FDA Warning Letter Report 2004 Published

GMP News No. 514

GMP News
14 February 2005
 

FDA Warning Letter Report 2004 Published

 
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:

CFR Paragraph

Title

Event

211.100

Written procedures; deviations
(incl. validation)
 
Subpart F – Production and Process Controls

The Risk-based Approach to Validation - With an Emphasis on Computer Systems and Electronic Records

211.67

Equipment cleaning and maintenance
 
Subpart D – Equipment

GMP Requirements on Cleaning and Disinfection Management

211.22

Responsibilities of quality control unit
 
Subpart B – Organization and Personnel

GMP and FDA Compliance in Quality Assurance Units
 
Out-of-Specification Results - With a Post-Course Workshop on Failure Investigation

211.166

Stability Testing
 
Subpart I – Laboratory Controls

In preparation: Stability Testing
If you would like to know the details, please send us an e-mail to info (at) gmp-compliance (dot) org.

211.192

Production record review
 
Subpart J – Records and Reports

In preparation: Batch Record Review
If you would like to know the details, please send us an email to info (at) gmp-compliance (dot) org.

211.160

General requirements
 
Subpart I – Laboratory Controls

Lab Equipment Qualification

211.165

Testing and release for distribution
 
Subpart I – Laboratory Controls

Validation of Analytical Test Procedures

211.113

Control of microbiological contamination
 
Subpart F – Production and Process Controls

-

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

Quality Testing of Pharmaceutical Packaging Materials
 
Validation of Microbiological Test Procedures
 
Validation of Analytical Test Procedures

211.42

Design and Construction Features
 
Subpart C – Buildings and Facilities

Pharmaceutical Engineering - Intensive Course Focussing on Key Tools

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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