Heparin or Over Sulfated Chondroitin Sulfate? That is the Question.

Armand Rossetti

Contributor

0 CommentsPrint ArticleSubscribe

In its natural form, chondroitin sulfate (itself a glycosaminoglycan) is used as a natural dietary supplement for the palliation of osteoarthritis. In fact, natural chondroitin sulfate is not a blood thinner like its analog, “over-sulfated chondroitin sulfate” (OSCS). Heparin is also a highly sulfated glycosaminoglycan.

A large unregulated Chinese manufacturer, Changsou, made the cheap heparin-like OSCS, mixed it with raw heparin (cut the heparin), and then sold the adulterated heparin at attractive prices to well-respected drug companies like Baxter International. Early on in the discovery of the OSCS contamination, many severe allergic reactions while using contaminated heparin, including 19 deaths resulted. To get a better understanding of how events surrounding the OSCS contamination unfolded, let’s take a look at the following, brief news, scholarly journal and FDA alert timeline:

February 11, 2008:

FDA News released an advisory warning that Baxter’s multiple-dose vial heparin was kinked to severe allergic reactions. Baxter stopped manufacturing the product while the FDA continued to investigate the root cause of the product’s adverse reactions. However, rather than issuing a recall, the FDA compromised and issued recommendations to physicians who might have to use the product that Baxter had already distributed.

February 16, 2008:

Because Changhou SPL had no drug certification, China’s drug agency did not inspect it. The US FDA said this week that it had not inspected the plant, either-a violation of its own policy-before allowing the company to become a major supplier of the blood thinner, heparin, to Baxter International in the United States.”

February 28, 2008:

The US FDA issued an alert to inform the public about reports of serious adverse events in patients who had received bolus injections of Baxter’s heparin. The FDA recommended not using Baxter’s heparin, but if there was no other source in an emergent situation to: not use a bolus dose; use the lowest dose necessary; closely monitor the patient for adverse events; and to consider pre-treating with corticosteroids or antihistamines before administering heparin.

The alert mentioned that Baxter, a major heparin supplier with over 50% market share, had withdrawn nine lots of heparin in January 2008 after receiving 350 adverse events, 40% of which were serious.

March 1, 2008:

Up until late February 2008, neither China nor the FDA had regulated China’s largest Heparin raw material ingredient producer, Changhou Scientific Protein Laboratories. The failure to regulate Changhou was a violation of the US FDA’s own inspection policy (CBS Video).

March 19, 2008:

China’s State Food and Drug Administration (SFDA) and the US FDA both identified OSCS in Baxter’s Heparin. The US FDA was investigating whether the chemical was purposefully or inadvertently added during manufacturing in China. The over-sulfated version of chondroitin sulfate does not occur in nature and must be manufactured. The FDA was attempting to determine whether the synthetic chondroitin sulfate was the cause of 19 deaths, hundreds of serious breathing problems and other reactions reported in the United States.

In March 2008, the US FDA knew that over sulfating chondroitin, which is substantially more abundant and available from a wide range of animal sources, was cheaper than processing raw heparin from pig intestines.

March 22, 2008:

China’s SFDA ordered its local bureaus to increase supervision over heparin production. Producers would now have to obtain raw material from registered suppliers. The US FDA called on importing countries to take responsibility for insuring heparin’s safety. China is the largest heparin material supplier in the world.

However, regulation would be a daunting task for the Chinese, because much of the then current supply chain included thousands of small workshops that gathered heparin from pig intestines and sold it to larger chemical companies (not drug companies) that produced the pure active ingredient in heparin. Here is a quote from the New York Times article:

“Much of China’s production of raw heparin begins in homes and tiny factories, where teams of three to five people transform pig intestines into a dry substance that is eventually sold to major pharmaceutical companies.

Most of the small factories are unlicensed and unregulated. They sell to traders and consolidators, who sell the raw heparin to companies like SPL that, purify it to produce the active ingredients. Many of them are not regulated by the Chinese drug agency, since they are considered chemical companies, not drug makers.

