The analysis result of the FDA warning letters sent to pharmaceutical
manufacturers in Fiscal Year 2004 (October 2003 to September 2004) is
quite surprising. There was a great number of violations of
§ 211.67 of the Code
of Federal Regulations (21 CFR). 18 out of the 33 warning letters
concerning Part 211 cite deficiencies in the field of "Equipment cleaning and maintenance"
(this is the title of § 211.67). In the previous fiscal year, 8 of the
total number of 46 warning letters issued on Part 211 (Drugs)
referred to this paragraph. Thus, this paragraph ranks second
in the top ten list of most frequent warning letter citations - just
behind § 211.100 (Written procedures; deviations), which is
mentioned in 19 warning letters. This paragraph always leads the
list, since
non-compliance with the GMP rules usually reveals itself in this area.
The compilation uncovers further surprising facts: "Control
of microbiological contamination" was referenced in 11(!) warning letters - in the previous
(fiscal) year, there had only been a single citation of this kind.
Another deficiency that is often cited is "Stability Testing":
17 warning letters compared to just 9 warning letters in FY 2003.
The following graph shows the top ten deviations cited in warning
letters addressed to pharmaceutical manufacturers in FY 2004 (in order to
compare with FY 2003 see our GMP
News of 1 July 2004):
About 3 years ago, the FDA introduced system-based inspections. This
means that a drug-manufacturing plant is divided into the following
6 systems:
-
Quality System
-
Facilities and Equipment System
-
Materials System
-
Production System
-
Packaging and Labeling System
-
Laboratory Control System
The assignment of these systems to the chapters of 21 CFR 211 is laid
down in the COMPLIANCE PROGRAM GUIDANCE MANUAL published by the FDA on 1
February 2002. This document, which is really worth reading, is directed
at the inspectors and contains instructions on how to implement the
system-based perspective during inspections on site.
The following table lists the 10 most frequent deviations and assigns
them to the respective systems:
|
CFR Paragraph |
Title |
Number of citations (number
of citations in FY 03) |
System |
|
211.100 |
Written procedures; deviations
Subpart F – Production and Process Controls |
19 (25) |
Quality System |
|
211.67 |
Equipment cleaning and maintenance
Subpart D – Equipment |
18 (8) |
Facilities and Equipment System |
|
211.22 |
Responsibilities of quality control unit
Subpart B – Organization and Personnel |
17 (18) |
Quality System |
|
211.166 |
Stability Testing
Subpart I – Laboratory Controls |
17 (9) |
Laboratory Control System |
|
211.192 |
Production record review
Subpart J – Records and Reports |
15 (18) |
Quality System |
|
211.160 |
General requirements
Subpart I – Laboratory Controls |
13 (16) |
Quality System + Laboratory Control System |
|
211.165 |
Testing and release for distribution
Subpart I – Laboratory Controls |
13 (24) |
Quality System + Laboratory Control System |
|
211.113 |
Control of microbiological contamination
Subpart F – Production and Process Controls |
11 (1) |
Production System |
|
211.84 |
Testing and approval or rejection of components, drug product
containers, and closures
Subpart E – Control of Components and Drug Product Containers
and Closures |
10 (15) |
Materials System |
|
211.188 |
Batch production and control records
Subpart J – Records and Reports |
9 (17) |
Production System |
|
211.186 |
Master production and control records
Subpart J – Records and Reports |
8 (11) |
Production System |
|
211.25 |
Personnel qualifications
Subpart B – Organization and Personnel |
7 (14) |
Quality System |
|
211.42 |
Design and Construction Features
Subpart C – Buildings and Facilities |
7 (3) |
Facilities and Equipment System |
If you have a close look at this table, you can see another trend quite
clearly: the total number of warning letters has been decreasing. The
exact numbers for the last three fiscal years (FY) are as follows:
-
FY 2002: 77 warning letters
-
FY 2003: 46 warning letters
-
FY 2004: 33 warning letters
However, it would be a mistake to come to the conclusion that the Agency has
become more "lenient" in its judgement of GMP deficiencies.
Quite the contrary is the case. Since March 2003, all warning letters
undergo a centralised review by CDER
(Center of Drug Evaluation and Research) before they are sent to the
companies. In this process, the CDER puts the finishing touch to the warning letters. So,
when you read the warning letters, you notice immediately the distinctly
higher quality of the assignment of the GMP deficiencies to the
"Predicate Rule", i.e. Part 211 of the CFR, as well as of the
sharpness and clarity of the wording in comparison to that of former
years. Every warning letter issued is therefore of even greater importance
than in the past and can hardly be contested any more.
On the whole, the FDA has become much more efficient with regard to
warning letters. At the GMP Conference in Athens 2003, the Deputy
Commissioner Lester Crawford said about the issuance of warning letters: "We
no longer intend to just send them like we send Christmas cards."
One interesting fact is that the proportion of warning letters
addressed to firms outside the US has increased. Among the pharmaceutical
manufacturers, at least 3 non-US companies received a warning letter
(of 33 WLs issued in FY 2004): one in Austria, one in Switzerland, and one in
France. However, most of the warning letters sent to "foreign
companies" were received by medical device manufacturers in the
following countries:
-
Canada (5 firms)
-
Italy (3 firms)
-
Norway (2 firms)
-
Czech Republic (2 firms)
-
China (2 firms)
And one firm in each of the following countries
-
Germany, Denmark, France, United Kingdom, The Netherlands, Israel, Japan, Korea, Mexico, Puerto Rico
Our warning letter report takes only warning letters regarding drugs,
biologics, and APIs into account. API manufacturers located outside the US
also received warning letters:
-
Czech Republic (1 firm)
-
China (2 firms)
The evaluation presented here is part of a comprehensive database and
analysis of the warning letters of the past three fiscal years.
On many of the subjects mentioned above, the European Compliance
Academy offers topical training courses with speakers from authorities and
the pharmaceutical industry:
Get a comprehensive update on the latest developments and trends!
Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG
PS If you would like to search the warning letters database for
specific keywords, you can do this on this website in the
"Search" section (see top menu).
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