GMP Warning Letter Use Remains Low In FY 2004

FDA's conservative approach to the use of warning letters to support its GMP enforcement strategy continued from fiscal year 2003 into 2004.

During the past fiscal year, FDA issued only 30 drug GMP-related warning letters - about the same number as in FY 2003, when 29 were issued. The numbers for the two years, in turn, represent a dramatic decline from the average over the previous decade, when the total ran as high as 100. The agency sent out 58 letters in FY 2002, 70 during FY '01 and 78 during FY '00.

The decline in the rate at which FDA was sending out warning letters accelerated during FY 2003 with the introduction of the quality systems approach to GMP inspections and the centralized review and clearance of warning letters by FDA headquarters (¹ (Also see "GMP Warning Letter Downward Trend Accelerates; Few Oral Solids Get Cited" - Pink Sheet, 3 May, 2004.), p. 46).

The FY 2004 tally suggests that the resulting cutback in GMP warning letter issuance will continue.

Though the number of letters issued was almost unchanged between FYs 2003 and 2004, the manufacturing problems on which the letters were focused showed some significant variation.

In FY 2004, the most frequently referenced of the GMP regulations was 21 CFR 211.166 on stability testing - cited in over half of the warning letters issued (16 of 30). By contrast, the stability regulation was not among the top 10 most common warning letter citations during FY 2003.

Another provision that appeared frequently in FY 2004 but was not among the top 10 entries during the previous year was 211.113, relating to microbial contamination.

On the other hand, the product testing requirements of 211.165 - the most often cited in the FY 2003 warning letter cohort - appeared on only 11 of the 30 letters in FY 2004 compared to 22 of 29 the previous year.

With these exceptions, however, the data on the types of problems receiving attention during the two years was very similar. Eight of the 10 most frequently referenced GMP provisions remained the same for the two years.

It is noteworthy that neither of the new entrants on the warning letter top 10 list - the 211.166 (stability) nor 211.113 (contamination) provisions - have been among the most frequently cited observations on FDA-483 inspection reports over the past few years.

Equipment cleaning and maintenance (211.67) is another provision that is being highlighted in warning letters more frequently than its appearance on FDA-483s would indicate. The equipment regulation was referenced in half of warning letters issued during FY 2003-2004. The other seven of the 10 most frequent warning letter citations over the past two years are also on the FDA-483 top 10 list.

There was a spike in the number of GMP warning letters addressing foreign facilities in FY 2004 from the previous year. Six, or one-fifth of the total for the year, were sent abroad. Two went to operations in China and four to European plants.

While the number of warning letters has remained stable, FDA indicated that it is embarking on a tougher policy towards manufacturing deficiencies - exemplified by the seizure of GlaxoSmithKline's Paxil CR and Avandamet (² (Also see "FDA Expects Consent Decree For GSK As Follow-Up To Seizure Action" - Pink Sheet, 21 Mar, 2005.), p. 15).

At the annual University of Georgia GMP conference in mid-March, FDA Office of Regulatory Affairs Senior Compliance Official Philip Campbell emphasized the importance of industry communication with FDA in avoiding enforcement actions and resolving GMP problems should they occur.

Campbell specifically noted that the agency still observes a reluctance on the part of drug companies to "reach out" to FDA. He noted that "there is even a reticence to engage the agency after an inspection has been conducted and deviations have been noted....If there was ever a time to reach out, that is it."

The field staffer pointed out that "it is certainly easier, quicker and more efficient for these types of [GMP] problems to be resolved in a voluntary, cooperative manner as opposed to us having to take an adversarial approach" and having to take more drastic enforcement actions. "We don't want to go there, and I think our history clearly shows that," he said.

[Editors' note: Complete analysis of the FY 2004 drug GMP warning letters as well as discussion of FDA inspection and enforcement policy can be found in the March 2005 issue of " ³ The Gold Sheet ." For a sample copy, call customer service at 800-332-2181.]