FDA's Inspection Program Under Scrutiny

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.

Jill Wechsler

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.

ROOT CAUSE REMAINS ELUSIVE

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.

MORE OVERSIGHT

FDA's inspection failure has raised questions about how well FDA can track drug manufacturers around the world and ensure that all ingredients fully meet GMPs. Rep. Frank Pallone (D-NJ), chairman of the House energy and commerce health subcommittee (E&C), said that the heparin case reflects "carelessness that seriously jeopardized the health of American patients." The House Energy and Commerce committee held a hearing last November to address FDA's capacity for overseeing the vast increase in drugs and APIs imported from abroad, and the heparin debacle provides added fuel for its investigation.

The SPL inspection also has generated questions about the adequacy of FDA's preapproval inspection (PAI) program for drugs and biologics. In a letter to FDA Commissioner Andrew von Eschenbach in February, Reps John Dingell (D-MI) and Bart Stupak (D-MI) of the E&C oversight and investigations subcommittee suggested that FDA might be "abandoning its preapproval inspection requirement" for medical products. The legislators said they assumed that FDA has to "approve each step of drug manufacturing, including all ingredient sources" to approve a drug for market. If that is not the case, Stupak added, Congress may be looking for legislative changes that would "prohibit the marketing of any drug from a plant that has not been properly inspected."

FDA officials explain that the agency has to ensure that all marketed drugs comply with GMPs and meet quality standards, but an on-site field inspection is only one way to verify regulatory compliance. If a manufacturer has a good GMP compliance history, and the product under review is relatively low risk, FDA may forego a PAI for a new or altered product from a plant that has been inspected within two years.

A statutory requirement that FDA conduct a PAI for every new drug coming to market would undermine the agency's efforts over the last decade to eliminate redundant inspections and better target its depleted field force to the most critical products and facilities. Throughout the 1990s, FDA conducted more than a thousand PAIs annually, but this volume became unsustainable as agency resources for field inspections became increasingly tight. The downward trend accelerated in recent years as FDA moved to modernize and streamline its oversight of drug manufacturing under its GMPs for the 21st-century initiative. FDA staffers now specify only a limited number of new drugs that would regularly warrant a PAI and leave it to field inspectors to use their discretion in expanding the list.

FDA is developing an important initiative to establish an electronic system for registering all drug manufacturing and labeling facilities and for listing all regulated products. The agency's current tracking system is not integrated with other FDA databases, generating confusion and errors. FDA's Bioinformatics Board is working to establish one system for tracking all regulated products and for adverse event reporting in all product areas. FDA hopes to move forward on this program this year, but the agency first has to finalize a proposed regulation for modifying current national drug codes in order to create a common coding system.

A larger issue is to what extent regulatory authorities are responsible for ensuring the quality of APIs. Although FDA inspects many API producers, the agency still relies on pharmaceutical and biotech companies to test the ingredient quality. This approach is standard overseas, where many foreign regulators leave this task entirely to manufacturers.

The finished product manufacturer has to take responsibility for problems with drug quality or safety, according to David Elder, director of ORA's Office of Enforcement. Too often, he said at a recent compliance conference, manufacturers want to blame suppliers for product failures. However, he specifically pointed to pharmaceutical companies in asserting that FDA "will continue to hold them accountable" for such problems.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase,MD,301.656.4634, jwechsler@advanstar.com