Baxter International recalled nearly all its Heparin injections in the US after some patients experienced extreme - and in some cases fatal - allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products. There have been similar recalls by other manufacturers of Chinese-sourced Heparin in Denmark, Italy, France Germany and Japan. In the US, Heparin has been associated with the deaths of more than 100 people since early 2007, according to the FDA. Of those, the vast majority - 62 to be exact - were associated with contaminated batches of Heparin. In March, the FDA confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin’s blood-clotting properties. That ingredient was supplied to Baxter by Changzhou SPL, a Chinese plant partially owned by Wisconsin-based Scientific Protein Laboratories LLC. While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
The news of Heparin contamination came almost one year after some pets in the US died as the result of a pet food ingredient shipped from China that contained toxic levels of melamine, which was added to make it appear higher in protein. In Panama around the same time, 120 people died because an unlicensed Chinese chemical plant sold a cheap counterfeit ingredient, diethylene glycol, that was mixed into cold medicine imported to that country. Diethylene glycol contamination also resulted in a recall of Chinese-made toothpaste in the US over the summer.
In March, Chinese regulators announced new restrictions on Heparin suppliers, but most experts agree that while those moves are welcome, the oversight of foreign-supplied drugs remains a problem for US consumers. For one thing, the FDA is not up to the task of policing overseas drug makers. The Chinese plant that made the tainted Heparin ingredients was never inspected by the FDA, as is required by law. Apparently, a computer error led the agency to believe it had been inspected.
Unfortunately, that's hardly surprising. In November, the Government Accountability Office found the FDA doesn’t know how many foreign firms are actually subject to inspection. The agency has a list of 3,249 firms, but at the current rate of inspection, it would take the FDA over 13 years to go through each firm on its list. The agency also could not confirm how many foreign firms have never been inspected. In those rare cases where the FDA actually does visit foreign plants, officials provide advance warning and rely on translators supplied by the companies being inspected, clearly a conflict of interest that compromises the integrity of the inspections.
No one expects improvement anytime soon. About 40 percent of pharmaceuticals and 80 percent of the chemical ingredients in drugs are imported, according to U.S. government statistics. A growing share comes from developing countries such as China, India and Mexico that are still building their own drug safety systems. With the FDA's foreign drug oversight program in such a shambles, there are bound to be more problems with defective and contaminated drugs coming from overseas.
The FDA requires drug companies to disclose the name and place of business for prescription medication manufacturers, packers, or distributors as well as active and inactive ingredients; raw materials or their origins, are considered "commercial confidential." Most medications are created in laboratories and synthesized from chemicals, but some are made with biological agents such as whale sperm and human blood parts; suppliers can be anyone or anything from a lone fishermen to a giant chemical corporation and one pill may contain dozens of fillers and bulking agents with each ingredient having its own unique, global supply chain.
Drug companies say publicizing would be neither practical nor helpful and that medications sold in the US must meet Good Manufacturing Practices set by the FDA. "The requirements, if it's made in Nutley, NJ, or a foreign country, are exactly the same," says Lori Reilly, vice president for policy and research at Pharmaceutical Research and Manufacturers of America, a drug-industry trade group. Ensuring these rules are met is up to the companies and the FDA does not have the resources to regularly inspect overseas facilities, where the overwhelming majority—80%—of the active ingredients in US drugs now originate. The Government Accountability Office has long been saying that, at its current rate, it would take the FDA 13 years to inspect each existing foreign establishment only once.
Some wonder if disclosing more information would or would not be beneficial. "The devil is in the details. Would you list the finished product, or the raw ingredient or the raw-er ingredient?" asks Peter Lurie, deputy director of the health research group at Public Citizen. "What level of detail would be meaningful to consumers? asks Karen Riley, an FDA spokeswoman. "What does it mean that most Heparin in the world is coming from China and you need Heparin?"
Industry executives suggest: Buy from US state-licensed pharmacies you trust and not from online sellers that don't include contact information, don't require a doctor's prescription, or don't bear a seal from the Verified Internet Pharmacy Practice Sites (VIPPS). Examine pills. "There should be no chips. Any embossing should be centered and properly done," says Wayne Pines, a former FDA spokesman and current drug company consultant. Watch out for changes in color, taste, or smell and ensure "tamper-evident" packaging is intact. Misalignments or sticky residue can indicate a seal has been broken and replaced. When taking medication, monitor how you feel. If your drug isn't working they way it is supposed to, let your doctor know.
The House Energy and Commerce Committee is reworking a bill to increase FDA's inspections overseas and is considering requests to require drug labels to list country-of-origin, at least for active ingredients.
Baxter recalled nearly all its Heparin injections in the US after some patients experienced extreme - and in some cases fatal - allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products. There have been similar recalls of Chinese-sourced Heparin in Denmark, Italy, France Germany and Japan.
In March, the FDA confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin’s blood-clotting properties. However, the agency has not yet determined if the chondroitin sulfate was responsible to the deaths and reactions associated with Heparin, although the chemical is the prime suspect.
Baxter gets some of that active ingredient from Changzhou SPL, a Chinese plant partially owned by Wisconsin-based Scientific Protein Laboratories LLC. The FDA said it had found contaminated crude Heparin at that plant. Changzhou buys its crude Heparin from two companies, called consolidators, that gather it from workshops that make it from pig intestines. Many workshops that make crude Heparin in China are unregulated family operations.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs. Once the FDA determined that the counterfeit ingredient likely originated in China, the agency began detaining all Heparin imports at the border so they could be tested for the contaminant. Shortly thereafter, several other companies, including B. Braun, American Health Packaging and Covidien Ltd. announced precautionary recalls of Heparin products in the US.
Earlier this year, the FDA said tainted Heparin was suspected in more than 700 adverse reactions and 19 deaths. But now it appears that dozens of earlier deaths had not been reported to the FDA until news of the contaminated Heparin was publicized. The jump in the allergic-type reactions linked to Heparin started in November, the FDA said, possibly marking the time period in which the contamination began. Allergic reactions have been reported with all brands of Heparin, not just Baxter's.
The FDA's data shows only three Heparin deaths reported in 2006 and a few in early 2007. Now the FDA has reports of eight such deaths last November, 12 in December, 16 in January and 11 in February.
