have made at least some heparin with "material from an unacceptable workshop vendor." The vendor was not identified.
Scientific Protein Laboratories, a Wisconsin company that is the majority owner of the Chinese plant, issued a statement Thursday saying the F.D.A.'s finding did not represent its final determination as to whether the plant complied with federal regulatory rules. S.P.L., the statement said, is committed to finding the root cause of the adverse reactions.
Erin Gardiner, a spokeswoman for Baxter, said the company was reviewing the F.D.A.'s report. "We expect S.P.L. to respond to those observations thoroughly and promptly," Ms. Gardiner said. "The observations are important and need to be addressed promptly but they are not necessarily indicative of the root cause."
The F.D.A.'s concern about heparin had previously centered on Baxter's multidose vials, but on Thursday Baxter agreed to voluntarily recall not only the multi-dose vials but also single-dose vials and a diluted solution of heparin used to keep blood clots from forming in intravenous lines. There have been no adverse reaction reports involving the latter product, called Hep-Lock heparin flush products.
"We have assurance from the U.S. Food and Drug Administration that there is an adequate supply in the market to meet the demand for these critical and lifesaving drugs," Peter J. Arduini, president of Baxter's Medication Delivery business, said in a statement released by the company.
The only heparin products made by Baxter that are still on the market are premixed bags of intravenous solutions, the Food and Drug Administration said.
"We at the F.D.A. understand how unsettling this whole situation with heparin is," said Dr. Sandra Kweder, the agency's deputy director, Office of New Drugs, Center for Drug Evaluation and Research. "We are determined to get to the root cause."
The F.D.A. estimates that more than one million multidose vials of heparin are sold per month in the United States, about half of which are manufactured and distributed by Baxter.
The problems with heparin, which is used to prevent blood clotting during dialysis and after some surgery, were first reported last month at a hospital in Missouri. Since then, the number of reported adverse reactions has risen to 448, the F.D.A. said. "Yes, we have gotten more and we are continuing to evaluate those reports," Dr. Kweder said.
At first, the agency said it believed that four people had died after allergic reactions to the drug. On Thursday, officials said as many as 17 more people may have died, but they described the links to heparin as more tenuous.
The adverse reactions have included decreased or low blood pressure and fast heart rate. Not all of them are known to involve Baxter products, but the drug agency did not issue warnings involving any other products.
The Chinese heparin market has been in turmoil 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.
As a result, even big companies have been turning increasingly to small village workshops, which are often unsanitary. In interviews this week at some of these workshops, employees told The Times that they had not been inspected by the government.
Scientific Protein Laboratories said it responded to the disease outbreak by buying less raw material in China. Its president, David Strunce, said in an interview this week that the Chinese plant bought supplies only from two reputable consolidators, and that its suppliers were audited.
The F.D.A has already finished inspecting one of the consolidators and is still looking at the second one, an agency spokeswoman said. The agency also plans, if necessary, to look at some of the small workshops that supply the consolidators.
"We will go where the investigation takes us," an agency official said.
March 10, 2008 WSJ
How Heparin Maker in China Tackles Risks
Inside Shenzhen Hepalink Pharmaceutical Co.'s high-tech factory in this southern China boomtown, workers in blue protective suits, surgical masks and gloves produce the active ingredient for heparin, the widely used blood-thinning medication.
Since a recall by Baxter International Inc. linked to tainted heparin from a different maker in China, Shenzhen Hepalink is the U.S.'s main supplier of the active ingredient in "large-dose" heparin, the type administered during heart surgery and kidney dialysis. It sells to APP Pharmaceuticals Inc., Baxter's main rival in the U.S. heparin market.
The Shenzhen Hepalink plant has been inspected and approved nine times in recent years by government health authorities, including the U.S. Food and Drug Administration, China's drug watchdog and German regulators. Buyers have done their own audits 25 times. To track a process that starts with crude heparin extracted from pig intestines, the company keeps more than 300 pages of data for each batch to "ensure traceability of each lot," Shenzhen Hepalink Chairman Li says.
Intense scrutiny of the supply chain and strict adherence to government-certified manufacturing practices are essential, he says. "Without this, there are huge risks in production."
The recent problems with heparin from China highlight the difficulty of monitoring the often diffuse and poorly regulated supply chains there -- for both Chinese drug makers and the multinational pharmaceutical companies that buy from them.
China's drug industry, now the world's biggest producer of active pharmaceutical ingredients, has come under heightened scrutiny following deaths and illnesses in the U.S. that led to Baxter's recall, and allergic reactions in Germany also connected to heparin from China. The problem is similar to last year's discovery of U.S. imports of tainted products including toothpaste, toys and pet food from China. But with medicines, the safety risks are especially big, and the ability to trace ingredients is even more critical to authorities' efforts to pinpoint the cause of adverse reactions and act quickly to limit further ill effects.
