Increase in FDA Warning Letters to European Pharmaceutical Companies

GMP News No. 613

GMP News
29 September 2005

Increase in FDA Warning Letters to European Pharmaceutical Companies

Within the framework of our systematic analysis of FDA Warning Letters (WLs), we have had a close look at those that were sent to European firms after a GMP inspection conducted by the FDA. Our report includes all warning letters issued between October 2001 and now, i.e. the observed range spans almost 4 complete fiscal years. 

In the following you will find the most important results:

While no warning letter was issued for a European company in fiscal years 02 and 03, as many as 3 warning letters were sent to EU firms in 2004. In 2005, 2 have been issued already - even though the fiscal year has not yet reached its end.

  • FY 04: 3 WLs
  • FY 05: 2 WLs

The WL addressees were located in the countries:

  • FY 04: Switzerland, Austria, France
  • FY 05: Switzerland, Italy

All 5 firms are manufacturers of sterile medicinal products.

The following GMP deficiencies were found most frequently:

  • No appropriate measures to prevent microbiological contamination 
    (21 CFR 211.113); in 4 of 5 WLs
  • Inadequate review of batch records, bad failure investigation
    (21 CFR 211.192); in 4 of 5 WLs
  • Test procedures are not suitable for the intended purpose or are not followed
    (21 CFR 211.160); in 3 of 5 WLs
  • Maintenance and cleaning of equipment are not documented sufficiently
    (21 CFR 211.67); in 3 of 5 WLs

According to its risk-based approach, the Agency inspects manufacturers of sterile medicinal products with the highest priority and - which can be deduced from this compilation - extreme strictness.

In the following we have listed excerpts from the warning letters in their original wording, each of them exemplary for one of the CFR paragraphs:

"Appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, were not established and followed. Specifically, written procedures were not established and followed to validate the … filling process because of deficiencies in media fill studies. 21 CFR 211.113."

"Failure of the quality control unit to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated [21 CFR 211.22 and 211.192]."

"Written control procedures were not always followed when changes were made to test methods and validated systems, … [21 CFR 211.160].

"There is not sufficient documentation to determine the effectiveness of your cleaning agent … 21 CFR 211.67."

A central theme in all of the findings is the FDA's general disapproval of the documentation and the written procedures in the different departments - be it with regard to cleaning (production), test procedures (quality control) or failure investigation (quality assurance). This is closely connected to the inconsequent observation of internal instructions by the personnel – a deviation that FDA investigators will hardly fail to notice in companies with low GMP status and that can be found time and again in warning letters.

The results of this analysis do not support the theory that the FDA might focus especially on Europe when selecting pharmaceutical companies for inspections. The above-mentioned frequently found GMP deficiencies are also among the first 6  top ten findings when considering all warning letters issued in FY 2004 (see our GMP News of 14 February 2005). In any case, firms expecting a visit from FDA inspectors are well-advised to include these topics very carefully into their inspection preparation.

On the topics mentioned in this GMP News, the European Compliance Academy is organising the following events with speakers from authorities and the pharmaceutical industry:
Dr Gerhard Becker
on behalf of ECA

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