Heparin is a blood thinner is administered in surgery and other critical care areas to prevent blood clots, is crucial in dialysis and heart surgery, and is used for the bedridden. Other drugs thin blood, but their effects are as quick or as easily reversed. Heparin, which has been manufactured since 1930, is administered to millions of patients yearly and although Heparin has been used safely by millions of Americans, a bad batch of the drug recently sickened hundreds and killed 19 because it contained a contaminated ingredient that's still under investigation. The batch was made in China at a plant never inspected by the US Food & Drug Administration."
Washington, DC pharmacist Harold Kramm was not surprised saying, "The FDA is supposed to check these things, but they can't check them all," adding that more and more of the drugs sitting on store shelves are manufactured in other countries like India, Europe, and the Carribbean. News4 reviewed the five most commonly prescribed drugs—cholesterol lowering Lipitor, narcotic pain reliever acetominiphin with hydrocodone, antibiotic amoxicillin, and high blood pressure fighters Toprol-XL and Norvasc—and found that three were manufactured overseas. The "FDA simply does not have the people to go to these foreign countries and inspect these facilities," said former Food and Drug Administration Associate Commissioner William Hubbard. Hubbard said contamination issues are not over because the FDA does not have the resources to inspect the thousands of manufacturing facilities worldwide.
Meanwhile, according to a recent federal audit, a November 2007 Government Accountability Office report indicated that the FDA doesn't know how many of plants are importing drugs and drug ingredients into the US. As a matter-of-fact, agency officials were unable to give an exact number of foreign manufacturers, saying there were somewhere between 3,000 and 6,800. These companies make 80 percent of the raw material used to manufacture drugs sold in the US So if a drug is made in the US, its ingredients could be made overseas. Worse, the reports states that such facilities are inspected, on average, once every 13 years.
"US manufacturers are being inspected every two years, but the foreign manufacturers are not being inspected and that's a real disconnect. We're inspecting where the drugs aren't being made and not where the drugs are being made," Hubbard said. "This is everybody's nightmare come to life," said Public Citizen's Peter Lurie. Lurie said consumers should be concerned since most people don't have access to manufacturer information, and even if they did, couldn't skip their medication. "Unfortunately, there isn't very much the consumer can do about it. You really are at the hands of the FDA, because you can't distinguish between those drugs that might be risky and those that are not."
Last week, agency officials announced plans to open eight new offices around the world, the first in China. A spokesman for Heparin's Manufacturer, Baxter Healthcare, said the company is forced to manufacture the drug's active ingredient in China because US manufacturers are unable to meet the huge demand for the drugs.
Two weeks ago, New York Senator Charles Schumer announced legislation to force the FDA to inspect overseas facilities more often.
Most cystic fibrosis patients take five large capsules at each meal to supply enzymes their bodies do not produce. This medication is life sustaining for most of the nearly 30,000 people in the US with cystic fibrosis, a hereditary disease that attacks the lungs and digestive tract. Leslie Hendeles, a University of Florida professor of pharmacy and pediatrics asks, “What would happen if there were a virus, a pig virus, something analogous to mad cow disease?” “A number of pharmaceutical firms are trying to eliminate all animal-sourced products from their raw material streams,” said Dr. Robert G. Rohwer, the director of a Department of Veterans Affairs neurovirology laboratory.
Currently, the Cystic Fibrosis Foundation is pursuing an alternative to pig-derived medications and is working with Altus Pharmaceuticals of Cambridge, Massachusetts, to develop a synthetic version of the enzyme capsules. Synthetic replacements are also being sought for other products, including the lung fluids called surfactants used in neonatal wards and for raw materials used in pharmaceutical production. Survanta, the most widely used lung surfactant for premature infants in the US, which is made by Abbott, comes from cows in New Zealand, an island thought to be safe from mad cow disease. Altus is in final stages of clinical studies and is planning to submit its new drug application with the FDA next year. Instead of five large pills with each meal and snack, people with cystic fibrosis would have to take only one small capsule.
Millions of Heparin vials are used annually in this country to prevent blood clots during major surgery and kidney dialysis. To date, no appropriate synthetic version has been found. Arixtra, a synthetic drug marketed by GlaxoSmithKline copies the most active portion of Heparin, has been successfully used for some surgeries, but it is about 10 times as expensive as Heparin and has no specific antidote to reverse its anti-clotting properties if a patient develops bleeding problems.
While the risk of transmitting disease from animal-based drugs is small, it does occur, according to Paul W. Brown, a retired National Institutes of Health senior investigator. “Any time you take a tissue or an extract process from a tissue from one species and put it into a another species or even another animal, you run the risk of unwanted pathogens that you didn’t know were there; that’s been responsible for repeated problems over the course of time,” Dr. Brown said. “If you can do something without taking tissue or a product from another being, you’re ahead of the game.”
Scientific Protein Laboratories also supplied contaminated ingredients to Baxter Healthcare, the company whose Heparin has been linked to more than 700 serious reactions and possibly 19 deaths among patient in the US. In the US, Baxter first recalled 9 lots of Heparin in January, after the drug was linked to serious, and sometimes fatal reactions in some patients. Those reported reactions to Baxter Heparin included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening. In February, Baxter expanded the Heparin recall to include all of its Heparin products, and suspended sales of its drug.
The Covidien Heparin recall came just a week after another company, B. Braun Medical, initiated its own Heparin recall as a precautionary measure, and American Health Packaging, a unit of AmerisourceBergen Corp, said it was voluntarily recalling 1,421 units of Heparin injection vials as part of Baxter’ broader recall. Heparin sourced from China has also been recalled in German, France, Italy, Denmark and Japan, and the US Food & Drug Administration (FDA) is currently detaining all Heparin imports to the US at their points of entry until they can be subjected to further testing.
Earlier this month, the FDA determined that Baxter Heparin had been tainted with an ingredient derived from animal cartilage. The substance, chondroitin sulfate, had been molecularly changed to mimic the blood clotting properties in Heparin’s active ingredient. Baxter procured the active ingredients for its Heparin from Changzhou SPL, a Chinese facility partially owned by Scientific Protein Laboratories. Changzhou in turn buys its Heparin from two companies, called consolidators, that gather crude Heparin from workshops that make it from pig intestines. Many Chinese workshops that make crude Heparin are unregulated family operations.
