FDA Inspection Program Under Scrutiny

Heparin contamination casts a shadow on regulatory oversight of product quality.
Apr 02, 2008
Volume 32, Issue 4

Jill Wechsler
Pharmaceutical manufacturing has become a global business and transformed the way drugs are produced, regulated, and marketed. This development has resulted in many challenges that were recently illustrated by the long investigation into the cause of serious adverse events related to Baxter International's (Deerfield, IL) heparin products. Following reports of as many as 20 deaths and hundreds of allergic reactions associated with this blood thinner, which is widely used in surgery and kidney dialysis patients, the company recalled thousands of vials and shut down production earlier this year.

Although the cause of product contamination was not readily apparent, the fact that the active pharmaceutical ingredient (API) came from a Chinese facility captured national attention. With unsafe Chinese food, toothpaste, and drugs making headlines, itnot surprising that the media focused on Baxter's Chinese API producer and had a field day running stories on small Chinese operators that obtain an extract from pig's intestines for processing into crude heparin. In fact, the problem has become global. Soon after Baxter reported increased adverse events, a similar situation emerged in Germany.

Compounding the problem in the US was the surprising discovery that the US Food and Drug Administration never inspected the manufacturer, Changzhou Scientific Protein Laboratories, nor did Chinese regulators. This debacle highlighted inadequacies in FDAtracking of drug production at home and abroad. 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 the limits of FDA's preapproval inspection program. And it emphasized the reality that manufacturers bear the ultimate responsibility for ensuring the quality of all ingredients in a drug product.

More imports

The enormous expansion in drug substance imports in recent years has stressed FDA's oversight capacity considerably. At a contentious hearing in Feb. 2008 before the House Appropriations subcommittee that approves FDA funding, Janet Woodcock, then acting director of the Center for Drug Evaluation and Research (CDER), reported that about 80% of APIs come from foreign manufacturers. Committee Chair Rosa DeLauro (D-CT) termed FDA's heparin inspection error as one more example of "FDA's myriad failures" in dealing with multiple drug-safety issues.

Woodcock predicted similar problems in the future with drug products. Although imports of finished drugs now are much lower than those of APIs, she said that this situation "is going to change" because operators in "many regions of the world have indicated that they want to take over drug manufacturing."

This trend will demand further changes in FDA's current good manufacturing practice (CGMP) compliance activities. The agency has been inspecting only about 10% of foreign drug producers each year because field-inspection operations are inadequately funded, Woodcock explained. And because FDA faces deadlines for conducting preapproval inspections (PAIs) of suppliers and producers of new drugs, many low-priority facilities seldom see an FDA agent.

In Washington This Month
"We have raised red flags for years," Woodcock said, noting that FDA staffers are well aware that drug manufacturing and clinical trials have been moving overseas. Agency experts have created various plans for improving the safety and oversight of imported food and drugs, she noted, and have repeatedly urged an expansion in FDA's field force. But these proposals have been low on the agency's priority list. FDA needs hundreds of additional inspectors and an updated data system to better control drug imports into the US and better ensure drug quality, Woodcock commented, acknowledging that resources to support that kind of expansion are not included in the agency's 2009 budget proposal.

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