GMP Warning Letters: FDA Approves 55% Of Field Recommendations

An FDA analysis of the agency's central review of good manufacturing practices warning letters has found the policy has been effective in creating consistency in the communications.

The analysis showed that center review added value to the cGMP warning letter process because it allowed for the identification of inconsistencies in the recommendations of the district, as well as the need to better clarify and communicate center policy, CDER Case Management & Guidance Branch Chief Frederick Blumenschein said.

"In many instances the recommendations were disapproved, or the enforcement strategy changed because the centers applied a risk management strategy which had not been yet completely conveyed to the field," Blumenschein told the PDA/FDA Regulatory Conference in Washington, D.C. Sept. 20.

FDA performed an assessment of the centralization of warning letters sent to the Center for Drug Evaluation & Research and the Center for Veterinary Medicine between March 1, 2003 and Aug. 31, 2003.

Of the 33 warning letters recommended by the field to CDER, only 18 were approved for issuance. "We hope that once that strategy is properly conveyed to the field and the field is trained in it that the disparity in the numbers...will probably go down," he said.

The assessment also found that neither CDER nor CVM met the goal of a 15-day average review time for warning letters. "We are working to bring the timeframes down. I don't know as far as averages go how successful we will be at ever meeting the 15 days."

The centralized warning letter review has also allowed industry to get a clearer view of agency policy, Pfizer VP-Global Quality Operations Gerry Migliaccio said.

"The center review of warning letters has had a significant impact on industry not reacting, I think, to issues that may not be center policy and I think that's been critical for us," Migliaccio said.

Before central review, "I think we reacted to each others warning letters when they were coming directly out of the district, not knowing whether it was agency policy but not wanting to take the risk that it was or wasn't."

"Well now we're sure that when something does come out, it is agency policy and we should react to it."

FDA shifted warning letter review back to the centers as part of its broader GMP initiative (¹ (Also see "FDA GMP Initiative Shifts Warning Letter Review Back To Agency Centers" - Pink Sheet, 24 Feb, 2003.), p. 3). The final report for the initiative will be released in October.

Industry should not use observations from FDA-483 reports as guidance, CDER Office of Compliance Director David Horowitz said.

"The fact that a lot of the information on GMPs is gleaned from 483s was something that we recognized as a problem at the start" of the initiative.

"We don't think 483 observations are guidance. They are observations of one investigator, and they may or may not reflect the views of the agency, and they may or may not be as significant as they would appear outside the context of a 483."

FDA's GMP "question and answer" forum will serve as a more reliable source for manufacturing guidance.

"We've been told that there is, in many respects...a vacuum on guidance on GMP issues," Horowitz said. In August, "we put up an example of a new approach...that involves GMP questions and answers, and it's intended to improve the transparency by offering real-time guidance."

"We hope that people, instead of looking to 483s over time, will be able to look at this body of Q&As that will build up over time that will better inform what the agency's current thinking is."

FDA has taken several steps under the GMP initiative to make 483 observation reports more consistent and to provide alternative means of GMP guidance. "The first is the dispute resolution process. When there are things in there that don't look right, the dispute resolution process is an opportunity to address those."

"Another is warning letter review that has gotten the centers and the field more involved in dialogue and coordination and consistency," Horowitz said

The development of a pharmaceutical inspectorate - a highly trained group of reviewers who will specialize in pharmaceutical inspections - will lead to greater consistency among 483s, Horowitz said.