FDA Warning Letter Report 2004 Published

FDA Warning LetterReport 2004 Published

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:

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.

Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG

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