The FDA has yet to determined if the ingredient substitution was intentional, but Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs. China has been the point of origin for many drug contamination and counterfeiting scandals. The news of Heparin contamination came almost one year after some pets in the US died as the result of a pet food ingredient shipped from China that contained toxic levels of melamine, which was added to make it appear higher in protein. In Panama around the same time, 120 people died because an unlicensed Chinese chemical plant sold a cheap counterfeit ingredient, diethylene glycol, that was mixed into cold medicine imported to that country. Diethylene glycol contamination also resulted in a recall of Chinese-made toothpaste in the US over the summer.
Recently, it appears that the Chinese have taken steps to crack down on Heparin producers. On March 21, the Chinese State Food and Drug Administration issued an order in a notice its Web site requiring Heparin producers to obtain the raw chemicals used to make the drug from registered suppliers. Raw Heparin suppliers in that country are now required to improve their management and tests on their products, it said. This was a reversal of the Chinese government’s earlier position, as the agency had insisted that ensuring the quality of exported chemicals like Heparin was the responsibility of importers and importing countries.
In the US, Baxter first recalled 9 lots of Heparin in January, after the drug was linked to serious, and sometimes fatal reactions in some patients. Those reported reactions to Baxter Heparin included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening. In February, Baxter expanded the Heparin recall to include all of its Heparin products, and suspended sales of its drug. Last week, B. Braun Medical initiated its own Heparin recall as a precautionary measure, and American Health Packaging, a unit of AmerisourceBergen Corp, said it was voluntarily recalling 1,421 units of Heparin injection vials as part of Baxter’ broader recall.
Both Baxter and B. Braun source the ingredients for their Heparin from Scientific Protein Laboratories, which manufactures some of the ingredients in China. The Food & Drug Administration (FDA) has confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin’s blood-clotting properties. However, the agency has not yet determined if the chondroitin sulfate was responsible for the deaths and reactions associated with Baxter Heparin. However, the FDA since has ordered that all Heparin imports be detained at the border until they can be subjected to further testing.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
There have been similar recalls of Chinese-sourced Heparin in Germany and Japan in the past month, and now, more European countries are following suit. France on Friday began recalling Heparin made by Rotexmedica GmbH, the same company that made Heparin which was recalled from Germany earlier this month. The active ingredient used to make Heparin is also being recalled in Italy and Denmark because it is contaminated. The chemical was made by an Italian company, Opocrin SpA, which used raw ingredients sourced in China. So far, only Germany has seen adverse reactions to Heparin in patients, but a spokesperson for the European Medicines Agency said regulators there presume the contaminant found in European Heparin is the same as the one identified in recalled US Heparin.
Heparin is a vital drug used in surgery, dialysis, and for the bedridden. Other drugs thin blood, but their effects are not as quick or easily reversed. Baxter manufactures about half of all multiple-dose Heparin vials sold in the U.S., while B. Braun Medical supplies 10%-15% of the U.S. supply of injectable Heparin. Despite the massive Heparin recalls, an FDA spokesperson told the Website Webmd.com that there is no shortage of Heparin.
Both Baxter and B. Braun obtain Heparin from Scientific Protein Laboratories, which manufactures some of the ingredients in China. Reported reactions to Baxter Heparin have included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening. To date, Baxter Heparin has been implicated in over 700 adverse reactions and possibly 19 deaths.
There have been similar recalls of Chinese-sourced Heparin in Germany and Japan. Last week, the FDA confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin’s blood-clotting properties. However, the agency has not yet determined if the chondroitin sulfate was responsible to the deaths and reactions associated with Baxter Heparin.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
The Heparin contamination scandal has once again raised questions about Chinese manufacturing. According to Consumer Affairs.com, China's exports of Heparin and its components totaled $57.8 million in the first half of 2007, a 13.7% increase from the same period a year earlier. The website said 49 companies exported Heparin and its ingredients. Many workshops that make crude Heparin are unregulated family operations. Baxter has said that its investigators have not been able to get permission from the Chinese to visit these operations, and the FDA has not yet done inspections on any of these facilities either.
Last week, the Chinese State Food and Drug Administration issued an order in a notice seen on its Web site that requires Heparin producers to obtain the raw chemicals used to make the drug from registered suppliers. Raw Heparin suppliers, meanwhile, are required to improve their management and tests on their products, it said. This was a reversal of the Chinese government’s earlier position, as the agency had earlier insisted that ensuring the quality of exported chemicals like Heparin was the responsibility of importers and importing countries.
B. Braun Medical Inc., of Irvine, California, said it was recalling the Heparin lots as a precautionary measure, after Scientific Protein Laboratories said that one lot of Heparin Sodium, USP Active Pharmaceutical Ingredient it bought has a Heparin-like contaminant. So far B. Braun Medical Inc. has not received any adverse event reports related to this issue.
Scientific Protein Laboratories is the same company that provided the active ingredient for Baxter International's Heparin. Baxter recalled nearly all its Heparin injections in the US after some patients experienced extreme allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products. There have been similar recalls of Chinese-sourced Heparin in Germany and Japan. Last week, the US Food and Drug Administration (FDA) confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin’s blood-clotting properties. However, the agency has not yet determined if the chondroitin sulfate was responsible to the deaths and reactions associated with Baxter Heparin.
Baxter gets some of that active ingredient from Changzhou SPL, a Chinese plant partially owned by Wisconsin-based Scientific Protein Laboratories LLC. The FDA said it had found contaminated crude Heparin at that plant. Changzhou buys its crude Heparin from two companies, called consolidators, that gather it from workshops that make it from pig intestines. Many workshops that make crude Heparin are unregulated family operations. Baxter has said that its investigators have not been able to get permission from the Chinese to visit these operations, and the FDA has not yet done inspections on any of these facilities either.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
Last Thursday, American Health Packaging, a unit of AmerisourceBergen Corp, said it was voluntarily recalling 1,421 units of Heparin injection vials as part of Baxter' broader recall of Heparin products. The vials were manufactured by Baxter and then placed by American Health Packaging into individually labeled bags for use in pharmacy automation equipment.
Baxter recalled nearly all its Heparin injections in the US after some patients experienced extreme allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products. There have been similar recalls of Chinese-sourced Heparin in Germany and Japan. Earlier this week, the US Food and Drug Administration (FDA) confirmed that it had found chondroitin sulfate in samples of the active ingredient used in Baxter Heparin. The FDA said the chondroitin sulfate was molecularly changed to mimic Heparin's blood-clotting properties. However, the agency has not yet determined if the chondroitin sulfate was responsible to the deaths and reactions associated with Baxter Heparin.
