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Safety of Chinese Heparin
SAFETY OF CHINESE HEPARIN: CONTAMINATED HEPARIN LINKED TO DEATH AND SEVERE ALLERGIC REACTIONS
Please, feel free to contact us (contact) in order to obtain more informations regarding our SRID and ELISA test intended for the control of the animal origin of heparin
More details on Biological Heparins and the TSE Risk: click here
Adverse effects linked to heparin
Why and oversulfated chrondroïtin sulfate?
Origin of the contaminated heparin
The Chinese heparin production and its control
Expansion of contaminated heparin to other countries
Counterfeiting and heparin safety control
INTRODUCTION
The Missouri Department of Health and Senior Services first notified the Center for Disease Control and Prevention (CDC) on January 7, 2008, of several severe allergic-type reactions to heparin that occurred at a single pediatric hospital beginning on November19, 2007. The CDC in turn alerted FDA and Baxter HealthCare Corporation, prompting the company’s voluntary recall of nine lots of heparin on Jan. 17, 2008. On February 11, 2008, Baxter announced that it would stop producing heparin and the FDA issued a public health advisory informing the public about reports of serious adverse events in patients who received bolus injections of heparin sodium primarily from multi-dose vials manufactured by Baxter.
Virtually all of the nation’s 450,000 dialysis patients use heparin regularly. 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. Back to the top
ADVERSE EFFECTS LINKED TO HEPARIN
Heparin sodium is an anticoagulant (blood thinner) that has been marketed in the United States for nearly 70 years.
Heparin is commonly administered intravenously. It is used in patients undergoing kidney dialysis, certain types of cardiac surgery, and treatment or prevention of other serious medical conditions, including deep venous thrombosis (DVT) and pulmonary emboli. In many settings heparin treatment is initiated using high doses (5000-50,000 units) given directly into the blood stream (intravenously) as a bolus (over a short period of time, usually a few minutes).
Serious adverse events have recently been reported in patients who received these higher bolus doses. The serious adverse events include allergic or hypersensitivity-type reactions, with symptoms of oral swelling, nausea, vomiting, sweating, shortness of breath, and cases of severe hypotension requiring treatment. Most events developed within minutes of heparin initiation although the possibility for a delayed response has not been excluded. The reports have largely involved use of multiple-dose vials. However there have been several cases in which product from multiple, single-dose vials have been combined to administer a bolus dose.
Since then, FDA has learned of adverse events that extend beyond the recalled lots and involve patients receiving heparin for other purposes besides hemodialysis. Recent cases have included patients undergoing cardiac surgery and a specialized blood cell treatment known as photopheresis.
Since late December 2007 FDA has received 785 reports of adverse reactions. About 40% of the cases were estimated as serious. Especially, 19 deaths had been linked to heparin since january 1, 2008, and FDA received word of another 27 deaths, while it seems that many of them do not fit the definition of this kind of event. Back to the top
A CONTAMINANT IN THE HEPARIN
On March 5, 2008, an unidentified contaminant in Baxter’s heparin was announced by U.S. Health Officials that may be linked to the deaths in the United States. Routine tests failed to distinguish the contaminant from the drug, heparin. Only sophisticated magnetic resonance imaging tests uncovered that as much as 5 percent to 20 percent 20 percent of the product’s active ingredient was a heparin mimic blended with the real thing.
On Wednesday, March 19, 2008 the FDA identified "oversulfated chondroitin sulfate" as the contaminant in the Baxter’s heparin. Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said at a press briefing the compound "did not come from the pig" and that it had been altered from its naturally occurring state". She said the contaminant comprised 2% to 50% of the lots of heparin active pharmaceutical ingredient tested at a heparin processing plant in Changzhou, China.
The F.D.A. has yet to prove that the heparin contaminant is the cause of the deaths and illnesses now associated with the use of Baxter’s product. But heparin batches associated with illnesses, all of which were produced with ingredients made in China, were found to contain the contaminant while batches not linked to illnesses proved to be untainted. Back to the top
WHY AN OVERSULFATED CHONDROITIN SULFATE ?
Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis. It is used in both capsules and functional drinks. The major cosmetic use of chondroitin sulphate is in skin creams. Chondroitin sulphate hold up 30 times its weight in water, an ability which gives it very good moisturizing properties.
Chondroitin sulfate is generally isolated from cattle or pigs tracheal cartilage or from shark cartilage using extensive papain or pepsine digestion (ineffective against BSE) and mild alkaline borohydride (reducing agent) treatment. The product represents a full spectrum of glycosaminoglycans including chondroitin-4-and-6 sulfates, plus dermatan sulfates, chondroitin polysulfates, heparin and hyaluronic acid. The final extract is then lyophilized or dried by other means and placed in capsules usually consisting of 500 to 800mg CS and in some cases may even contain papain or pepsin.
