Warning Letter Analysis.

Details of key FDA warning letters released the weeks of June 18 & 25, 2001 and July 2 & 9, 2001 that contain citations for validation. Each letter is $7 plus retrieval. By Bruce FlickingerP&G hit for air systems for micronization process

A May 4 letter cited Procter & Gamble (P&G) in Manati, PR, for lacking controls on a compressed air system to assure the system was not in use simultaneously by a micronizer and other equipment.

"There were no controls to assure that other areas of the plant did not use the compressed air system during the micronization process and no checks on air pressure being delivered to the micronization system were recorded during the process," the letter said.

P&G's response was found to be inadequate because it did not explain how manufacturing and other operations would be staggered. Additionally, the letter said that records collected by the investigators, who inspected the plant Jan. 25-March 2, found that the current compressed-air system "is not capable of producing the compressed air pressure needed for a reproducible micronization process."

This was one of two items that FDA found wanting in P&G's March 16 response to the 483. "We responded to the 483, and there were two items in the letter for which FDA said our proposed timing was unacceptable," said Marlene Feder, public relations manager for P&G Pharmaceuticals. "We've had a meeting with FDA and came to mutual agreement on how we will remedy these issues."

She said: "The specifics of our solution were acceptable but it would have been difficult to meet FDA's deadline. We have interim systems in place, which we will validate on an ongoing basis."

The second issue of contention in the letter was that P&G's processing of dantrolene sodium was not evaluated for stability after rehydration. The agency noted an increase since 1997 in the number of lots requiring reprocessing, work that sometimes requires a rehydration step that can cause an increase in particle size. This then calls for another remicronization step and possible rehydration. "No limits have been set for the number of times the API [active pharmaceutical ingredients] can be remicronized and rehydrated," the letter said.

Several shortcomings were found in the validation of the rehydration process. FDA noted P&G did not have written procedures to ensure reprocessed batches will conform to established standards, specifications and characteristics.

The agency also said the 1997 validation of dantro-lene production composited samples drawn from different levels from a drum rather than evaluating the samples individually for particle size.

Additionally, P&G's quality system took in a citation for failure to assure that the validation for dantrolene, an ingredient in the firm's Dantrium prescription product for malignant hypothermia, was conducted "in a timely manner." It also failed to evaluate the need for revalidation of production of three drugs in various dose forms that FDA stated were validated retrospectively in 1984.

Feder noted that "at no time were we asked to stop manufacturing nor were any of our products recalled." Doc. 10578W