Validation Findings in FDA Warning Letters 2008

The GMP news from 18 February 2009 comprised information on the FDA Warning Letters Report 2008, including the Top 5 deficiencies.

It did not cover deficiencies regarding validation (validation/qualification/calibration) though. This is due to the fact that the findings are listed according to the paragraphs in the 21 CFR 210/211, which does not contain a separate paragraph addressing (process) validation. For that reason the following information does provide an individual validation issues analysis:

In the 22 Warning Letters in the fiscal year 2008 issues regarding validation were criticised 15 times. Top of the list were deficiencies relative to process validation (9 Warning Letters). Five of the letters referred to deficiencies concerning solid dosage forms, 2 concerned semi-solid forms, one addressed radio pharmaceuticals, and one product classification remained unclear.

Two Warning Letters per subject covered issues like inappropriate validation of the sterilisation process, filter validation, "smoke studies" and cleaning validation the authority issued like

Exemplary findings for the issues mentioned above are:

  • Exclusion of validation batches without providing reasons within a retrospective validation
  • Missing sampling details in the validation plan
  • It seems like you did not understand the meaning of a cleaning validation
  • The cleaning validation master plan does not contain any "scientific rationale" for specific products, sampling locations and acceptance criteria
  • Swab surfaces are too small
  • Not all loading patterns were mapped in the validation of the sterilisation process
  • Inadequate Air Flow Pattern

Further deficiencies concerned issues like

  • An inadequate calibration of thermocouples
  • A Media Fill not representing a commercial process
  • Undocumented removal of filled vials within Media Fills

Conclusion: Although the subject validation is not specifically listed in the 21 CFR 210/211, it still is among the top deficiencies in the Warning Letters issued. Almost 70% of all letters contained one or several findings relative to this subject. 41% were related to process validation.

Sven Pommeranz
On behalf of the European Compliance Academy (ECA)

By the way: One of the sessions conducted during the 3rd European GMP Conference in Heidelberg, Germany on 23/24 June 2009 will also cover the new FDA Guidance on process validation.

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