Chondroitin sulfate isolated from cartitage is less sulfated than heparin and has no natural anticoagulant properties. Chemical oversulfatation using sulfuric acid increases the probability of obtaining pentasaccharides adequately sulfated such as in the heparin molecule and having anticoagulant properties.
Such an oversulfated chondroitin sulfate is more difficult to distinguish from porcine heparin by usual analytical methods. Oversulfation is also used by unscrupulous heparin manufacturers to "porcinise" ruminant heparins (less sulfated than the porcine heparin) in order to render similar to the porcine heparin.
According to Jake Hooker (The New York Times, March 19, 2008), scientists who have examined batches of the contaminated heparin distributed by Baxter International in the United States said in interviews that they suspected that the heparin-like molecule was intentionally mixed into the drug. “A child could tell you it’s counterfeiting,” said Dr. Jawed Fareed, a professor of pathology and pharmacology at Loyola University Chicago, who has been studying batches of heparin since the problems with the drug were discovered. “This is a deliberate act of chemically manipulating a heparin-like substance and mixing it with heparin to increase the yield.
Chondroitin sulfate is available as a dietary supplement,and is cheaper than heparin, as little as one-twentieth the cost. Many chinese pharmaceutical producers supply both chondroitin sulfate and heparine sodium (see figure 1). However, hypersulfated chondroitin sulfate is not approved for use in human.
Figure 1. Supply of both chondroitin and heparin by SinoSource Enterprise Co, Ltd.
ORIGIN OF THE CONTAMINATED HEPARIN
Baxter buys its heparin through a middleman, Wisconsin-based Scientific Protein Laboratories (SPL) which in turn owns a Chinese factory — Changzhou SPL (northwest of Shanghai)— and buys additional raw heparin from other Chinese suppliers. Analysts at the Changzhou plant used the tests recommended by FDA (capillary electrophoresis and magnetic resonance spectroscopy) to control raw heparin coming into the plant and concluded that the contaminant was in the material before it reached the plant. That means that this contaminant was very likely introduced at the workshop or consolidator level,
Changzou SPL gets raw heparin from two wholesalers who gather it from a dozen small workshops. Thus, SPL can’t fully trace its heparin supplies.
Changzhou SPL is registered as a producer of chemical ingredient company and thus was not checked by health authorities. Moreover, the F.D.A. admitted that it had violated its own policy by failing to inspect Changzou SPL before the factory began shipping the heparin ingredient to Baxter in 2004.
In March 2008, FDA inspected Changzou SPL and said that the teams’ inspectional observations related to deficiencies in the plant’s evaluation of the steps it takes to remove impurities; its investigation revealed data out of specification results, issues related to waste material flow and deficiencies related to equipment. Back to the top
THE CHINESE HEPARIN PRODUCTION AND ITS CONTROL
China has become by far the largest supplier of pharmaceutical ingredients in the world, but there is growing concern about the quality of the products made there. Last year, the F.D.A. discovered toxic levels of melamine –a substance added to increase the protein level - in a pet food ingredient shipped from China. Many pets became ill, and some died. More recently, 115 Panamain people died from a counterfeit cold medicine linked to an unlicensed Chinese chemical plant.
China is the world’s largest heparin exporter, shipping more than half the world’s heparin, that is more than $100 million of the substance a year.
As much as 70% of the China’s crude heparin comes from small workshops unlicensed and unregulated. Gordon Fairclough (Wall Street Journal, February 21, 2008) visited such worshops in China and reported edifying pictures and a video of one of them, the Yuan Intestine & Casing Factory. According to the Journal, Yuan Changkun, the owner of this small factory, doesn’t keep records of where he acquires the intestines he uses and health regulators don’t visit his plant. Gordon Fairclough also reported that Wang Jiewen, who runs a sizable heparin and sausage-casing factory in China’s eastern province of Anhui (6000 pigs a day), says inspectors routinely check his sausage-casing production lines, but not his heparin operations. "There’s not really much regulation for the heparin," he says.
The worshops sale their output to middlemen and the raw heparin ends up in the hands of about 50 export companies which sell to customers overseas. Some of these heparin producers are registered as chemical makers, not drug producers, and are not inspected by the China’s State Food and Drug Administration. Thus, if there’s a problem with the final medication, it can be nearly impossible to trace the raw heparin back to the source, the pigs whose tissue was used to make it.
