Validation Aspects in US FDA Warning Letters

GMP News No. 870

GMP News
16 January 2007

Validation Aspects in US FDA Warning Letters

In theGMP News of 10 January 2007, the FDA Warning Letters Report with a"top five" list of pharma-relevant warning letters issued in Fiscal Year2006 was presented.

With regard to the production area, there were detail deficienciesconcerning validation/qualification and calibration in the warningletters of FY 2006.

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

There are far more findings referencing 21 CFR 211.100 (writtenprocedures, deviations). Three of the seven warning letters refer toprocess validation. A process validation deviation is also mentionedagain with regard to 21 CFR 211.110 (IPC). Therefore, most of thedeficiencies in the field of validation/ qualification/ calibration inFY 2006 warning letters concern process validation just like in previousFiscal Years.

It is striking that the FDA quite often criticises deficiencies inHVAC qualification (21 CFR 211.46). In this area, there are twocitations on inappropriate qualification and one on insufficientrequalification.

In further citations, the FDA is criticising:

  • The qualification (IQ/OQ) and validation of water systems (2times)
  • The validation of the sterilisation process (steamsterilisation, 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 trailcan be found.

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

One example referencing 21 CFR § 211.63:

"Your firm has not properly validated either (1) the plant purifiedwater system or (2) the production laboratory water system. Propervalidation should include the following elements: (1) a description ofthe water system along with a print (i.e., drawing that shows allequipment 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 watersystem will consistently produce the desired water quality when operatedin conformance with established SOPs over a long period of time."

This example even mentions details in drawings!


Deviations cited by the FDA in FY 2006 are among the topics of the following events:

Sven Pommeranz
On behalf of ECA



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