As we analysed in previous blog posts, in recent years there have been substantial changes in pharmaceutical regulation, which respond, mostly, to the need of redefining the quality strategy to ensure the safety, quality and effectiveness of medicines. These changes have been progressively established by following the criteria set by the ICH Harmonized Guides Q8, Q9 and Q10.

One of the results of these initiatives has been the elaboration of new interpretation of what Process Validation is and what the expectations should be from a regulatory standpoint. Annex 15 of the EUGMP and FDA Guidance propose a much more scientific way of considering the validation of manufacturing processes of drug products and APIs.

With these changes, the retrospective validation – and even in some cases, the concurrent validation – are not acceptable anymore. The Magic Rule of the “three first batches” lacks also a sound justification under this view. Process validation should be an exercise that starts at the early drug development stages and never ends, throughout the lifecycle of the product (product and process design, process qualification and continuous process verification).

In addition, process risk analysis should be carried out collecting the information available from the development and supported by experimental data and scientific criteria and conclusions. Process risk analysis is the base of the selection of parameters and testing to be performed during all stages of process validation.



Currently, these changes have become effective, from the EU standpoint, in the medicines manufacturing, but are not still formally required for API manufacturing.

In the pursuit of maximizing value for our customers, current AFA audits to API manufacturers are considering a scientific and robust approach for the process validation as a requirement, mainly for the identification of critical process parameters, the process risk assessment and the basis for the actual process giving rise to the commercial batches, more than a strict and sometimes unjustified adherence to Annex 15 or other guidances.