Warning Letter Analysis for Process Validation

The Warning Letters Report 2009 presented an overview about the most frequent drug findings (deficiencies) of the US FDA  in the fiscal year 2009. Process validation was not mentioned separately as the 21 Code of Federal Regulation 210/211 does not address it independently. Following you will find an analysis of the Warning Letters issued in 2009 relative to GMP deficiencies in process validation.

The deficiencies objected to in 2009 also comprise "classics" as "no validation conducted" (4x) or "no existing validation plans respectively standards for validation" (3x).

Further deficiencies are: Missing identification of process parameters and lack of validation for critical parameters (as e.g. mixing time, compression, maximum machine speed) (both 3x).

In three cases the Warning Letters explicitly mention that the batch needs to be consistent and reproducible from "batch" to "batch". Moreover, an "additional periodic process verification" is suggested in one case. This is already going towards live cycle model - as mentioned in the new FDA Draft on Process Validation.

In one case the authority criticised the application of a "general validation plan" for all processes. Here the FDA required specific validations for every product and every process. Also unique was the critique with regard to

  • an arbitrary sampling plan,
  • a missing rationale for the number of PQ runs,
  • a missing rationale for the comparison of data from old and new PQ runs,
  • a not adhered to SOP with the request to "maintaining the process in state of control",
  • a missing "root cause analysis" as request in the validation plan for evaluating inadequate results

The criticism relative to an insufficient process control can be rather seen as a consequence of a poorly implemented validation.

Further interesting are the criticised deficiencies regarding Change Control (3x). Once they related to lacking stability tests following process changes. In other cases the evaluation or the scientific rationale with regard to the effects of the changes on the process was missing.

The authority also criticised a missing cleaning validation and an insufficient media fill (missing rationale for the volume, missing contacting of the entire product contact machine surface).

The findings with regard to process validation are becoming more "modern". Not only missing or insufficient validations are criticised, but by now also specifically missing risk analysis and rationales for process changes. The FDA also explicitly mentions process consistency and reproducibility - from batch to batch. Even modern requirements for a "periodic process verification" are no taboo any longer.

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

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