Warning Letters Report 2006

GMP News No. 864

GMP News
10 January 2007
 

Warning Letters Report 2006

 
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".
   

Do you want to learn more about FDA Compliance? Then we recommend the following new Training Course:

With regard to the most frequent deviation (21 CFR 211.22 - Responsibilities of Quality Control Unit) we are currently preparing the Training Course "FDA Compliance in Analytical Labs". Please send an e-mail to info (at) gmp-compliance (dot) org if you are interested in this course.

The most frequent statement regarding 21 CFR 211.22 was: "Failure to thoroughly investigate the failure…"
FDA's Frederick W. Blumenschein will give a presentation about the authority's current thinking in the GMP Education Course

21 CFR 211.42 (Design and Construction Features) was among the Top Five Deviations in 2005. A 4-day intensive GMP Education Course will inform you about the current GMP requirements:

As Quality Risk Management is one of the key elements of the new FDA cGMP approach, we recommend the following courses:

 
Inform yourself comprehensively about the latest developments and trends.

Author:
Dr Gerhard Becker
On behalf of ECA
 

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