Baxter gets some of that active ingredient from Changzhou SPL, a Chinese plant partially owned by Wisconsin-based Scientific Protein Laboratories LLC. The FDA said it had found contaminated crude Heparin at that plant. Changzhou buys its crude Heparin from two companies, called consolidators, that gather it from workshops that make it from pig intestines. Many workshops that make crude Heparin are unregulated family operations. Baxter has said that its investigators have not been able to get permission from the Chinese to visit these operations, and the FDA has not yet done inspections on any of these facilities either.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
According to a report in The Wall Street Journal, the Chinese State Food and Drug Administration issued an order in a notice seen Friday on its Web site that requires Heparin producers to obtain the raw chemicals used to make the drug from registered suppliers. Raw Heparin suppliers, meanwhile, are required to improve their management and tests on their products, it said. This was a reversal of the Chinese government's earlier position, as the agency had earlier insisted that ensuring the quality of exported chemicals like Heparin was the responsibility of importers and importing countries.
The news of Heparin contamination comes almost one year after some pets in the US died as the result of a pet food ingredient shipped from China that contained toxic levels of melamine, which was added to make it appear higher in protein. In Panama around the same time, 120 people died because an unlicensed Chinese chemical plant sold a cheap counterfeit ingredient, diethylene glycol, that was mixed into cold medicine imported to that country. Diethylene glycol contamination also resulted in a recall of Chinese-made toothpaste in the US over the summer.
In the US, Baxter Heparin has been linked to over 700 allergy type reactions and possibly 19 deaths. In Germany, there have been about 80 similar reactions to Heparin made by another company, but no deaths. Baxter International began recalling Heparin in January after the FDA received an unusually high number of adverse reaction reports linked to the drug. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening.
Baxter stopped selling multiple-dose Heparin in early February, and the FDA advised doctors to prescribe alternatives. Baxter recalled all of its remaining Heparin products on Feb. 29, after the FDA determined that other suppliers could make up for the lack of Baxter Heparin. In early March, the FDA said its investigators found a contaminant in some batches of the active ingredient used in Baxter Heparin. That ingredient is made by a Chinese facility, as well as a U.S. plant, both owned by Wisconsin-based Scientific Protein Laboratories LLC.
According to The New York Times, the FDA. said it had found contaminated Heparin at Changzhou SPL, the Chinese plant that supplies the active ingredient to Baxter. Changzhou in turn buys its Heparin from two companies, called consolidators, that gather crude Heparin from workshops that make it from pig intestines. Many workshops that make crude Heparin are unregulated family operations. Baxter has said that its investigators have not been able to get permission from the Chinese to visit these operations, and the FDA has not yet done inspections on any of these facilities either.
While the FDA maintains that it has not yet determined if the ingredient substitution was intentional, several sources told The New York Times that it was likely not accidental. Some Heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. It costs a fraction of the ingredient usually used in Heparin, and producers may have used it in an attempt to cut costs.
The news of Heparin contamination comes almost one year after some pets in the US died as the result of a pet food ingredient shipped from China that contained toxic levels of melamine, which was added to make it appear higher in protein. In Panama around the same time, 120 people died because an unlicensed Chinese chemical plant sold a cheap counterfeit ingredient, diethylene glycol, that was mixed into cold medicine imported to that country. Diethylene glycol contamination also resulted in a recall of Chinese-made toothpaste in the US over the summer.
In the US, Baxter Heparin has been linked to over 700 allergy type reactions and possibly 19 deaths. In Germany, there have been about 80 similar reactions to Heparin made by another company, but no deaths. Baxter International began recalling Heparin in January after the FDA received an unusually high number of adverse reaction reports linked to the drug. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening.
Baxter stopped selling multiple-dose Heparin in early February, and the FDA advised doctors to prescribe alternatives. Baxter recalled all of its remaining Heparin products on Feb. 29, after the FDA determined that other suppliers could make up for the lack of Baxter Heparin.
In early March, the FDA said its investigators found a contaminant in some batches of the active ingredient used in Baxter Heparin. That ingredient is made by a Chinese facility, as well as a U.S. plant, both owned by Wisconsin-based Scientific Protein Laboratories LLC. Last Friday, the FDA announced it would be detaining all Heparin imports at their points of entry and testing them before allowing the drug into the country.
Earlier today, The New York Times ireported that scientists involved in the Heparin investigation suspected that a chemical called over-sulfated chondroitin sulfate was used in place of the active ingredient usually found in the drug. Chondroitin sulfate is a widely used supplement to treat joint pain. In its unaltered state, it does not have the blood-thinning properties found in the contaminant. But scientists and researchers say the act of changing the molecule gives the substance anti-coagulating properties. They told The New York Times that the chemical would have been used intentionally. One Chinese professor of Pharmaceutical Sciences told the paper that counterfeiters would likely choose chondroitin sulfate as a base substance to create a Heparin-like molecule because it is cheap.
The FDA has now confirmed that the chemical was found in samples of Heparin it tested. But neither the agency or those interviewed for the New York Times article can yet say with certainty that chondroitin sulfate had caused the dangerous side effects. That's because some batches of Heparin containing the chemical did not cause any adverse reactions. Some experts interviewed even said that they doubted all of the varied symptoms seen in Heparin patients could have been caused by only one chemical.
Baxter’s Heparin comes in 10 unit vials for babies and vials up to 10,000 units for adults. The twins were dosed from 10,000 unit vials with two separate over-dosages. The babies began to bleed out just before midnight and were transferred to the neo-natal intensive care. Pharmacy technicians stock Heparin for use in preventing clots and for flushing IVs. Hospital protocol is to keep the different units separated, but a technician accidentally put the 10,000 unit vials in the drawer where the 10 unit vials were stored.
Quaid has said that as many as 100,000 Americans are killed in hospitals by medical mistakes. "These mistakes that happened to us are not unique ... they happen in every hospital, in every state in this country," said Quaid who was speaking in his first TV interview regarding his twins’ overdose. "It's bigger than AIDS. It's bigger than breast cancer. It's bigger than automobile accidents and, yet, no one seems to really be aware of the problem." A 1999 report by the U.S. Institute of Medicine agreed stating, "Good people are working in bad systems that need to be made safer."