Finally, more than 85% of these heparin exports went to 42 countries and regions, mostly in the U.S., France, Italy, Austria, and Germany. Back to the top
EXPANSION OF CONTAMINATED HEPARIN TO OTHER COUNTRIES
On March 7, 2008, Germany has recalled heparin from Rotexmedica, a manufacturer owned by Groupe Panpharma, based in Fougeres. This heparin believed to be linked to contaminated ingredients from China after 80 patients suffered adverse reactions such as shortness of breath, low blood pressure and episodes of an overly rapid heart shock. Most patients who suffered a reaction were undergoing dialysis treatment.
On March 19, 2008, three Japanese companies have recalled heparin products made with raw materials from China that were processed by Scientific Protein Laboratories.
On March 21, 2008, in the U.S and Canada, Braun Medical recalled 23 lots of infusion bags made with an active ingredient that came from Changzhou SPL and contaminated with chondroitin sulfate.
On March 25, 2008, batches of heparin, and some ingredients used to make it, are being recalled in France, Italy and Denmark by the European Medicines Agency (EMEA) because they are contaminated or suspected of being contaminated by chondrotin sulmfate.the same as the one identified in U.S. batches of heparin: over-sulfated chondroitin sulfate. The active pharmaceutical ingredient was made by an Italian company, Opocrin SpA, which used raw ingredients from Shenzen Hepalink Pharmaceutical (Shangai) and Yantai Dongcheng Biochemicals. Back to the top
COUNTERFEITING AND HEPARIN SAFETY CONTROL
China last year substantially reduced the availability of the starting materials needed to make the active ingredient in heparin, that could be an enticement for counterfeiters. After the outbreak of blue ear pig disease, prices soared due to pig stocks depleting and many drug suppliers had to scramble for new sources of raw material and to look to the small workshops which are unregulated and often unsanitary.
Gordon Fairclough (Wall Street Journal, March 10, 2008) reported that crude heparin manufacturers describe enormous variations in everything from record-keeping to what animals they use. Moreover, Wang Xiangyang, a factory director at the Zhaoyang Intestine & Casing Factory in Shandong, 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."
This attitude is very worrying for human safety since 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. Prions, the particles that cause these devastating illnesses, could be transmitted to humans through ingredients derived from cows or sheep. In this respect, intestinal mucosa is considered by the veterinary services as a "risk specified product" due to the risk of containing prion.
In case of residual prions in injectable heparin, the consequences for the human safety would be far greater than that issued from the chondroitin sulfate contamination and would only be discovered probably after decades of incubation.
Scientific Protein says to the Wall Street Journal that it tests all crude heparin to make sure it is from pigs and doesn’t contain heparin extracted from sheep or other animals. However it is known that such tests applied to the heparin molecule are not really effective since ruminant and porcine heparin cannot be differenciated with sufficient sensitivity by current physico-chemical analytical methods such HPLC or nuclear magnetic resonance. As a consequence, new methods have been developed to detect species specific contaminant in the crude heparins. Such contaminants include proteins (quantified by ELISA tests ) or DNA (detected by PCR). These methods also are not fully effective since the contaminants concentration greatly varies according to the process quality. Crude heparin can be rich or completely devoided of such contaminants, depending on sourcing or batches (see figure 2). Thus, a high quality crude bovine or ovine heparin cannot be sensitively detected in a porcine low or high grade crude heparin.
Figure 2. Three different batches of chinese crude heparin differing in quality
These analytical difficulties highlight the importance to firstly control the true raw material: the intestinal mucosa. Sensitive radial immunodiffusion assays - SRID Test have been developed to ensure its porcine origin and the absence of ruminant tissues (see also. Strangely, these tests are routinely applied in Europe and America on the mucosa batches used for heparin extraction but not in China, the world’s largest heparin producer. The scattering of some unregulated small worshops can be an explanation for the difficulties to exhaustively control all the processed mucosa in China. However it cannot be excuse for the whole absence of control. In the present scientific knowledge, heparin producers and Heath authorities would be fully responsible in case of sanitary problems with an heparin contamination by a bovine or ovine prion.
FDA considers that the numerous purification steps in the drug-making process are sufficient to produce a safety product from pig intestine, and that "companies are responsible for sourcing the materials" and "appropriately processing the material." The recent heparin contamination of chinese heparins by chondroitine highlight that these parameters cannot be totally under control. Moreover, the shortage of porcine mucosa will incite heparin manufacters to use more bovine or ovine intestinal mucosa. As a consequence, the analytical monitoring of the strictly porcine origin of the intestinal mucosa used for heparin production must be extended to all regulated heparin producers in order to avoid bigger safety problems in humans.
Didier LEVIEUX
Doctor in Veterinary Medicine
Director of Research Emeritus, National Institute for Agronomical Research (INRA), France
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