The active ingredients, in turn, are sold to pharmaceutical companies like Baxter that produce the finished drug.”

April 2, 2008:

After receiving notification from Scientific Protein Laboratories, LLC (SPL), Covidien, formerly Tyco Healthcare, voluntarily recalled its injectable heparin products.

April 20, 2008:

Baxter International had begun distributing contaminated heparin in November 2007. The contaminated heparin base had reached nine countries not including the United States. The US FDA had traced the contaminated heparin to 12 Chinese manufacturers. Now there were 81 deaths due to the contaminated heparin. Yet, the Chinese remained skeptical that investigators could make a connection between OSCS and the illness and deaths that had resulted.

The FDA still did not know where in the Chinese supply chain processors had introduced the OSCS, but the FDA was fairly certain that OSCS had caused the illnesses and deaths. Investigators had observed similar reactions in animal studies and had conducted in vitro testing that had confirmed that such reactions might occur.

April 23, 2008 (published in June 2008)

National Biotechnology published Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events, suggesting that traditional methods of analysis could not OSCS detect contamination:

“Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here.”

May 15, 2008:

Atrium Medical Corporation and Medtronic, Inc. initiated voluntary recalls for their contaminated heparin products.

October 18, 2008:

The FDA requested that US Marshals enter Celsus, an Ohio heparin Manufacturer and seize 11 lots of heparin contaminated with OSCS. The seized material had entered the US prior to import controls that were established earlier in 2008. Celsus President Case Van Gorp informed CNN that Celsus had quarantined the contaminated lots at least since April 2008, and had notified its customers of the problem in March.

The FDA had inspected Celsus in April and May, and that since then no contaminants had been identified in Celsus heparin products. However, the FDA had told Celsus that its actions to notify customers about the company’s contaminated heparin were insufficient to assure an effective recall.

Conclusion:

While it is evident that the US FDA did pay close attention to developments concerning contaminated heparin after the problem arose, it is evident that the FDA did not do enough to prevent the possibility of such widespread contamination from occurring in the first place. However, the FDA is not alone in its inability to prevent such pharmaceutical manufacturing disasters. In addition to China, India provides a good example of a country that is not currently prepared to deal with untoward manufacturing problems. Here is an excerpt from “Story of Heparin Recall: What India can do?” published in the Journal of Postgraduate Medicine (one of the oldest medical journals from India):

“Traditionally very little is done to address drug safety issues in India by pharmaceutical companies. Implementation of amended Schedule 'Y' of the Drugs and Cosmetics Act, has not improved the situation yet. The NPP has achieved very little, if anything, until now. A lot needs to be done to put in place a pharmacovigilance system robust enough to verify such important medication safety signals as observed in case of heparin. Also, we are way behind the western countries in identifying safety signals to new drugs and quantifying the risks.”

Regarding the US FDA's inability to address foreign active ingredient supply problems, perhaps Susan Briones said it best in her essay, Heparin Recall: Another Crisis for China & the FDA:

“And what of the FDA’s own admission of failing to follow its own procedures? Can injured patients hold it accountable? -Probably not. The FDA is one of many overburdened, under-funded, and liability immune government agencies that let consumers fall through the cracks. This time, however, the result was the death of Americans. It is imperative that the FDA be better funded and managed so that inspections of production facilities outside of the U.S. can be done on a comprehensive level. The U.S. and Europe have been expanding their production of medical products globally for several years because it is cheaper to do so. Approximately 40% of drugs and 80% of their chemical ingredients are imported from countries like China and India that do not have ample inspection and safety procedures in place. According to Dr. Bryan Liang, an advisor to the Partnership for Safe Medicines, “the problem is only going to get worse as more materials come from suspect sources.” This is not news, however. The FDA knows it does not have the manpower or resources to inspect every overseas facility, as do Congress and the President, all of whom have been calling for more funding. Perhaps holding the FDA liable for the damages experienced by the harmed patients is the only way to prod our government into properly funding this all-important agency and keeping American consumers safe.”