In a statement last year, the Quaid’s said, "We were told by upper Cedars-Sinai administration that our children had received only one 10,000 unit dose of Heparin when in fact they had received two 10,000 unit doses over an eight-hour period that we now know of. The hospital's lack of candor has left us with the uneasy feeling that we may never know the whole story,". Hospital staff gave the Quaid’s two-week-old twins—Thomas Boone and Zoe Grace—1,000 times the recommended dose of the blood thinner Heparin. "It basically turned their blood to the consistency of water, where it had a complete inability to clot. They were basically bleeding out at that point," Quaid said. Even worse, the hospital did not notify the Quaid’s that anything was wrong until the next day. And, still worse, the Quaids believe someone at the hospital leaked information about the error to the news media.
Baxter International is at the epicenter of another Heparin storm in which 21 deaths and over 700 adverse reactions have been reported in the US. It is suspected that a contaminated ingredient from an uninspected Chinese manufacturer might be responsible for those Baxter Heparin problems.
Baxter began recalling Heparin after the FDA reported that, since the end of 2007, it received about 350 reports of health problems associated with Baxter’s multiple-dose injectable Heparin; 40 percent were deemed serious and four resulted in death. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—was life threatening. Baxter stopped selling multiple-dose Heparin in early February, and the FDA has advised doctors to prescribe alternatives.
Baxter recalled all of its remaining Heparin products on Feb. 29, after the FDA determined that other suppliers could make up for the lack of Baxter Heparin. By that time, Baxter Heparin had been implicated in more than 400 adverse reactions and at least four deaths. To date, the FDA has received more than 785 reports of Heparin reactions including 19 deaths in patients treated with some brand of Heparin. Baxter said only four fatalities might be related to its Heparin and there was not yet enough data to say the drug was the cause.
In early March, the FDA said its investigators found a contaminant in some batches of the active ingredient used in Baxter Heparin. That ingredient is made by a Chinese facility, as well as a U.S. plant, both owned by Wisconsin-based Scientific Protein Laboratories LLC.
Last week Germany reported that here had been similar reactions to Heparin among dialysis patients in that country. The Heparin involved in the German reactions was made by the German company Rotexmedica. Germany later issued its own Heparin recall. Because of the events in Germany, the FDA cautioned all Heparin manufacturers of the need to conduct specialized nuclear magnetic resonance spectroscopy tests to ensure a safe supply of the blood thinner, derived from an enzyme found in the mucous lining of pig intestines.
On Friday, the FDA announced that it was detaining all Heparin imports and testing them at their points of entry. Five companies have agreed to test for the contaminant, FDA officials said. The agency would not name the companies or say where they are located, but said they represented the majority of the U.S. Heparin market. Baxter and APP Pharmaceuticals Inc have been the two major U.S. Heparin suppliers, but other smaller companies manufacture and sell the drug. Both Baxter and APP said they have agreed to the additional testing.
Chinese drug imports have more than quadrupled in the US in the past five years to $401 million in 2007, according to the International Trade Administration, part of the US Department of Commerce. Approximately 3,000 Chinese companies are registered with the Food & Drug Administration (FDA) to market medical devices in the US. But even the FDA says many of those Chinese manufacturers are not up-to-snuff. "While some Chinese [drug] companies are state-of-the art in technology and manufacturing expertise, many are at the opposite end of the spectrum," FDA deputy commissioner Murray Lumpkin told Congress last year.
Meanwhile, the life sciences industry here continues to create close business ties in China, despite countless reports of tainted medicines, foods, and consumer goods sickening and killing US consumers. Massachusetts Governor Deval Patrick led a trade mission there last year that included a stop at Shanghai drug manufacturer WuXi PharmaTech Co., which reports 20 US customers, including Vertex Pharmaceuticals of Cambridge. Vertex is developing a hepatitis C treatment and has hired WuXi to manufacture chemicals. WuXi, which said it works with many of the world's biggest drug companies, reported that Vertex is one of its largest customers and is quadrupling its Shanghai plant to meet Vertex's need.
Other US companies maintain Chinese plants, including Covidien Ltd. of Mansfield and Inverness Medical Innovations Inc. of Waltham, which are both expanding Chinese production. Gensyme Corporation—a Cambridge biotech organization—is considering building a Beijing plant. Last month, Waltham's Inverness, which makes pregnancy tests and diagnostic products, said it plans to close its Bedford, England plant and transfer the majority of work to low-cost Chinese facilities; it already has plants in Hangzhou and Shanghai. Covidien, which makes surgical instruments and respiratory equipment in Shanghai, said it will triple its workforce there.
Operating in China is tempting with its lower costs and the benefit of creating a presence in the booming Asian market; however, risks are real and costly. Take the Baxter Heparin tragedy, which remains ongoing with the number of dead and sick rising daily. "Reasonable people understand that there is some level of concern about Chinese manufacturing," said one lawyer handling Heparin suits, adding that jurors will likely conclude companies that make products in China cut costs at the expense of safety.
Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, predicted there will be more injuries from Chinese medical imports because the FDA rarely inspects Chinese plants. Over 700 Chinese drug makers are registered with the FDA, but the agency only conducted 14 inspections in China last fiscal year and visits are generally planned since the Chinese government warns companies in advance. Worse, Chinese regulators do not inspect plants exporting to the US and other countries. "It's inevitable that we will keep seeing more problems until this is taken care of," Wolfe said.
Government reports of serious reactions linked to Heparin now number over 700 with an estimated 21 deaths. Baxter International, Inc., has recalled virtually all of its Heparin products in the US; companies in Germany and Japan have recalled their Heparin products, as well.
Hospital staff immediately contacted Elward who saw two children with swollen tongues and eyelids, quickening heartbeats, and dropping blood pressure minutes after being hooked up to dialysis machines for treatment. The doctor saw the reactions in one of the patients, as well as a third child, last November. Elward assumed the problem was with sterilization of the dialysis equipment; however, switching the sterilizing chemical didn't eliminate the symptoms.
In January, Elward and 20 physicians and nurses secured equipment, took samples of medicines given to the sick children, and reviewed patient records. Elward contacted other pediatricians through an online physician list, notified the local health department, and warned the Food & Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC). "My initial reaction was: It sounds like a chemical exposure. The next thought was: We really need to report this," said Elward.
Elward was not the first doctor to notice problems. A Baxter spokeswoman said the company began investigating when other physicians notified it of problems late December. Some dialysis centers notified equipment makers, believing there were problems with contaminated dialysis machines; however, Elward was the first to advise federal authorities, which launched the CDC search for side effects. Government scientists posted a notice on relevant Internet sites and issued public health advisories.
