In the initial stage of processing, operators place the intestines into equipment that separates the mucosa, the inner lining of the intestine, from other intestine components such as the casing material sold to sausage makers.
The room where this takes place has the pungent smell of fresh meat. The mucosa is then piped into large vessels for an enzymatic reaction that separates proteins and impurities from the glycosaminoglycans from which heparin is later extracted.
Subsequent operations yield crude heparin powder, which is either sold to other companies or processed into pharmaceutical-grade heparin by Enoray itself. Each operation conducted by Enoray, all the way back to the slaughterhouse, is documented and individually signed by the operators involved, according to Peter J. Werth, chief executive officer of the U. ChemWerth represents Enoray products in the U.
Enoray passed a surprise inspection by FDA inspectors last year, Mei says. During the plant tour, Mei points to an operator who is conducting polymerase chain reaction testing on crude heparin before it is purified into the pharmaceutical grade. Although some countries allow other animal sources, only porcine heparin is permitted in the U. FDA started requiring the test in to reduce the risk that heparin from sheep, goats, or cattle enters commerce as an active pharmaceutical ingredient, or API.
Bovine heparin was discontinued in the U. Some heparin from sheep or other unapproved animal sources could still be entering the supply chain. On commercial websites in China, it is relatively easy to find advertisements for crude sheep heparin costing far less than the porcine product.
Fudged data in hand, Tiandong processed the crude heparin into purified API and sold it as porcine-derived. Manipulating PCR data may not be the only nefarious activity engaged in by dodgy heparin makers. FDA issued a warning letter to the firm and banned its products from the U. Califf highlighting their concerns about the heparin supply chain.
Perhaps their most damning claim was that China just does not have enough pigs to make all the heparin it produces. Chinese regulators require that heparin be extracted only from intestines produced at regulated slaughterhouses. In , such facilities accounted for just more than half of the pigs that China butchered. China, Miao adds, has more than enough pigs to supply its own heparin needs as well as the export market.
Owing to productivity improvements, it now takes about 1, intestines to produce 1 kg of heparin, not 2, intestines as U. And unlike in , most major slaughterhouses are now overseen by the government, he says, meaning that far more than half of slaughtered pigs are available to heparin producers.
So China has spare production capacity. With the beefed-up FDA requirements, it is almost impossible to contaminate heparin with oversulfated chondroitin sulfate, Miao argues. Using other animals remains a vulnerability, he concedes, but all in all, raising compliance requirements much further could raise costs to the point that heparin shortages would start to occur, he says.
Shortages nearly occurred in when numerous batches of contaminated heparin were recalled in the U. Bovine heparin was available in the U.
Bovine heparin is still sold in Brazil, a major cattle producer. FDA says it is working with USP and foreign regulatory agencies, as well as heparin experts, to develop new standards to characterize and quality test heparin from bovine sources. But some scientists contend that reintroducing bovine heparin could compromise heparin safety. Pigs are more genetically similar to humans than cattle are, Yu says, so porcine heparin poses less of a risk of allergic reaction. It will take a lot of work, and new clinical trials, to determine when and how bovine heparin can perform like the porcine version.
To get around the problem that sourcing heparin from animals poses, one solution could be synthetic heparin or a synthetic drug that performs like heparin.
Several groups of researchers around the world are trying to do just that, despite the long odds against succeeding. Liu is confident that his group will have a clinical drug candidate within a couple of years. His group has also come up with an agent that can reverse the effect of the drug for patients who respond negatively.
Because his firm advises Enoray on regulatory compliance and audits its quality-control systems, Werth is confident that quality will not be an issue.
But he cannot vouch for other companies, even with the higher standards that FDA has imposed in recent years. The problem, he says, is human nature. If there is a way to make more money by adulterating a product, some will be tempted. Contact us to opt out anytime. Contact the reporter. Submit a Letter to the Editor for publication.
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All we need is few more details to create your reading experience. Not you? Sign in with a different account. Need Help? Membership Categories. Regular or Affiliate Member. Graduate Student Member. Undergraduate Student Member. Benefits Enjoy these benefits no matter which membership you pick. Thank you! Medicinal Chemistry Making heparin safe Although manufacturing fraud remains possible, Chinese firms have upgraded their processes to meet stricter U.
The pig is king in China. All other measures used to prevent contaminated heparin products from entering the US should remain in place, and we request that all heparin suppliers and manufacturers continue reporting results to FDA as outlined in the section " Heparin Test Results " until further notice.
To ensure safety of heparin products in the United States, FDA asked manufacturers of heparin-containing products to test the heparin active pharmaceutical ingredient API used in these products with the two screening methods posted to FDA's website, capillary electrophoresis CE and proton nuclear magnetic resonance H-NMR. FDA wants to extend its appreciation to all companies who expeditiously adopted these methods and provided monthly updates.
These methods have been included in the United States Pharmacopeia monograph since June , and are to be used for all products intended for the U. Adherence to an appropriate testing regimen will be monitored by our inspection program and enforced by FDA. Beginning with the month of March , monthly updates on heparin test results are no longer required.
However, please continue to notify FDA of any positive results within 3 days of the testing. Provide your positive results, with the associated H-NMR spectra and CE electropherograms to support the test results, using the below template via email to cderrecalls cder.
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