FDA Warning Letter Statistics 2010 regarding Process Validation and Qualification

In the Warning Letter Report 2010 (GMP News from 2 February 2011), we presented an overview of the most frequent GMP Findings of the FDA in the fiscal year 2010. The topic "Process Validation/Qualification" was not specifically mentioned since it is not an independent part of the cGMP Guide (21 CFR 210/211). In the following you will find a summary concerning GMP Findings with regard to process validation and qualification in the manufacturing environment.

  • Among the findings from 2010 such "classics" like "no validation performed" (4x) or "deficient validation batches marketed" (4x) can be found.
  • We can notice that the large number of insufficiently validated processes (11x) mainly concern Chapter 21 CFR 211.100. The missing reproduction of the process is mentioned explicitly. Further deviations are listed: the size of the validation batches doesn't correspond to the commercial batches size and the uncritical use of an "concurrent validation".
  • With regard to Chapter 21 CFR 211.110, there are also objections in the field of process validation: non-validated processes (2x, also with the notice concerning missing reproducibility), one process validation showed considerable deviations, and twice the authority missed the in-process control.
  • Relating to different chapters, missing or uncompleted performed change control (7x, out of which 2 concern computerised systems) are listed. It is striking that the most frequent statements on change control concern the missing of a scientific rationale. This formulation can also be found in further findings.
  • With regard to 21 CFR 211.67 deficiencies in cleaning validation (7x) were also found: the authority objected to a complete missing cleaning validation (5x), but also to missing hold time validation and insufficient "swab-recovery"-studies. 
  • Deficiencies relative to the validation/qualification of water systems were quoted 5x, including dead legs and design failures in general.
    The FDA found insufficient Media Fills 4x.The authority also partly missed a scientific approach and the scope of the media fill. i.e. the use of air gassing during the simulation of inert gassing with a reference on worst case-conditions. 
  • Remarks on missing/insufficient "smoke studies" (3x) refer to 21 CFR 211.42, 1x room qualification as a whole was criticised.
  • Further single deviations concern insufficient/missing gowning validation, the sterilisation revalidation, the revalidation with regard to sterilisation security, the validation of the stability chamber, the validation of washing cycles of the stopper washing machine with regard to endotoxin, the qualification of a filling machine, the qualification of a packaging machine, the PQ of system software and the insufficient calibration.  

Conclusion: Deviations regarding process validation are again among the most frequent FDA findings. Other frequent deviations the US authority objected to frequently concern change control and cleaning validation. The frequency of deviations relative to validation/qualification of water systems, media fills and room qualification keep on increasing.

Sven Pommeranz
CONCEPT HEIDELLBERG (a service provider entrusted by the ECA Foundation)

PS. The events planned within the GMP Certification Programme "ECA certified Validation Manager" will intensively deal with deviations on validation/qualification discovered during inspections.

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