Within two days, physicians, dialysis centers, and dialysis supply companies flooded the CDC with reports of 50 similar reactions among adult dialysis patients in six states. "We were already very concerned, but that made us more concerned," said Dr. Priti Patel of the CDC, which is trying to determine if there's still a problem now that most Baxter products have been withdrawn.
Heparin investigators are focusing on why recalled products contained a contaminant that mimicked the drug's key ingredient and are investigating whether the possible counterfeit was responsible. Since the key ingredient came from China, fears about the integrity of exports from China and the adequacy of inspections by the FDA were heightened, prompting congressional hearings. "I don't think the pharmaceutical industry knows what it's doing in China and I don't think the US government knows what it's doing in China," said Michael Santoro, a Rutgers University business professor who has written about the drug industry's business in China. Santoro said the Baxter recalls show the need for serious restrictions on Chinese drug imports.
Baxter Pharmaceuticals’ Heparin has been linked to 21 deaths and hundreds of severe reactions in the United States; the drug’s raw materials were imported from China. The German Heparin was manufactured by RotexMedica, a subsidiary of the French company Groupe Panpharma. Health authorities in the northern German state of Schleswig-Holstein, where RotexMedica is located, issued the recall order to the company. Germany is the only European country reporting severe reactions to Heparin, to date.
Late last month, the US Food and Drug Administration (FDA) reported that, since the end of 2007, it received about 350 reports of health problems associated with Baxter's multiple-dose injectable Heparin; 40 percent were deemed serious and four resulted in death. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—was life threatening. Baxter stopped selling multiple-dose Heparin vials earlier this month and the FDA advised doctors to prescribe alternatives. Now, the FDA reports the number of possible deaths associated with Heparin has risen to 21, the number of adverse reactions to 448, and they found “potential deficiencies” at a Chinese plant that supplied much of the active ingredient for Heparin; Baxter International, Heparin’s manufacturer, announced it is expanding the recall to include most Heparin products.
China is a massive producer of pigs and the largest supplier of the enzyme found in the mucous lining of the animal's intestines needed to produce Heparin. China, which exported Heparin products to 42 countries and regions early last year, exported the most—about 13 tons—to Germany, according to a report by the China Chamber of Commerce for Import and Export of Medicines and Health Products. China’s Heparin market has been in turmoil over the last year as pig disease has swept the country, depleting stocks and leading some farmers to sell sick pigs into the market; some large companies have used small village workshops, which are often unsanitary and not inspected.
In the US, the FDA has not identified the cause of the Heparin contamination and admitted this month it violated its own policy by failing to inspect the Chinese plant that manufactured the Baxter Heparin prior to shipping the Heparin ingredient to Baxter in 2004; China’s drug agency did not inspect the plant. Last week, the agency sent inspectors to the plant and found a failure to properly follow the steps for identifying impurities and deficiencies related to manufacturing equipment and, according to an inspection report released by the agency, the SPL plant appeared to have made at least some Heparin with “material from an unacceptable workshop vendor.”
Today, approximately 80 percent of all active drug ingredients come from abroad; however, the FDA has no answer on the percentage of foreign manufacturing facilities it has inspected. Worse, many of these plants are in developing countries that don't have infrastructure that meets U.S. safety standards. In the Heparin case, China said ensuring drug safety is the importing country's responsibility.
The FDA has been under fire for this glaring lack in drug safety for over a decade but has not yet taken steps to correct it, claiming that funding is the main problem. The FDA does not have the resources to meet its statutory mandate to inspect domestic plants every two years, let alone handle the plants overseas. The FDA focuses on domestic companies, with about 1,200 inspections conducted annually in the US; however, only about 300 foreign facilities are inspected annually and, of these, at least10 percent of the firms ship pharmaceuticals here.
In November, the Government Accountability Office found the FDA doesn't know how many foreign firms are actually subject to inspection. The agency has a list of 3,249 firms, but at the current rate of inspection, it would take the FDA over 13 years to go through each firm on its list. The agency also could not confirm how many foreign firms have never been inspected. In those rare cases where the FDA actually does visit foreign plants, officials provide advance warning and rely on translators supplied by the companies being inspected, clearly a conflict of interest that compromises the integrity of the inspections. The FDA has also been criticized for using antiquated, incomplete, and incompatible computer databases. Because of these system problems, FDA officials believed they had actually inspected the Heparin plant in China when, in fact, it had inspected a different plant with a similar name. Funding for foreign inspections fell nearly 30 percent under the Bush administration even though the number of firms requiring inspecting increased.
Clearly, the agency needs more money, either through appropriations or user fees, which under current law can't be used for follow-up surveillance inspections. Because FDA officials won't say how much more money or inspectors are needed—claiming it's not their responsibility to make dollar decisions—no one knows what is needed to correct its problems. It remains unclear why the agency is keeping mum on these issues and many wonder if threats are originating from the Bush camp. Lawmakers—who gave the FDA more money than what was asked for by the Bush administration—can only assist with funding if they are told what is needed.
Baxter International began recalling Heparin after the FDA reported that, since the end of 2007, it received about 350 reports of health problems associated with Baxter’s multiple-dose injectable Heparin; 40 percent were deemed serious and four resulted in death. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—was life threatening. Baxter stopped selling multiple-dose Heparin in early February, and the FDA has advised doctors to prescribe alternatives. Baxter recalled all of its remaining Heparin products on Feb. 29, after the FDA determined that other suppliers could make up for the lack of Baxter Heparin. By that time, Baxter Heparin had been implicated in more than 400 adverse reactions and at least four deaths. Now the FDA is saying that it is investigating 19 deaths possibly tied to Baxter Heparin.
In Germany, the FDA said there had been similar reactions to Heparin among dialysis patients in that country. The Heparin involved in the German reactions is made by the German company Rotexmedica. The FDA did not say where the German company gets raw ingredients for its Heparin, but said it ruled out Scientific Protein Laboratories, which uses a Chinese supplier. Earlier this week, the FDA said an inspection of the Chinese plant that makes the ingredient for Baxter had turned up serious deficiencies. The FDA said there have been less than 100 incidents in Germany and no deaths.
