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.
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