Current Trends in FDA Warning Letters

GMP News No. 120

GMP News
24 July 2001

CurrentTrends in FDA Warning Letters


Warning Letters are a very helpful tool with regard tothe evaluation of focal points in FDA's GMP inspections. They representthe second of 3 steps that are important in the assessment of GMPdeviations. Step 1 are those deviations that are listed on the well-knownForm FDA-483 by an FDA inspector on the occasion of an inspection.

A Warning Letter is issued if the EIR (EstablishmentInspection Report) written by the inspector after inspection has beenchecked by the head office and the deviations have been evaluated assignificant or the statement on the elimination of the faults has beenclassified as insufficient.

If the answer to the Warning Letter is also insufficientfrom FDA's point of view, step 3 comes into force, which means that theinspected site must not manufacture products for the US-American marketany more.

During the fiscal year 2000 (until the end of September2000) 71 Warning Letters were issued. This is the same number as in theprevious fiscal year. The following illustration shows the affectedproduction areas.

Above all in the field of sterile products (18 WarningLetters) many companies outside the USA were affected, which indicatesthat FDA has increased its activities here. Concerning the 8 APImanufacturers, the Warning Letters were addressed to 6 US companies and 2Chinese enterprises.

The following illustration shows the mostfrequently mentioned deviations:

Other frequentdeviations:

  • Maintenance of the Equipment
  • Media Fill
  • Change Control
  • Environmental Monitoring
  • Reprocessing

When evaluating Warning Letters it is important to keepin mind the definition of the topics. Thus, in its edition of April 2001,the Gold Sheet infers the order: ProcessValidation, OOS Results, Stability Testing. In contrast to theabove-mentioned illustration, in the evaluation mentioned here, thedeviations in the batch documentation incl. release and review have beensummarised. If the deviations are summarised by departments, a clearpicture emerges. Almost every Warning Letter criticises deviations in thelaboratory unit. The most important topics are OOS Handling and StabilityTesting, which we have already mentioned, and also:

  • Laboratory Records, incl. Archiving, Reviews
  • Raw Data Handling
  • Analytical Method Validation
  • Impurities Testing

Often (16 times) the 'quality control unit'itself was mentioned as deviation. This means that FDA assumes that the qualitycontrol unit does not or cannot perform its function. In surprisinglymany companies (especially with manufacturers of sterile products andcontract laboratories for quality control) the employee training wascalled a deviation.


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