The analysis of the warning letters issued in the fiscal year 2005 (from
Oct. 2004 to Sept. 2005) and referring to the Code of Federal Regulations
(CFR) Part 211 yields a surprising result: while in the previous year 33
warning letters were issued, the number decreased by almost half in 2005
to 17. The number of letters for firms processing blood or blood products
and manufacturing biologic products as well as for manufacturers of
medical devices remained the same, as the following table shows:
| |
FY 2004 |
FY 2005 |
|
WLs relative to Part 211 (Drugs) |
33 |
17 |
|
WLs relative to Part 600, 606, 610, 630, 640, 680 (Blood, Blood
Products, Biologicals) |
9 |
9 |
|
WLs relative to Part 820 (Medical Devices) |
104 |
107 |
Comparing the most frequently mentioned deficiencies in the two years
also shows some striking differences, as the following summary
demonstrates:
- Similar to last year, Production Record Review (211.192) and
Responsibilities of the quality control unit (211.22) are at the
top of the frequent GMP deficiencies. However, Control of
microbiological contamination (211.113) climbed from
position 6 to 3 in the top ten findings in 2005.
- Compared to last year, the agency also found more deficiencies in
batch documentation: Batch Production and Control Records
(211.188) rank 4th in the top ten list compared to 8th
in the fiscal year 2004.
- FDA investigators also focused on Equipment cleaning and
maintenance (211.67), which was mentioned in this year's warning
letters almost as often as last year.
The following table compares the most frequent deficiencies in 2004
with 2005.
The ten most frequent GMP deficiencies in the fiscal years 2004 and
2005 warning letters
|
Top Ten List No. |
Fiscal Year 2004 |
Fiscal Year 2005 |
|
1 |
211.100
Subpart F – Production
and Process Controls
Written procedures;
deviations |
211.192
Subpart J – Records and
Reports
Production record review |
|
2 |
211.67
Subpart D – Equipment
Equipment cleaning and
maintenance |
211.22
Subpart B –
Organization and Personnel
Responsibilities of
quality control unit |
|
3 |
211.22
Subpart B –
Organization and Personnel
Responsibilities of
quality control unit
211.166
Subpart I – Laboratory
Controls
Stability Testing |
211.113
Subpart F – Production
and Process Controls
Control of
microbiological contamination |
|
4 |
211.192
Subpart J – Records and
Reports
Production record review |
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 |
|
5 |
211.160
Subpart I – Laboratory
Controls
General requirements
211.165
Subpart I – Laboratory
Controls
Testing and release for
distribution |
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 |
|
6 |
211.113
Subpart F – Production
and Process Controls
Control of
microbiological contamination |
211.165
Subpart I – Laboratory
Controls
Testing and release for
distribution |
|
7 |
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 |
211.25
Subpart B –
Organization and Personnel
Personnel qualifications
211.68
Subpart D – Equipment
Automatic, mechanical,
and electronic equipment
|
|
8 |
211.188
Subpart J – Records and
Reports
Batch production and
control records |
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
211.122
Subpart G – Packaging
and Labelling Control
Materials examination and
usage criteria
211.137
Subpart G – Packaging
and Labelling Control
Expiration dating |
|
9 |
211.186
Subpart J – Records and
Reports
Master production and
control records |
211.46
Subpart C – Buildings
and Facilities
Ventilation, air
filtration, air heating and cooling
211.94
Subpart E – Control of
Components and Drug Product Containers and Closures
Drug product containers,
and closures
211.110
Subpart F – Production
and Process Controls
Sampling and testing of
in-process materials and drug products
211.125
Subpart G – Packaging
and Labelling Control
Labelling issuance |
|
10 |
211.25
Subpart B –
Organization and Personnel
Personnel qualifications
211.42
Subpart C – Buildings
and Facilities
Design and Construction
Features
|
211.63
Subpart D – Equipment
Equipment design, size,
and location
211.80
Subpart E – Control of
Components and Drug Product Containers and Closures
General requirements
211.130
Subpart G– Packaging
and Labelling Control
Packaging and labelling
operations
211.167
Subpart I – Laboratory
Controls
Special testing
requirements
211.176
Subpart I – Laboratory
Controls
Penicillin contamination
211.180
Subpart J – Records and
Reports
General requirements
211.204
Subpart K – Returned
and Salvaged Drug Products
Returned drug products |
FDA inspections are based on a systems oriented approach, mainly
focusing on the quality system. Accordingly, the agency often finds
failures and neglected duties in the quality unit. Related topics like
insufficient Production Record Review or the handling of deviations and
written procedures are also frequent matters of objections. Most likely,
these findings will also be on the top of the list in the future, together
with inadequate control of microbial contaminations or equipment cleaning.
Among the companies receiving a warning letter last year were 4 outside
the US: one in Puerto Rico, one in Canada and two companies in Europe –
in Italy and in Switzerland.
In the same period, 2 (US-based) API manufacturers received a warning
letter, coming down from 3 the year before (one in the Czech Rep. and two
in China).
|
The European Compliance Academy will organise the following conferences
and intensive courses relative to the FDA Top Deviations:
Environmental
Monitoring - Compliant and Reasonable
18./19. May 2006, Copenhagen,
Denmark
FDA's
and ICH's New Quality Systems Approach
1./2. June 2006, Prague, Czech
Rep.
FDA
Compliance in Analytical Laboratories
4.-6. October 2006, Prague,
Czech Rep.
How
to Pass EU and FDA Inspections - GMP-Compliance Auditor
4.-6. October 2006, Barcelona,
Spain
GMP
and FDA Compliance in Quality Assurance Units
8.-10. November 2006, Prague,
Czech Rep.
Microbial
Contamination - Corrective Actions, Preventive Actions
23./24. November 2006, Vienna,
Austria
|
