FDA Inspection Program Under Scrutiny - Pharmaceutical Technology

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FDA Inspection Program Under Scrutiny
Heparin contamination casts a shadow on regulatory oversight of product quality.


Pharmaceutical Technology


Limiting preapproval inspections

The heparin debacle has raised questions from Congressional leaders about the adequacy of the US Food and Drug Administration's preapproval inspection program for medical products. In a letter to FDA Commissioner Andrew von Eschenbach, House Energy and Commerce Committee Chairman John Dingell (D-MI) and Oversight and Investigations Subcommittee Chairman Bart Stupak (D-MI) said they assume that FDA is required to "approve each step of drug manufacturing, including all ingredient sources" before approving any drug for market. If that is not the case, Stupak added, Congress may "prohibit the marketing of any drug from a plant that has not been properly inspected."

FDA officials explain that the agency must ensure that all marketed drugs comply with good manufacturing practices (GMPs) and meet quality standards, but that 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 has relatively low risk, FDA may forego a preapproval inspection (PAI) of a plant that has been inspected within two years. Normally, however, a new active-ingredient supplier that has never been inspected would warrant a visit from FDA staff.

A statutory requirement that FDA conduct a PAI for every new drug coming to market would undermine agency efforts during the last decade to eliminate redundant inspections and better target its depleted field force to the most critical products and facilities. FDA expanded PAIs for drugs about 20 years ago, following an investigation led by Rep. Dingell into fraud and data falsification in the burgeoning generic drug industry. The aim of the PAI policy was to ensure that all drug manufacturers comply with GMPs and provide accurate and authentic data to the agency about manufacturing capabilities and product testing.

Throughout the 1990s, FDA conducted thousands of PAIs covering all new chemical entities, widely used generics, and narrow therapeutic drugs, as well as new manufacturers and new plants. This high PAI volume became unsustainable as agency resources for field inspections became tighter and tighter. And as the generic-drug regulatory program became firmly established by the late 1990s, the agency concluded that recently inspected plants and common products might not warrant a full PAI for every new drug or generic coming to market.

This approach fits FDA's efforts to modernize and streamline oversight of drug manufacturing under its GMPs for the 21st Century initiative. One component of this program is to further target field inspections to products and plants that warrant high risk designations. Along those lines, Office of Compliance (OC) staffers now divide PAI inspection requests to the field into those that would "regularly" lead to an inspection and those that can be decided by district offices. The first category includes new molecular entities, priority new drug applications (NDAs), new dosage forms of priority products, and initial generic-drug applications, explained Edwin Rivera-Martinez, chief of OC's manufacturing assessment and preapproval compliance branch, at the Food and Drug Law Institute compliance conference in Feb. 2008.

Field investigators have discretion to conduct PAIs for most other drugs, Rivera-Martinez emphasized, an approach that fits efforts to give district offices greater flexibility in determining when a PAI is necessary. The Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) also can request a "for cause" inspection separate from the PAI and GMP inspection programs. This will most likely occur when a CDER review division notices something troubling in an application, when a specific inspection request comes from a foreign regulatory body, or when competitors or informants provide information about a company's violative behavior. FDA is working to further refine the categories that would prompt a PAI request from CDER to the field.

Interestingly enough, FDA projects that in 2009 it will conduct more PAIs overseas (nearly 400) than at home (about 300) for brand drugs and generics. The numbers are significantly different for GMP inspections: 1400 domestic inspections are anticipated, compared with less than 300 abroad. Capitol Hill shows considerable interest in boosting the foreign inspection numbers, but it will take a sizeable budget increase to expand this high-cost activity to a significant degree.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634,


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