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

GMP News No. 205

GMP News
18 June 2002

Warning Letter 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 the number of FDA inspections of pharmaceutical manufacturing plants (incl. API manufacturers).

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

On the whole, FDA published 65 warning letters through CDER in the FY 2001. This number was only slightly smaller than in the previous years (FY 00 and 99: 71 each). It is striking that the number of warning letters addressed to manufacturers of APIs and solid oral dosage forms increased. The number of warning letters to solid oral manufacturers even more than doubled (FY 00: 6, FY 01: 14). Apart from the 65 warning letters issued by CDER, the CBER sent 5 warning letters to manufacturers of biological products.

Illustration 2 shows an overview of the frequency 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 out within the framework of an FDA pilot project (see GMP News of 28 February 2002), uncovered the greatest number of deficiencies in the production systems, followed by the quality system and the 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 even counted 25 warning letters referring to cleaning because we considered not only cleaning itself, but also cleaning validation and missing SOPs regarding cleaning validation.

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

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

What does FDA expect with regard to GMP-compliant cleaning?

  • Clearly written and defined cleaning SOPs

  • Documented evidence of cleaning validation studies

  • A well-maintained operator training and qualification regimen

  • Validated analytical methods in cleaning validation studies

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

Although the absolute number of warning letters directed at manufacturers of injectables diminished in FY 2001, FDA still keeps the assurance of sterility in focus. This is due to the 135 recalls since 1999, which were often caused by insufficient media fills. In some cases, individual companies even had to recall several products and batches at a time.

Another item that is often cited in warning letters is process validation. However, this term is interpreted very broadly by FDA and encompasses - apart from performance qualification - also inappropriate analytical methods for cleaning validation, inadequate change control and insufficient validation documentation, just to name the most important ones.

What is also still frequently mentioned is OOS handling.

Nevertheless the deviations have the following profile:

Complaints in warning letters:

Ill. 3 Complaints in warning letters 

If you consider exclusively the letters directed at API manufacturers, you will find the following percentages of complaints:

Ill. 4 Complaints in warning letters to API manufacturers 

The following graph gives the number of warning letters according to manufacturing plants. Here you can see that 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 in which kinds of manufacturing plants OOS gave rise to complaints.

Ill. 6 Complaints about OOS according to manufacturing plants

The same evaluation as for OOS considers in the following in which plants the adherence to written procedures or missing procedures were a problem.

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

The evaluation in hand includes the evaluation published in The Gold Sheet, April 2002. In addition, we have carried out an evaluation of our own, the results of which diverge from those of The Gold Sheet. The reason for the differences lies with the fact that we have counted the complaints in a different way. An example: A missing procedure on stability testing can be counted as "missing procedure" on the one hand or as deviation in "stability testing" 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. Apart from this, different sets of criteria lead to different results. In our evaluation, we have paid attention to the fact that logically related deviations should be classified under the same criterion. As deviations in the quality unit (QC/QA Unit), for example, we have classified all those deviations that indicate that a general problem (e.g. a lack of resources) has been detected in the area of the quality unit.

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

The annual evaluation of FDA warning letters is - next to other sources of information - the starting point for a systematic planning of GMP trainings and conferences. Especially those who want to achieve and maintain compliance with FDA requirements will find further information in the following list.

FDA Concern FDA Compliance Seminar Date, Venue
Quality Unit FDA and GMP Compliance in Quality Assurance Units 25-27 September 2002, Madrid, Spain
Design of Equipment FDA-/GMP-compliant Design of Equipment 8-9 October 2002, Barcelona, Spain

What is to be expected from FDA in 2002 and 2003?

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

Another inspection trend that becomes apparent is FDA's tendency to focus their attention more and more on GMP implementation in development (among others manufacture of investigational medicinal products). In this context we organise the Education Course EU-GMP and FDA Compliance in Pharmaceutical Development with 4 experts from industry and supervision in Madrid on 17 and 18 October 2002.

We hope that this evaluation of FDA warning letters 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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