Warning Letters Report 2008 - Frequent Deficiencies in Deviation Reviews

During the fiscal year 2008 there was a change in the trend concerning the frequency of warning letters issued with regard to CFR Part 211: compared to the previous fiscal year there was a distinct increase in the number of warning letters issued to drug manufacturers. Medical device manufacturers were also more closely scrutinised by the FDA – here the increase in warning letters is immense. But only five firms specialising in blood products and the processing of blood received warning letters. The following table indicates the development in the number of warning letters issued in the last three fiscal years.


With regard to topics and frequency of GMP deficiencies, it is apparent that similar violations were criticised as in previous years:

  • Production record review (CFR 211.192
  • Laboratory controls, general requirements (CFR 211.160)
  • Written procedures, deviations (CFR 211.100)
  • Responsibilities of the quality control unit (CFR 211.22)

In its warning letters during the fiscal year 2008 the FDA often criticised deficiencies in batch documentation reviews and in the follow-up of deviations. Another point concerned the non-existence of scientifically-sound and appropriate test procedures in quality control laboratories. Some typical examples are:

"Failure to thoroughly investigate a batch that does not meet its specifications [21 CFR § 211.192]. For example, no adequate laboratory investigation was performed ... "

"Failure to thoroughly investogate unexplained discrepancies or a batch or any of its components not meeting any of its specifications, failure to extend investogations to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy, and failure to ensure that written records of the investigation include conclusions and follow-up [21 C.F.R. § 211.192]."

"Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures ... "

"Failure to establish written procedures for production and process control ... "

The following table depicts a comparison between the five most frequent deficiencies in the fiscal years 2006, 2007 and 2008:

As the survey indicates, the topics are mainly the same as found in the most frequently quoted Warning Letters in the last three fiscal years. The areas quality control, batch documentation review, follow-up of deviations as well as the other principal competencies of quality control will most probably be closely scrutinised in future inspections by the FDA. It remains to be seen whether the trend towards issuing more warning letters to drug manufacturers will continue in the future.

A detailed analysis of the Warning Letters is available as FDA Navigator with Warning Letters Report, comprising a CD and a handbook. The package contains

  • the 200 most important GMP regulations, guidelines and interpretations by FDA - all in all about 5000 pages
  • the Warning Letters on GMP deviations of the last three years
  • Warning Letters with detailed analyses
  • and more

Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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