The number of good manufacturing practices warning letters issued to pharmaceutical firms by FDA fell by half in fiscal 2003.

An analysis by "The Gold Sheet" of drug GMP warning letters (excluding medical gas) shows that they plunged from 58 in FY 2002 to only 29 in FY 2003.

A quarter-by-quarter analysis indicates that the rate of decline significantly increased as the fiscal year progressed. The number fell from 16 in the first quarter - a pace similar to FY 2002 - to eight in the second quarter, to two and three in the last two quarters, respectively.

The drug GMP warning letter numbers had already been on a downtrend in recent years. In the mid-1990s, the number peaked at over 100 and has dropped steadily since then.

In general, the trend in the letters over the past decade parallels a decline in drug GMP inspections that has been ongoing since the early 1980s. However, the drop-off in warning letters during FY 2003 is not attributable to this factor since FDA conducted about the same number of drug GMP inspections this past year as in FY 2002.

What does correspond to the 2003 drop in warning letter issuance are inspection program changes that have been instituted under the agency's drug quality initiative. These include field-wide implementation of a new quality systems-based inspection approach and increased centralized review and clearance of the letters to make sure that they are consistent across the field operations and have the intended enforcement impact.

The extra layers of review are creating leeway for the implicated firms to work out a more concerted response to the inspection findings and present a convincing enough case to the agency to forestall a warning letter. These post-inspection interactions are overcoming enforcement action recommendations by investigators.

The decline in drug GMP warning letters this past year may also reflect the number of other pressing enforcement issues on the FDA radar screen, stretching the agency's already thin inspection resources. From a risk-oriented vantage point, GMP deviations were not necessarily the most immediate health threat. The agency faced new challenges in the areas of: bioterrorism/food safety; dietary supplements; transmissible spongiform encephalopathies (TSE); and drug enforcement, including counterfeiting, imports, promotional practices and internet sales.

The decline in warning letters was particularly noticeable among oral solid and repackaging firms during FY 2003 - in line with FDA's risk-based inspection prioritization model for the year.

Only four warning letters focused on oral solid manufacturing alone during the year, down from 12 and 14 in the two previous years, respectively. The dosage form receiving the most GMP warning letter attention in FY 2003 was topicals - eight of the 29 letters issued went to topical product manufacturers. All topicals referenced in the letters were over-the-counter (OTC) products.

In spite of FDA's inspection focus on sterile drug manufacturers during the fiscal year, only three warning letters were issued addressing injectable operations per se. Two of the letters - to Abbott and Organon - centered on the prevention of and response to problems with metal particulates.

The other injectable warning letter went to Melbourne, Australia-based Mayne Pharma in November 2002, following an inspection the previous April which resulted in a 46-item FDA-483. Mayne was the only foreign-based firm to receive a warning letter during FY 2003.

Amgen, the largest of the biopharmaceutical manufacturers, was the only biotech firm to receive a warning letter from FDA in FY 2003.

The May 2003 letter focuses on the findings of an inspection conducted the previous January at Amgen's Boulder, Colo. facility where it makes bulk recombinant methionyl human interleukin-1 receptor antagonist (IL-1ra). As in the Abbott and Organon letters, the control and investigation of metal particulates was a key concern addressed.

- Bill Paulson

[Editor's note: A detailed analysis of FDA drug GMP warning letters for FY 2003 is included in the April issue of ¹ 'The Gold Sheet'].

Drug GMP Warning Letter Downtrend Accelerates in FY 2003

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