The FDA says it found significant amounts of a contaminant in the heparin active ingredients used by Baxter, which came from Scientific Protein Laboratories LLC of Wisconsin and that company's China joint venture, Changzhou SPL. It is still unclear what the contaminant is and how it ended up in the heparin. It is also unclear whether the contaminant is the cause of patients' allergic reactions to Baxter's heparin.
Changzhou SPL registered itself in China as a chemical manufacturer rather than a drug company. As such, it doesn't fall under the jurisdiction of China's State Food and Drug Agency. The U.S. FDA, in an oversight, also failed to inspect the facility when it began making the active ingredient for the U.S. market.
But inspections don't always eliminate problems. China's SFDA approved the two Chinese companies that made the active ingredient for the heparin now recalled in Germany: Changzhou Qianhong Bio-Pharma Co. and Yantai Dongcheng Biochemicals Co. Both companies have declined to comment. The SFDA didn't respond to phone calls for comment on Friday.
The U.S. FDA says it has tested heparin from Shenzhen Hepalink and found no sign of the contaminant discovered in Baxter's ingredient supplies, and APP says it has received no reports of adverse reactions to its heparin.
Shenzhen Hepalink's Mr. Li started in the heparin business 24 years ago, setting up an operation in Chongqing in southwest China. In 1998, he says, he started building the more-sophisticated Shenzhen factory, designing it from the ground up to pass tough FDA standards. Getting the hardware right, he says, was only part of the battle. The more difficult task was to build a corporate culture of strict adherence to the myriad rules meant to ensure quality and safety.
The process of heparin production has a grisly start in workshops that extract crude heparin from the intestines of slaughtered pigs. These crude heparin producers operate with essentially no oversight by Chinese health authorities. Many are small, rudimentary operations in farming communities.
The output of these heparin producers is bought up by trading companies, and may change hands several times before it ends up with consolidators who sell it in bulk to drug companies.
For the heparin supplied to Baxter, Changzhou SPL says that it relied on two wholesalers who bought heparin from six to 12 smaller workshops. Scientific Protein says it can trace supplies back to the slaughterhouses where the workshops got their raw materials.
Shenzhen Hepalink says it can trace the crude heparin it uses back to specific groups of pigs. It deals only with suppliers who get pig innards 内臓from government-regulated slaughterhouses and follow strict rules to minimize contamination. A key step, Mr. Li says, is stationing Shenzhen Hepalink employees in quality-assurance labs on the premises of each supplier whose material is destined for the U.S., to make sure his company's rules are followed.
This kind of direct oversight can be important in China, where enforcement is often spotty even in regulated businesses. Crude heparin manufacturers describe enormous variations in everything from record-keeping to what animals they use. They say that rising prices for pigs in China has prompted some crude suppliers to cut corners.
Wang Xiangyang, a factory director at the Zhaoyang Intestine & Casing Factory in Shandong, for instance, says his company has been forced to use sheep innards in addition to pig intestines because of a shortage of pig supplies. "We can't get enough pig intestines," Mr. Wang says. "There are a lot of people around who need them."
The U.S. and Europe stopped using heparin extracted from sheep and cow organs more than a decade ago after scientists became concerned about bovine spongiform encephalitis, or mad-cow disease, and a similar disorder in sheep known as scrapie. The fear was that prions, the tiny particles that cause these devastating illnesses, could be transmitted to humans through ingredients derived from cows or sheep.
Other crude-heparin makers say they suspect that to cut costs, some in the industry have used intestines from pigs infected with a virus, commonly known as blue-ear disease, that has been widespread in Chinese swine herds since mid-2006. Those animals are supposed to be destroyed and not used for food or drug production.
If the companies that buy this crude heparin for use in drugs don't know what potential impurities there are in the raw materials they buy, they may not use the proper measures to remove them, scientists say. Scientific Protein says that it tests all crude heparin to make sure it is from pigs and doesn't contain heparin extracted from sheep or other animals.
At its plant, Shenzhen Hepalink uses three steps -- involving chemical and physical processes -- to remove or deactivate all known pig viruses mixed in with the heparin. These measures have been checked by an independent German lab.
Some of "the products we make are directly injected into people's bloodstreams," says Mr. Li. "So we have great responsibilities."
When FDA officials last month toured the Changzhou SPL factory at the center of Baxter's heparin recall, they described findings that indicated flaws in record-keeping and a lack of evidence that appropriate steps were being taken to effectively rid crude heparin of possible contaminants.
An inspection report released by the FDA late last month says that Changzhou SPL's processes for the "repeated and efficient removal of impurities" have "not been evaluated" to determine their effectiveness. The report also says that "manufacturing instructions" followed at the plant were "incomplete."
Baxter audited Changzhou SPL in September, Baxter spokeswoman Deborah Spak says. Baxter officials made "several observations," including "a few touching on the same areas" as those identified by the FDA.
Ms. Spak says Baxter approved the Changzhou SPL factory for heparin production "pending satisfactory responses" to the concerns its officials raised. Changzhou SPL provided those responses in January, she says, and Baxter continued to buy its heparin.