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Since 2002, Concept Heidelberg has annually created the Warning Letters Report on
behalf of ECA. This report analyses the findings mentioned in warning
letters of the previous Fiscal Year systematically. From this material,
one can easily draw conclusions about GMP inspections conducted by the FDA.
Whereas observations noted on 483 forms mirror the personal viewpoint of
a GMP inspector, warning letters include only those deviations that have
actually had consequences. Therefore, FDA warning letters can be seen as
the "compliance indicator" for FDA's cGMP requirements.
After the warning letters addressed to manufacturers of medicinal
products had decreased in number over the previous five fiscal years,
this trend seems to have come to a halt. In the last fiscal year
(October 2005 to September 2006), 20 warning letters were issued
compared to 17 in the (fiscal) year before. The number of warning
letters to manufacturers of blood and blood products has practically
remained the same. The greatest part of the warning letters is still
directed at manufacturers of medical devices; however, their number has
slightly gone down.
| |
FY 2005 |
FY 2006 |
| WLs regarding Part 211
(Drugs) |
17 |
20 |
| WLs regarding Part 600,
606, 610, 630, 640, 680 (Blood, Blood Products, Biologicals) |
9 |
10 |
| WLs regarding Part 820
(Medical Devices) |
107 |
79 |
As to their subjects and frequency, the deficiencies are about the
same as in 2005. Again, the most frequently referenced paragraphs of
the Code of Federal Regulations (CFR) are:
- Responsibilities of quality control unit (211.22)
- Production record review (211.192)
- Equipment cleaning and maintenance (211.67)
- Stability Testing (211.166)
- Written procedures; deviations (211.100)
- Laboratory Controls, general requirements (211.160)
- Testing and release for distribution (211.165)
However, one citation that was last mentioned in a warning letter of
August 2004 and not heard of after that has reappeared
surprisingly among the most frequent deviations: Laboratory Records! As
many as 6 warning letters feature this deviation with reference to
the corresponding CFR paragraph 211.194. The following original
quotations explain in detail which facts were considered to be
non-compliant with
current GMP.
"Laboratory records did not always include a description and
identification of the sample received for testing, the date the sample
was taken; the date the sample was received for testing and the data
derived from the testing."
"There were not always the initials or signature of a second person
showing that the original records have been adequately reviewed for
accuracy, completeness, and compliance with established standards."
"Laboratory records do not include a complete record of all data
secured in the course of each test, including all graphs, charts, and
spectra from laboratory instrumentation, properly identified to show the
specific drug product and lot tested.
Review of stability data by our
investigative team disclosed that
your firm did not maintain
documentation of
conditions and
settings used for
analysis nor the
complete raw data."
Evidently, inappropriate raw data handling is a reality faced by FDA
inspectors more frequently again.
The following table places the 5 most frequent deficiencies of the
fiscal years 2005 and 2006 next to each other.
The five most frequent GMP deviations in the warning letters issued
during fiscal year 2005 and 2006 respectively.
| Top Ten List
No. |
Fiscal Year 2005 |
Fiscal Year 2006 |
| 1 |
211.192 Subpart J
Records and Reports
Production record review |
211.22 Subpart B
Organization and Personnel
Responsibilities of quality control unit |
| 2 |
211.22 Subpart B
Organization and Personnel
Responsibilities of quality control unit |
211.192 Subpart J
Records and Reports
Production record review |
| 3 |
211.113 Subpart F
Production and Process Controls
Control of microbiological contamination |
211.67 Subpart D
Equipment
Equipment cleaning and maintenance
211.166
Subpart I Laboratory Controls
Stability Testing |
| 4 |
211.67 Subpart D
Equipment
Equipment cleaning and maintenance
211.100
Subpart F Production and Process Controls
Written procedures; deviations
211.160
Subpart I Laboratory Controls
General requirements
211.188
Subpart J Records and Reports
Batch production and control records |
211.100 Subpart F
Production and Process Controls
Written procedures; deviations
211.160
Subpart I Laboratory Controls
General requirements
211.165
Subpart I Laboratory Controls
Testing and Release for Distribution
211.194
Subpart I Laboratory Controls
Laboratory Records |
| 5 |
211.42 Subpart C
Buildings and Facilities
Design and Construction Features
211.166
Subpart I Laboratory Controls
Stability Testing
211.198
Subpart J Records and Reports
Complaint files |
211.25 Subpart B
Organization and Personnel
Personnel qualifications
211.84
Subpart E Control of Components and Drug Product Containers
and Closures
Testing and approval or rejection of components, drug product
containers, and closures
211.137
Subpart G Packaging and Labeling Control
Expiration dating |
It is striking that the laboratory control system is mentioned so
often, namely with such pivotal functions as "testing and release for
distribution", "laboratory records" (especially raw data
handling) and, of course, like in the previous year, "stability
testing".
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19-20 June 2013 