Yesterday, the FDA said it had found significant quantities of a chemical that looks like the key ingredient in the drug and was apparently substituted for it. All of the ingredient came from China. Dr. Janet Woodcock, the FDA's deputy commissioner said the agency is trying to determine if the contamination with the counterfeit ingredient was deliberate. Despite this discovery, the FDA has not yet definitively tied this fake ingredient to the adverse reactions.
Because of the events in Germany, the FDA yesterday cautioned all Heparin manufacturers of the need to conduct specialized nuclear magnetic resonance spectroscopy tests to ensure a safe supply of the blood thinner, derived from an enzyme found in the mucous lining of pig intestines.
Baxter began recalling Heparin after the FDA reported that, since the end of 2007, it received about 350 reports of health problems associated with Baxter’s multiple-dose injectable Heparin; 40 percent were deemed serious and four resulted in death. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—was life threatening. Baxter stopped selling multiple-dose Heparin in early February, and the FDA has advised doctors to prescribe alternatives.
Baxter recalled all of its remaining Heparin products on Feb. 29, after the FDA determined that other suppliers could make up for the lack of Baxter Heparin. By that time, Baxter Heparin had been implicated in more than 400 adverse reactions and at least four deaths.
The FDA inspection of Baxter's Chinese supplier uncovered a variety of problems, which the FDA detailed in a letter to the Chinese company. The FDA cited Changzhou SPL Company, Ltd. for a number of violations, including:
- Incomplete manufacturing instructions
- Lack of critical processing steps or annual test results
- Lack of an impurity profile for Heparin
- Incomplete manufacturing instructions for Heparin Sodium USP
- Investigations into failed lots were approved as complete, but no cause was listed
- Inadequate control of material flow in the processing area
Today, the FDA said its investigators found a contaminant in some batches of the active ingredient used in Baxter Heparin. FDA Deputy Commissioner Janet Woodcock told reporters that the agency has not yet determined if the contaminant was responsible for the Heparin reactions.
For its part, Baxter said today that its own investigation is also pointing to contamination in the ingredient made by the Chinese manufacturer. Baxter said it had found chemical differences in the active pharmaceutical ingredient used in lots of Heparin associated with adverse reactions. That ingredient is made by the Chinese facility, as well as a U.S. plant, both owned by Wisconsin-based Scientific Protein Laboratories LLC. The company said its findings "suggest that the root cause may be associated with the crude Heparin, sourced from China, or from the subsequent processing of that product before it reaches Baxter". Baxter also said that it ruled out its Cherry Hill, New Jersey, facility, where Heparin is manufactured in a later step in the process, as a source of the problem.
Last week, FDA inspectors visited the Chinese plant owned by Baxter supplier Scientific Protein Laboratories (SPL) of Waunakee, Wisconsin where they discovered lax hygiene and safety standards; testing procedures at the plant were inadequate and—in some cases—testing records were missing and some batches were untraceable. Worse, when Heparin produced at the plant did not pass quality tests, workers failed to diagnose what caused the failures and dismissed the results in some cases. A congressional committee is now wondering if the FDA's lapses are part of a larger problem.
Although drug imports increased in the past five years, inspection funds dropped. While 3,250 non-US plants were subject to FDA inspections last year, it only conducted 1,445 foreign inspections in the last five years, according to a Government Accountability Office study, significantly less than the requirement to inspect each plant every two years. It’s worse in China where the FDA averages just 15 inspections in China in each of the last five years, despite that there are 714 plants shipping drug products to the US. If China's flourishing 17 percent annual growth rate for drug exports continues, they will produce about 25 percent of the world's pharmaceutical ingredients by 2010, according to the investment firm Credit Suisse.
The FDA claims it inspects every foreign plant sending medical products to the US, but its own data contradicts this. An FDA-appointed commission that studied the agency's inspection record last fall found the FDA is short of financial resources, has cut personnel, has outdated data management systems, and is struggling to meet oversight obligations. "Millions of FDA-regulated products are imported into the country each year from foreign facilities that have never been inspected by FDA and, with current appropriations, never will be," according to a report in November by the FDA Science Board's subcommittee on science and technology. The head of the FDA study group, in an interview, held out little hope the FDA is coming to grips with its challenges. The Heparin case is a warning signal, said Gail Cassell, vice president of scientific affairs at drug giant Eli Lilly & Co. "Unless the deficiencies can be addressed rather urgently, this is not the last such situation," said Cassell. "We will have more of them."
Baxter began recalling Heparin late last month, after the FDA reported that, since the end of 2007, it received about 350 reports of health problems associated with Baxter's multiple-dose injectable Heparin; 40 percent were deemed serious and four resulted in death. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—was life threatening. Baxter stopped selling multiple-dose Heparin vials earlier this month and the FDA has advised doctors to prescribe alternatives.
Though Baxter produces much of the Heparin used in the US, regulators said the other major supplier would be able to meet the demand, a change from concerns expressed last month over shortages.
The FDA has not identified the root cause of the problem and said it was investigating two Chinese wholesalers — also called consolidators — that supplied crude Heparin to Changzhou SPL, as well as those that sold raw ingredients to consolidators. At least one consolidator received supplies from small, unregulated family workshops where conditions are questionable and, in many cases, unsanitary. The FDA admitted this month it had violated its own policy by failing to inspect SPL before it began shipping the Heparin ingredient to Baxter in 2004. China’s drug agency did not inspect the plant.
Last week, the agency sent inspectors to the plant and found a failure to properly follow the steps for identifying impurities and deficiencies related to manufacturing equipment. According to an inspection report released by the agency, the SPL plant appeared to have made at least some Heparin with “material from an unacceptable workshop vendor.” Scientific Protein Laboratories (SPL), a Wisconsin company that is the majority owner of the Chinese plant, argued that the FDA’s finding did not represent its final determination as to whether the plant complied with federal regulatory rules. Erin Gardiner, a spokeswoman for Baxter, said the company was reviewing the FDA’s report adding, “We expect SPL to respond to those observations thoroughly and promptly.”
The FDA’ concern about Heparin had focused on Baxter’s multidose vials, which were recalled. Baxter has since recalled single-dose vials and a diluted solution of Heparin used to keep blood clots from forming in intravenous lines. The only Baxter Heparin products available are premixed bags of intravenous solutions, the FDA said. The FDA estimates over one million multidose vials of Heparin are sold monthly in the US; about half are manufactured and distributed by Baxter.
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; even big companies have turned to small village workshops, which are often unsanitary and not inspected.
