FDA Warning Letter Report 2004 Published

GMP News No. 514

14 February 2005

FDA Warning LetterReport 2004 Published

The analysis result of the FDA warning letters sent to pharmaceuticalmanufacturers in Fiscal Year 2004 (October 2003 to September 2004) isquite surprising. There was a great number of violations of§ 211.67 of the Codeof Federal Regulations (21 CFR). 18 out of the 33 warning lettersconcerning 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 thetotal number of 46 warning letters issued on Part 211 (Drugs)referred to this paragraph. Thus, this paragraph ranks secondin the top ten list of most frequent warning letter citations - justbehind § 211.100 (Written procedures; deviations), which ismentioned in 19 warning letters. This paragraph always leads thelist, sincenon-compliance with the GMP rules usually reveals itself in this area.

The compilation uncovers further surprising facts: "Controlof 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 warningletters addressed to pharmaceutical manufacturers in FY 2004 (in order tocompare with FY 2003 see our GMPNews of 1 July 2004):

About 3 years ago, the FDA introduced system-based inspections. Thismeans that a drug-manufacturing plant is divided into the following6 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 laiddown in the COMPLIANCE PROGRAM GUIDANCE MANUAL published by the FDA on 1February 2002. This document, which is really worth reading, is directedat the inspectors and contains instructions on how to implement thesystem-based perspective during inspections on site.

The following table lists the 10 most frequent deviations and assignsthem to the respective systems:

CFR Paragraph


Number of citations (numberof citations in FY 03)



Written procedures; deviations

Subpart F – Production and Process Controls

19 (25)

Quality System


Equipment cleaning and maintenance

Subpart D – Equipment

18 (8)

Facilities and Equipment System


Responsibilities of quality control unit

Subpart B – Organization and Personnel

17 (18)

Quality System


Stability Testing

Subpart I – Laboratory Controls

17 (9)

Laboratory Control System


Production record review

Subpart J – Records and Reports

15 (18)

Quality System


General requirements

Subpart I – Laboratory Controls

13 (16)

Quality System + Laboratory Control System


Testing and release for distribution

Subpart I – Laboratory Controls

13 (24)

Quality System + Laboratory Control System


Control of microbiological contamination

Subpart F – Production and Process Controls

11 (1)

Production System


Testing and approval or rejection of components, drug productcontainers, and closures

Subpart E – Control of Components and Drug Product Containersand Closures

10 (15)

Materials System


Batch production and control records

Subpart J – Records and Reports

9 (17)

Production System


Master production and control records

Subpart J – Records and Reports

8 (11)

Production System


Personnel qualifications

Subpart B – Organization and Personnel

7 (14)

Quality System


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 quiteclearly: the total number of warning letters has been decreasing. Theexact 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 hasbecome more "lenient" in its judgement of GMP deficiencies.Quite the contrary is the case. Since March 2003, all warning lettersundergo a centralised review by CDER(Center of Drug Evaluation and Research) before they are sent to thecompanies. In this process, the CDER puts the finishing touch to the warning letters. So,when you read the warning letters, you notice immediately the distinctlyhigher quality of the assignment of the GMP deficiencies to the"Predicate Rule", i.e. Part 211 of the CFR, as well as of thesharpness and clarity of the wording in comparison to that of formeryears. Every warning letter issued is therefore of even greater importancethan in the past and can hardly be contested any more.

On the whole, the FDA has become much more efficient with regard towarning letters. At the GMP Conference in Athens 2003, the DeputyCommissioner Lester Crawford said about the issuance of warning letters: "Weno longer intend to just send them like we send Christmas cards."

One interesting fact is that the proportion of warning lettersaddressed to firms outside the US has increased. Among the pharmaceuticalmanufacturers, 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 inFrance. However, most of the warning letters sent to "foreigncompanies" were received by medical device manufacturers in thefollowing 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 USalso received warning letters:

  • Czech Republic (1 firm)
  • China (2 firms)

The evaluation presented here is part of a comprehensive database andanalysis of the warning letters of the past three fiscal years.


Dr Gerhard Becker

PS  If you would like to search the warning letters database forspecific keywords, you can do this on this website in the"Search" section (see top menu).



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