FDA's Inspection Program Under Scrutiny

The heparin safety crisis puts a spotlight on manufacturing processes and regulatory oversight
Apr 01, 2008
Volume 21, Issue 4

Jill Wechsler
Questions have been multiplying about the US Food and Drug Administration's ability to monitor the quality and manufacturing processes of drugs and medical therapies produced at home and abroad. These issues gained headlines recently following a wave of serious adverse events involving the blood-thinning drug heparin. Baxter International (Deerfield, IL) had to recall most of its heparin product line and shut down production as the manufacturer and FDA sought to uncover the root cause of several deaths and hundreds of serious reactions to this commonly used injectable for surgery and kidney dialyses patients.

Although the cause of the adverse events initially was a mystery, the fact that Baxter's active pharmaceutical ingredient (API) came from China made headlines. The media focused on the Chinese API producer, Changzhou SPL (owned by Scientific Protein Laboratories [SPL, Waunakee, WI]) and the small Chinese operators that process an extract from pigs' intestines into crude heparin. The crisis became even more international as similar adverse events arose in Germany.

At home, the heparin debacle highlights the inadequacies of FDA's tracking of drug production in the US and abroad, a problem that has escalated with the proliferation of API and drug imports. FDA officials admit that their system is so obsolete that they have only a vague idea of what drugs are manufactured where and which overseas facilities have been inspected. The case also focused attention on FDA's preapproval inspection policy and raised the prospect that more sophisticated analysis of complex, biologically derived substances like heparin may be required in the future.


The heparin-related adverse events prompted a global investigation into the source of the problem. First, it turned out that the Changzhou plant was never inspected by FDA or by Chinese regulatory authorities. Four years ago, SPL, the supplier of API to Baxter, began sourcing the API from the plant in Changzhou. That required Baxter to file a manufacturing supplement with FDA to add the Chinese plant as an alternate API supplier.

Because of an error in identifying the facility, US inspectors did not carry out the usual inspection of a newly listed API producer. It was not until January of this year, when hundreds of adverse event reports poured in, that FDA discovered the inspection error. "Unfortunately, FDA staffers confused Changzhou SPL's name with a plant that had a similar name," explained Joseph Famulare, deputy director of the Office of Compliance in the Center for Drug Evaluation and Research (CDER). Because the other firm, which had been inspected, was entered into the record, Changzhou SPL was not visited. In addition, because the API was being produced only for foreign use, China's State Food and Drug Administration did not conduct an inspection, as fits its policy.

To uncover the root cause of the adverse events, FDA inspectors swarmed over SPL, its Chinese facility, and Baxter's operations. "We go back to the original raw material and to every production step," explained Michael Rogers, director of FDA's Division of Field Investigation, Office of Regulatory Affairs (ORA), at a press briefing. "We identify the manufacturing process and the raw materials used to make the product."

FDA inspectors ruled out problems with components or packaging at Baxter's Cherry Hill, NJ, finishing plant. But when they visited Changzhou SPL in February, they uncovered a number of "potential deficiencies" in procedures for removing impurities, process validation, equipment cleaning, waste handling, and product testing. Baxter says it also found similar problems during its own audit of the Chinese plant last September, but evidently the problems were not fixed.

Meanwhile, the hunt for the source of product contamination moved into the laboratories. The usual battery of API tests provided no clues. But nuclear magnetic resonance (NMR) spectroscopy and capillary electrophoresis revealed the presence of a heparin-like substance in API from both Wisconsin and China. FDA hesitated to directly link this contaminant to patient allergic reactions, but offered no other explanation. FDA posted information on the effective test, and urged all producers of heparin API and finished products to conduct this analysis.

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