Contaminated heparin investigation highlights medication safety issues

An outbreak of Serratia marcescens bloodstream infections between October 2007 and February 2008 appear to have been caused by the contamination of prefilled heparin and saline syringes made by a single manufacturing company, according to a report published today in Archives of Internal Medicine.

An on-site inspection of the company — referred to in the report as company X — revealed that the manufacturer did not comply with the FDA’s Good Manufacturing Practices and quality system regulations. Within days of the inspection, the company discontinued production and voluntarily recalled the contaminated lot.

The outbreak

In 2007, the CDC received reports of bloodstream infections caused by S. marcescens from several health care facilities, including an outpatient infusion center in Texas and from clinicians in Chicago who were treating patients receiving supplies through a local home care company. In 2008, the CDC received an additional outbreak report from a second infusion center in Texas.

S. marcescens is an aerobic gram-negative bacterium and a well-known cause of health care-associated infections. Patients who receive central venous catheters are at increased risk for bloodstream infections because the catheters are frequently flushed with heparin and saline. In fact, 91.2% of the patients in this outbreak had central venous catheters.

David Blossom, MD, of the CDC, and colleagues conducted the investigation. Initial information suggested that the outbreak stemmed from prefilled syringes of heparin and saline, all manufactured by company X.

Company X was able to provide records for other facilities that had received the same syringes. Anyone who had received the same lot of syringes was contacted and culture specimens were taken from unopened syringes. Specimens were also taken from unopened product at company X.

Blossom and colleagues found 162 S. marcescens bloodstream infections among patients at facilities using syringes from company X. In addition, cultures of unopened prefilled heparin and saline syringes manufactured by this company grew S. marcescens. Of the 83 blood samples that contained S. marcescens submitted to the CDC from seven states, 84% contained bacteria genetically related to that grown in the prefilled syringes.

The outbreak revealed several challenges to medical product tracking that need to be addressed in the future, according to Blossom.

First, a large number of distributors acted as intermediaries between the manufacturer and the health care facilities that used the products. In addition, none of the contaminated syringes bore the company’s name on the label but rather had the names of subsidiaries or different companies.

Finally, some syringe batches were contaminated and others were not. This intermittent nature made identifying the source of the outbreak more difficult, therefore, making the recall more challenging.

Is safety a problem?

Despite the FDA’s record of success, the agency has come under increased scrutiny for its ability to ensure drug manufacturing safety once a drug has been approved, according to William K. Hubbard, BA, MA, a former FDA associate commissioner, who wrote an accompanying editorial.

In addition to this outbreak, a more recent case of heparin contamination, which resulted in deaths and serious injuries, occurred in a foreign manufacturing facility. “Indeed, today, 80% of Americans’ pharmaceutical ingredients are imported,” Hubbard wrote. He pointed out that in the future, an increasing amount of U.S. pharmaceuticals will be produced outside the United States, and although the FDA has stringent requirements for inspections of U.S. drug manufacturers, there is no requirement for inspecting foreign facilities.

“Drugs made in the United States under the FDA’s rigorous quality control standards have an extraordinarily good safety record, as measured by the paucity of manufacturing defects and deaths and illnesses related to manufacturing deficiencies,” he wrote. “But it is obvious that foreign sources do not share in that record of success. It does no good to have rules if they are not obeyed, no good to set standards if they are not used, and no good to develop advanced scientific skills if they are not employed.”

Blossom D. Arch Intern Med. 2009;169:1705-1711.

Hubbard WK. Arch Intern Med. 2009;169:1655-1656.