FDA finds unidentified substance in Baxter’s blood-thinning drug heparin

A significant amount of an un-identified foreign substance contaminated Baxter International Inc.’s blood-thinning drug heparin, the U.S. Food and Drug Administration said Wednesday, raising the possibility of intentional tampering in a supply chain that begins with pig farms in China
.The mysterious substance, which has a chemical makeup similar to heparin, comprises as much as 20 percent of the active ingredient in nine suspect lots produced by Baxter since September, the FDA said Wednesday. The suspect lots are connected to at least four deaths reported nationwide since Baxter noted a spike in adverse reactions to the drug in late December.

The FDA on Wednesday said heparin is connected to as many as 19 deaths and 785 serious illnesses since

Jan. 1, 2007
Jan. 1, 2007

. But the FDA timeline extends well beyond the period from September to November, when Baxter’s Cherry Hill, N.J., plant produced the heparin connected to the recent rash of serious allergic reactions. The suspect active ingredient in heparin originated at a Changzhou, China, plant owned by Scientific Protein Laboratories, a Baxter supplier based in Waunakee, Wis.
“We don’t know whether the introduction of the contaminant was accidental, as part of the biological process, or if it was deliberate,” said Dr. Janet Woodcock, acting director of the FDA’s center for drug evaluation and research.
At least one former top FDA official who helped lead the fight against counterfeit drugs indicated that some Chinese suppliers in the past have introduced foreign substances to boost production when supplies are tight. That’s what happened in the early 1990s with an antibiotic known as gentamicin sulphate, which produced adverse reactions and some deaths in the U.S.
“The obvious question is, ‘Are these plants back-dooring their supply in order to supplement their capacity?'” asked Benjamin England, who chaired the FDA’s Counterfeit Drug Working Group before leaving for a private law practice in

Washington, D.C.
, in 2003.Epidemic in

China
China

Heparin is produced from an enzyme in the mucous lining of pig intestines. The suspect lots of heparin were made beginning in September, just after the peak in an epidemic of an often-fatal disease known as “blue ear” that afflicted more than 250,000 pigs throughout

China
. More than half those pigs died or were exterminated.An FDA official at the press conference said it is possible supplies of the adulterated ingredient came from pig intestines. But FDA officials emphasized they have not pinpointed the source.

Conventional quality and safety testing typically does not discover a foreign substance,

England
England

added, because the tests are not designed for that purpose.The FDA in its press conference Wednesday said conventional tests performed by Baxter and Scientific Protein did not show any variation because the contaminant is so similar to heparin.

“It acts like heparin in this test, so it looks like everything is fine in the test,” Woodcock said.

Only after further testing, using nuclear magnetic resonance spectroscopy, did the differences in chemical makeup become apparent, the FDA said.
Scientific Protein’s plant obtains heparin from bulk providers of raw material. From its plant in

Changzhou, Scientific Protein ships raw heparin to the company’s headquarters outside Madison, Wis., then on to Baxter’s Cherry Hill
Changzhou, Scientific Protein ships raw heparin to the company’s headquarters outside Madison, Wis., then on to Baxter’s Cherry Hill

plant for final processing, packaging and shipping.Pointing fingers

Baxter, in its own press conference, sought to point the investigative spotlight back to

China
China

. Baxter executives said the active pharmaceutical ingredient sourced from its China-based supplier is the focus of the company’s investigation.”Either the problem lies further back in the supply chain, somewhere before the material gets to the processing plant, or there’s something in the processing before it comes to Baxter,” said Peter Arduini, president of Baxter’s medication delivery business.

Arduini said the company’s

Cherry Hill
Cherry Hill

manufacturing plant, where multidose vials of heparin are finished and filled before shipment to hospitals and dialysis centers, recently passed an FDA inspection.Arduini said Baxter’s investigation centers further into the “supply stream” in

China
China

. There could be “process issues” associated with Scientific Protein’s Chinese manufacturing plant, he said.Baxter also took issue with the numbers provided by the FDA, which said heparin has played a role in 19 patient deaths since

Jan. 1, 2007
Jan. 1, 2007

. Baxter insists that four deaths so far may be connected to adverse reactions to the suspect heparin.For its part, Scientific Protein disagreed with the FDA’s interpretation of test results that seems to focus the investigation on a possible adulterated material being added during Scientific Protein’s production process.

“During the call with the media, FDA speculated that the source of the adverse events may be a contaminant,” Scientific Protein said in a statement. “It is important to note that this theory is speculation at this point, and [Scientific Protein] is participating actively in working with the FDA to pursue this theory as well as others so that we can understand the cause of the adverse events.”
Scientific Protein’s

Changzhou
Changzhou

plant, owned in a joint venture with a Chinese partner, is preparing a response to an FDA inspection report last week that criticized the plant’s record-keeping, reporting and processes. “It is important to emphasize that the root cause of the heparin adverse events has not been tied to any of the agency’s observations,” Scientific Protein said in a statement.FDA inspections

Dr. Andrew C. von Eschenbach, commissioner of the FDA, declined to say whether the FDA physically inspects the more than 700 Chinese facilities that ship pharmaceutical ingredients and drug products to the

U.S. The FDA has deployed a “risk-based” system that seeks to focus inspection on plants that might potentially cause the most harm to U.S.
U.S. The FDA has deployed a “risk-based” system that seeks to focus inspection on plants that might potentially cause the most harm to U.S.

consumers.Von Eschenbach said the agency is beginning to reallocate resources to better address the problems presented by the huge growth in foreign-made drugs. “We recognize that the number of sites that we must pay attention to that are beyond our borders are going to require us to address this systematically,” he said.

The FDA plans to increase the number of inspectors, base inspectors in key foreign cities, and build stronger working relationships with foreign regulators, Von Eschenbach added.