Validation Aspects in US FDA Warning Letters

In the GMP News of 10 January 2007, the FDA Warning Letters Report with a "top five" list of pharma-relevant warning letters issued in Fiscal Year 2006 was presented.

With regard to the production area, there were detail deficiencies concerning validation/qualification and calibration in the warning letters of FY 2006.

Compared to the previous years, in the eight warning letters on the topic of cleaning (21 CFR 211.67) only one citation on cleaning validation can be found.

There are far more findings referencing 21 CFR 211.100 (written procedures, deviations). Three of the seven warning letters refer to process validation. A process validation deviation is also mentioned again with regard to 21 CFR 211.110 (IPC). Therefore, most of the deficiencies in the field of validation/ qualification/ calibration in FY 2006 warning letters concern process validation just like in previous Fiscal Years.

It is striking that the FDA quite often criticises deficiencies in HVAC qualification (21 CFR 211.46). In this area, there are two citations on inappropriate qualification and one on insufficient requalification.

In further citations, the FDA is criticising:

  • The qualification (IQ/OQ) and validation of water systems (2 times)
  • The validation of the sterilisation process (steam sterilisation, dry heat sterilisation)
  • There is one finding for media fills and smoke studies each

It comes as a surprise that two deviations regarding the audit trail can be found.

Our conclusion: The number of deficiencies concerning the subject of validation/ qualification/ calibration within the production area decreased slightly compared to the previous years. Here, deviations regarding process validation still rank first. Most of the deficiencies are found in aseptic manufacture. It is noticeable that the citations are much more detailed than before. Whereas in the past, the wording ofthe criticism was quite general, now there are detailed references to what is wrong.

One example referencing 21 CFR § 211.63:

"Your firm has not properly validated either (1) the plant purified water system or (2) the production laboratory water system. Proper validation should include the following elements: (1) a description ofthe water system along with a print (i.e., drawing that shows all equipment in the system from the water feed to points of use); (2) operational parameters (including cleaning and sanitization procedures); and (3) a demonstration (with appropriate sampling plans) that the water system will consistently produce the desired water quality when operated in conformance with established SOPs over a long period of time."

This example even mentions details in drawings!

Sven Pommeranz
On behalf of ECA


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