Some of Baxter International's recalled blood thinner heparin contained large amounts of a contaminant that might explain hundreds of serious side effects. And the government said Wednesday it's investigating whether what appears to be a fake ingredient got there by accident or by fraud.
The Food and Drug Administration said 19 deaths from allergic-type reactions are now associated with the recalled drug, up from four.
Baxter insisted the contaminant further points suspicion at ingredient suppliers in China, which are under increasing scrutiny after a wave of recalls involving food, drug and toy imports.
The FDA stopped short of ruling out a U.S. connection and cautioned that while the contaminant is a prime suspect, officials haven't yet proved it harmed patients.
"We still don't know whether this inadvertently got into the supply or whether it was actually added," said FDA drug chief Dr. Janet Woodcock. "We can't tell you where the contamination originated."
High-tech testing by Baxter and other groups uncovered a heparin-like compound in batches of the problem drug - a substance not found in batches of problem-free heparin.
The contaminant accounted for between 5 percent and 20 percent of some of the samples tested, what FDA's Woodcock called "significant quantities."
At those amounts, batches of heparin should have been flagged as subpotent in Baxter's routine quality tests - but they didn't, because the contaminant is so chemically close to real heparin that standard testing couldn't tell the difference, Woodcock said.
The FDA is so concerned that later this week it will give manufacturers and other regulatory agencies worldwide instructions on how to check other heparin supplies to be sure the contaminant isn't sneaking in.
Remaining U.S. supplies of heparin, made by Baxter competitor APP Pharmaceuticals, do not show contamination, the FDA stressed.
Heparin is derived from pig intestines, and the heparin-like contaminant is related to a complex group of chemicals also in those intestines, FDA officials said. That's part of the difficulty in determining how the contaminant got into bulk ingredients used to make vials of the injected blood thinner, which are used in patients undergoing dialysis and heart surgery.
Counterfeit ingredients from China are a perennial headache for the FDA. If the heparin contamination turns out to be deliberate, it would be reminiscent of last year's scandal when a Chinese company was charged with adding the toxic chemical melamine to an ingredient used in U.S. pet food, killing thousands of dogs and cats. The melamine let the ingredient pass chemical inspections for protein content.
But Baxter referred to the heparin-like compound as "naturally derived," and FDA said it would take more specific identification of the contaminant, among other things, to tell if it could have slipped into the bulk ingredient accidentally, during processing of the pig intestines.
Baxter, which had provided about half the nation's supply, halted production last month after its brand was linked to hundreds of reports of allergic-style reactions, including vomiting, nausea and difficulty breathing. Baxter purchases bulk heparin from Wisconsin-based Scientific Protein Laboratories, or SPL, which in turn owns a Chinese factory and buys additional crude heparin from other Chinese suppliers.
Baxter said it found the contaminant in samples of the ingredient from the China plant, Changzhou SPL, and in samples processed at the Wisconsin factory that came from Chinese-made crude heparin.
"These results suggest that the root cause may be associated with the crude heparin, sourced from China, or from the subsequent processing of that product before it reaches Baxter," the company said.
The vast majority of the world's heparin comes from Chinese ingredients, Baxter officials noted.
"It is premature to conclude that the heparin active pharmaceutical ingredient sourced from China and provided by SPL to Baxter is responsible for these adverse events," the Wisconsin-based SPL said in a statement.
FDA inspectors last week found quality-control problems at the Changzhou factory, a facility the agency had never before inspected - in violation of its own rules - because of a mix-up with the company's name. But the FDA isn't yet sure if those problems are linked to the allergic-style reactions.
The FDA now has 785 reports of side effects among patients taking heparin from any manufacturer, but can't yet say how many are the complications of concern. Last week, the agency put that number at 215. FDA also has a total of 46 reports of deaths, but ruled out a link with many of them and concluded that 19 deaths since January 2007 appear related to allergic-type reactions that triggered Baxter's recall.
