The same five sets of cGMP violations have shown up for at least the past five fiscal years when FDA inspects drug manufacturers, according to a database the agency recently made public.

The top five violations, which have been responsible for 75% to 85% of all Form 483s FDA has issued for drug manufacturing cGMP problems from fiscal 2006 through 2010, are:

Quality control unit responsibilities and procedures are not in writing and/or not fully followed;
Written production and process control standard operating procedures are not followed and/or not documented at the time of performance;
Failure to thoroughly review any unexplained discrepancy, e.g. failure of a batch or any of its components to meet any of its specifications, whether or not the batch already has been distributed;
Lack of scientifically sound laboratory controls, including specifications, standards, sampling plans or test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling or drug products conform to appropriate standards of identity, strength, quality and purity; and
Lack of control procedures to monitor and validate performance of manufacturing processes that have caused variability in the characteristics of in-process material and the drug product.

The number of 483s the agency issued in this area fell and then grew over the five years, while the range of problems cited was much more consistent (see chart).

FDA Form 483s
Fiscal Year	Number of 483s	Types of Citations
2006	628	337
2007	559	332
2008	470	327
2009	550	332
2010	646	335

The most frequently cited violation all five years was failure to put quality control unit responsibilities and procedures in writing and/or not fully following them; most of the other categories traded places over the years (see chart, "Drug Manufacturing cGMP Violations: An Endless Cycle").

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The inspections database, which FDA made public on May 26 as part of Phase II of its Transparency Initiative, also reveals that the Center for Drug Evaluation and Research conducted a total of 3,329 inspections in fiscal 2009-2010, resulting in 136 findings of "official action indicated."

There were also 1,226 "voluntary action indicated" findings and 1,967 of "no action indicated" in those two years. An OAI finding can result in such steps as warning letters or "voluntary" recalls, whereas a VAI finding means that while "objectionable conditions were found and documented," the agency is not prepared to take or recommend such regulatory action "since the objectionable conditions do not meet the threshold for regulatory action," FDA explains on its website.

However, in the latter case the agency may use a notice of violation (untitled) letter or a regulatory meeting with the company to make it aware of the findings. NAI means that "no objectionable conditions or practices were found during the inspection (or the significance of the documented objectionable conditions found does not justify further action)."

By the end of the year, FDA said it also will begin to disclose additional information about its evaluations of filers and expand disclosure of notice of violation letters.

Among the goals are disclosing company practices that may jeopardize public health, pointing out companies that have had satisfactory FDA inspections, creating an incentive for companies to bring their practices into compliance with the law and helping consumers.

Those objectives seem very similar to the aims of the close-out letter program that FDA launched in September 2009 but so far has failed to produce many results (Also see "GMP Close-out Letter Program Shows Few Benefits After 20 Months" - Pink Sheet, 16 May, 2011.).

By Martin Berman-Gorvine

GMP Violations Are A Consistent But Well-Shuffled Deck, FDA Data Show

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