Current Trends in FDA Warning Letters

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

A Warning Letter is issued if the EIR (Establishment Inspection Report) written by the inspector after inspection has been checked by the head office and the deviations have been evaluated as significant or the statement on the elimination of the faults has been classified as insufficient.

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

During the fiscal year 2000 (until the end of September 2000) 71 Warning Letters were issued. This is the same number as in the previous fiscal year. The following illustration shows the affected production areas.

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

The following illustration shows the most frequently mentioned deviations:

Other frequent deviations:

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

When evaluating Warning Letters it is important to keep in mind the definition of the topics. Thus, in its edition of April 2001, the Gold Sheet infers the order: Process Validation, OOS Results, Stability Testing. In contrast to the above-mentioned illustration, in the evaluation mentioned here, the deviations in the batch documentation incl. release and review have been summarised. If the deviations are summarised by departments, a clear picture emerges. Almost every Warning Letter criticises deviations in the laboratory unit. The most important topics are OOS Handling and Stability Testing, 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 quality control unit does not or cannot perform its function. In surprisingly many companies (especially with manufacturers of sterile products and contract laboratories for quality control) the employee training was called a deviation.

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