Warning Letter Report: Overview of the FDA Warning Letters of the Year 2001

GMP News No. 205

GMP News
18 June 2002

WarningLetter Report
Overview of the FDA Warning Letters of the Year 2001

With a time-lag, FDA has published its official numbers for the past fiscal year (FY)2001 (September 2000 - September 2001). The following graph shows thenumber of FDA inspections of pharmaceutical manufacturing plants (incl.API manufacturers).

Ill. 1 FDA Inspections of Manufacturing Plants; source: CDERReport to the Nation 2001

On the whole, FDA published 65 warning lettersthrough CDER in the FY 2001. This number was only slightly smaller than in theprevious years (FY 00 and 99: 71 each). It is striking that the number of warning lettersaddressed to manufacturers of APIs and solid oral dosage forms increased. Thenumber of warning letters to solid oral manufacturers even more thandoubled (FY 00: 6, FY 01: 14). Apart from the 65 warning lettersissued by CDER, the CBER sent 5 warning letters to manufacturers ofbiological products.

Illustration 2 shows an overview of thefrequency of FDA compliance inspections for the countries outside the US(without pre-approval).

Ill. 2 Number of FDA Inspections, FY 01

The new System-Based Inspections carried outwithin the framework of an FDA pilot project (see GMPNews of 28 February 2002), uncovered the greatest number ofdeficiencies in the production systems, followed by the quality system andthe quality control system.

One third of all complaints in the 65 warning letters referred to cleaning,with 6 of these 23 complaints concerning APIs and topical products each(source: The Gold Sheet, April 2002). In our internal evaluation we evencounted 25 warning letters referring to cleaning because weconsidered not only cleaning itself, but also cleaning validation andmissing SOPs regarding cleaning validation.

More than 30% of the complaints (7 of 23)referred to multi-use equipment. 40% of the warning letters to APImanufacturers cited cleaning, among those to biologics manufacturersthe share was even 60% (!).

This means that the complaints in warning lettersregarding cleaning are at a level comparable to that of the previous years(FY 99: 28%, FY 00: 40%).

What does FDA expect with regard toGMP-compliant cleaning?

  • Clearly written and defined cleaning SOPs

  • Documented evidence of cleaning validationstudies

  • A well-maintained operator trainingand qualification regimen

  • Validated analytical methods in cleaning validation studies

What makes the implementation difficult isFDA's requirement that all cleaning processes have to be "grounded insound scientific rationale" (G. Bird, Eli Lilly).

Although the absolute number of warning lettersdirected at manufacturers of injectables diminished in FY 2001, FDA still keepsthe assurance of sterility in focus. This is due to the 135 recallssince 1999, which were often caused by insufficient media fills. In somecases, individual companies even had to recall several products andbatches at a time.

Another item that is often cited inwarning letters is process validation. However, this term isinterpreted very broadly by FDA and encompasses - apart from performancequalification - also inappropriate analytical methods for cleaningvalidation, inadequate change control and insufficient validationdocumentation, just to name the most important ones.

What is also still frequently mentioned is OOS handling.

Nevertheless the deviations have thefollowing profile:

Complaints inwarning letters:

Ill. 3 Complaints in warning letters 

If you consider exclusively the letters directed at APImanufacturers, you will find the following percentages ofcomplaints:

Ill. 4 Complaints in warning letters to API manufacturers 

The following graph gives the number of warningletters according to manufacturing plants. Here you can seethat API manufacturers still hold the leading position in this group:

Ill. 5 Number of warning letters according to manufacturing plants

OOS was the second most frequent complaint. The following graph shows inwhich kinds of manufacturing plants OOS gave rise to complaints.

Ill. 6 Complaints about OOS according to manufacturing plants

The same evaluation as for OOS considersin the following in which plants theadherence to written procedures or missing procedures were aproblem.

Ill. 7 Complaints about "adherence to written procedures ormissing procedures" according to
        manufacturing plants

The evaluation in hand includes theevaluation published in The Gold Sheet, April 2002. In addition, we havecarried out an evaluation of our own, the results of which diverge fromthose of The Gold Sheet. The reason for the differences lies with the factthat we have counted the complaints in a different way. An example: Amissing procedure on stability testing can be counted as "missingprocedure" on the one hand or as deviation in "stabilitytesting" on the other hand. Or you can put it into both categories.This last possibility is the one we have chosen because, in our opinion,this is the only way to compare the frequencies of the complaints. Apartfrom this, different sets of criteria lead to different results. In ourevaluation, we havepaid attention to the fact that logically related deviations should beclassified under the same criterion. As deviations in the quality unit(QC/QA Unit), for example, we have classified all those deviations thatindicate that a general problem (e.g. a lack of resources) has beendetected in the area of the quality unit.

As you may know, the European ComplianceAcademy (ECA) has engaged CONCEPT HEIDELBERG to develop new seminar topics with project managers who bring their GMP know-how to bearin the event concepts - a knowledge gathered during both their education(studying pharmacy, chemistry, biology, or engineering) and their work inpharmaceutical companies (like Pfizer, Fresenius, and Merck).

The annual evaluation of FDA warning lettersis - next to other sources of information - the starting point for asystematic planning of GMP trainings and conferences. Especially those whowant to achieve and maintain compliance with FDA requirements will findfurther information in the following list.

What is to be expectedfrom FDA in 2002 and 2003?

A report by Jill Wechsler (USA), published inthe journal "Pharmaceutical Technology" in April 2002, prepares usfor FDA's plans to conduct a significantly higher number of inspections in thefuture. Due to the considerably increased budget, Wechsler assures that "GMP inspections of foreign drugs manufacturers willskyrocket [...]." Therefore it becomes more and more important to beaware of FDA's valid cGMP requirements and to put them accordingly intopractice. We of CONCEPT HEIDELBERG will go on watching the GMP/FDA trends andoffer you high-level GMP courses in this field.


We hope that this evaluation of FDA warningletters will be of use to you.


  • Sven Pommeranz
  • Oliver Schmidt


  • The Gold Sheet 2002
  • CONCEPT HEIDELBERG: Internal evaluation of warning letters
  • Pharmaceutical Technology Europe, April 2002
  • CDER Report to the Nation 2001



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