Heparin Contamination More Widespread than First Thought

The contamination of heparin is far more widespread, and began earlier, than first believed, FDA officials announced yesterday.

Heparin contaminated with over-sulfated chondroitin sulfate has turned up in at least 11 countries in lots manufactured as early as 2006, said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, in an April 21 media conference call.

The contamination has been found in lots of the active pharmaceutical ingredient (API) lots that were manufactured as early as 2006 but did not enter the world market until 2007. The FDA is currently aware of 10 Chinese firms in the supply chain of the contaminated heparin. Woodcock said that the regulatory agencies are currently tracking down and testing the products that have been contaminated, including drug products, IV flush products, medical devices, and possibly in vitro diagnostic tests.

According to Woodcock, adverse events were only reported in patients who received an intravenous bolus dose of heparin. The lack of adverse events in patients receiving the other dosage forms may explain why the breadth of the contamination was not discovered earlier.
On April 17–18, the FDA held a meeting with international regulators from more than 10 countries. They met to share inspectional methods and findings on heparin. Woodcock said that this team of regulators plans to hold an inspection summit in 2009 “to apply lessons learned from the heparin situation, particularly on how regulators worldwide can continue to build on existing collaborations.”

Woodcock said that a solid mechanistic link has been identified between over-sulfated chondroitin sulfate and the adverse reactions, and details will soon be published for evaluation. Woodcock acknowledges that “our Chinese colleagues are skeptical that such a link has been established,” and said that further dialogue with them should help resolve the situation.

Manufacturers of low molecular weight heparin, which was previously not included in product recalls, are now being asked to test their products and API, because heparin is used as a source of low molecular weight heparin. Testing by some manufacturers has revealed some contamination of low molecular weight heparin by over-sulfated chondroitin sulfate.
The FDA has also announced that a new 483 warning letter has been issued to Changzhou SPL (Changzhou, China), the API supplier to Baxter Healthcare (Deerfield, IL). This warning letter was issued after Changzhou SPL submitted its responses to another warning letter that was issued on February 26, 2008. The new warning letter, dated April 21, 2008, says that the responses that Changzhou SPL made to the February warning letter did not adequately address certain deficiencies, such as:

• Lack of assurance that processing steps can effectively remove impurities;

• The failure to have an adequate system in place for evaluating suppliers of crude heparin;

• The failure to verify testing methods for heparin have not been verified under actual conditions for use; and

• The use of unsuitable equipment used for the manufacture of heparin.

In response to the new warning letter, Changzhou SPL issued a joint press release saying that Changzhou SPL is committed to cooperating with the FDA and that it will provide a detailed response to the warning letter. They also added that there is nothing in the observations made in the warning letter that would have caused of contributed to the presence of the contaminant at issue in heparin products.

At the end of 2007, the FDA began receiving reports of adverse reactions from Baxter heparin products. To date, the FDA has received reports of 81 people who have died after using heparin products since January 1, 2007, and hundreds of adverse reactions to heparin products.

The API for Baxter’s recalled heparin products is produced by Scientific Protein Laboratories’ (SPL, Waunakee, WI) manufacturing sites in Wisconsin and Changzhou, China. On February 29, 2008, Baxter recalled multi-dose vials, single-dose vials, and HEP-LOCK heparin flush products, which all contain the API that is produced by the Changzhou SPL plant.
In March, three more US companies announced voluntary recalls of heparin products after being notified by their supplier, SPL of a nationwide recall of heparin sodium USP API because of the heparin-like contaminant. None of the three companies have reported receiving adverse event reports related to their products.

On March 6, 2008, German authorities initiated a precautionary recall of heparin products after receiving reports of adverse reactions that were similar to those reported to the FDA. Germany is the only country other than the US where adverse events have been reported.
On March 19, the FDA identified the contaminant in the API of Baxter Healthcare’s recalled heparin products to be over-sulfated chondroitin sulfate, a commonly available, “heparin-like,” cheap chemical compound.

For more information on the heparin situation, see BioPharm’s previous news coverage.
Three Companies Recall Heparin Products Because of ContaminantHeparin Contaminant Identified by FDA FDA Issues Border Alert for All Heparin ProductsGerman Ministry of Health Recalls Heparin ProductsFDA Finds "Heparin-like" Contaminant in Heparin APIBaxter Expands Heparin Recall, FDA Issues 483 to China FacilityLetters Sent to Baxter and FDA Request Answers on Heparin Situation