Baxter International recalled 9 lots of its Heparin in January, following reports of 100 allergy type reactions in patients who had received the drug. According to the Baxter Heparin recall notice sent out at the time, a variety of reactions were been reported in relation to the recalled Heparin, including abdominal pain, decreased blood pressure, burning sensation, chest pain, diarrhea, dizziness, drug ineffectiveness, dyspepsia, dyspnea, erythema, flushing, headache, hyperhidrosis, hypoesthesia, hypotension, lacrimation increased, loss of consciousness, malaise, nausea, pallor, palpitations, paresthesia, paresthesia (oral), pharyngeal edema, restlessness, vomiting/retching, stomach discomfort, tachycardia, thirst, trismus, and unresponsiveness to stimuli. Since the January recall, Baxter Heparin has been implicated in more than 400 reactions, including four deaths.
Following the January Baxter Heparin recall, the company had suspended making Heparin and the FDA warned doctors to avoid using the Baxter drug. Baxter said yesterday that it had waited to issue the full-scale Heparin recall because the company wanted to avoid causing a Heparin shortage. Heparin is a vital drug used in surgery, dialysis, and for the bedridden. Other drugs thin blood, but their effects are not as quick or easily reversed. Baxter manufactures about half of all multiple-dose Heparin vials sold in the U.S. The company said that because other manufacturers had been able to step in and increase the supply of the drug, it was now going ahead with a full-scale Heparin recall.
Meanwhile, the FDA has finished its inspection of the Chinese plant that had made a raw ingredient for Baxter Heparin. The FDA said it had found "irregularities" at that plant, but had not determined if they were responsible for the tainted Heparin. The agency also said it was also investigating two Chinese wholesalers that supplied crude Heparin to the Chinese plant, as well as those that sold raw ingredients to the wholesalers.
Among the potential problems the FDA found during the inspection of the Chinese Heparin plant 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 plant appeared to have made at least some Heparin with “material from an unacceptable workshop vendor.” According to the New York Times, Scientific Protein Laboratories, a Wisconsin company that is the majority owner of the Chinese plant, issued a statement Thursday saying the FDA’s finding did not represent its final determination as to whether the plant complied with federal regulatory rules.
Following the first Baxter Heparin recall in January, the FDA revealed that it had never inspected the Chinese plant before the factory began shipping the Heparin ingredient to Baxter in 2004, a clear violation of US policy. China’s drug agency also did not inspect the plant.
Heparin is a blood thinner administered in surgery and other critical care areas to prevent blood clots, is crucial in dialysis and heart surgery, and is used for the bedridden. Heparin is administered to millions of patients yearly; Baxter manufactures about half of all multiple-dose Heparin vials sold in the U.S. Heparin is made from pig intestines from which mucous membrane is collected and cooked, producing dry crude Heparin which is then sold to companies—like Baxter—that produce the final product. Some feel as much as 70 percent of China’s crude Heparin comes from small factories in poor villages, which act as Heparin production centers, some for 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.
“We have a collection chain in place and we stick with that,” said David Strunce, president of Scientific Protein Laboratories, an American company that owns a majority of Changzhou SPL. But, interviews with producers and traders in several Chinese provinces indicate a convoluted and unregulated supply chain comprised mostly of small family. After an outbreak of blue ear pig disease plagued much of China, prices soared and many suppliers used small workshops. A sales manager for a large Shandong slaughterhouse said he was approached by an SPL buyer offering cheap prices for crude Heparin. Ruihua Biochemical said it provided a mix of crude Heparin it manufactured and some it bought “from small factories nearby in several villages,” according to owner, Hua Ruihua, who said he never inspected the small factories. “We are not the government. We have no right to inspect their pigs or intestines or facilities,” he added. The owner of one workshop, Fan Yinan, said, “I sold to Ruihua several times before.” American officials certified SPL’s Changzhou plant, although neither government inspected it; the plant has exported to Baxter since 2004. The Chinese FDA believed the SPL factory produced the chemical ingredients and was not a drug factory, therefore, was not inspected.
Strunce says his company only buys through its wholesalers, but sales manager, Chen Jianjun, for major supplier, Nantong Koulong, said he sells directly to SPL, “We provided crude Heparin to Changzhou SPL.” “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 SPL and sells to Koulong. “We are really a traditional family-style plant,” she said. “We have no certificate.” Two officials of Zhejiang Willing Animal Byproducts Processing said they sold to SPL, “We supply Heparin to Changzhou SPL,” said Fang Weicai, general manager.
Heparin is used in surgery, dialysis, and for the bedridden. Other drugs thin blood, but their effects are not as quick, easily reversed, and broadly appropriate. Heparin has been manufactured since 1930 and is administered to millions yearly; Baxter manufactures about half of all multiple-dose Heparin vials sold in the U.S. The FDA said it received reports of four deaths and about 350 other health problems associated with Baxter's Heparin since late 2007; 40 percent were deemed serious. Reactions included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that—in some—led to life-threatening shock and, in others, death.
Baxter's issues are the latest a never-ending stream of life-threatening problems stemming from China—tainted toys, toothpaste, tires, pet food—and increase U.S. concerns with suppliers from less-developed countries. Baxter stopped manufacturing Heparin last week; the FDA began reviewing the plant in China on Wednesday. With over 700 Chinese plants producing active ingredients for drugs, Americans rely on their imports for a significant portion of pharmaceutical products. The FDA said Chinese regulators do not inspect plants that produce strictly for export.
Joseph Acker, president of trade group Synthetic Organic Chemical Manufacturers Association, said quality control falls on Baxter and other firms relying on China for pharmaceuticals. "We have to be sure that the standards that we set in this country are upheld," he said. "If that's not certain, then you just don't buy material from China until they can demonstrate that they can meet our standards.” Dr. Patrick Soon-Shiong, CEO of competing Heparin supplier American Pharmaceutical Products Inc., said his company helped establish procedures and "quality control" to monitor their China suppliers. "The best way to ensure the highest quality of raw material is to have feet on the ground in China who are American-trained and who understand the high level of good manufacturing guidelines with the FDA," he said.
Trouble with Heparin began surfacing in November when cases in Missouri led to a flood of reports about adverse reactions, some serious. Baxter identified nine lots of suspect product, recalling those lots in January. Parkinson said a top priority is to return Heparin to the market. "It's a small product for the industry, but it's significant in terms of its importance to clinical care. We have, as a company, an obligation to the medical and the patient community to get the product available," said Parkinson.