Response to a question received on one of my webinars on V& V:

My response:

“John, I understand the concept of "Freeze changes" for the Validation Planning, but does "Freeze" mean absolutely no changes, or are minor changes which do not impact on safety and effectiveness permissible?  I struggle with this part of validation, because there is never perfect information at the start of a validation.  No argument that the changes must be frozen but let me give some examples:

  

 During a mixing step for a liquid bulk reagent, one step states to mix at room temperature for 15 - 30 minutes.  If it turns out that this time interval is not convenient, and objective data can be used to justify a change, could the mix at room temperature be revised to stir for at least 15 minutes, but no more than 10 hours?

1. A raw material is stored frozen, until time of use, and then it is thawed the night prior to the liquid bulking process.  Again, if objective data can be used to justify the change, and it is known the material thaws to room conditions within 3 hours, can the procedure be revised to thaw the material, and the material may be used within 10 hours.

Revising a protocol will cause a new revision level, which immediately catches attention with QA, who insists the revision level is not permissible as part of the validation.  Again, the changes can be mitigated as not impacting on product design.

 

Thank you for any thoughts and suggestions.”

 

ANS: I won't comment on your specifics as I would have to know more, and that becomes a consulting project.  However, some basics:

•  The definition of "change" should be in your company's SOP. In your example, some questions - "What is room temperature?"  "Thaws within 3 hrs?" Acceptable for use "within 10 hrs"?, etc. Changes of any sort would need to be verified / tested, as the very least in a lab book, for your "objective evidence".  Temp at freezing, and thawed should be defined / repeatable / verified by instrumentation, everything verified. 
• Not sure what you mean by "changes can be mitigated as not impacting on product design" - that's not a complete CGMP definition of change. Many CGMP-defined controlled changes do not impact product design, yet must be controlled, or otherwise can lead to the FDA's claim of "adulterated product", in this case meaning that a review of an SOP, et al, to see what was done to a lot/batch, may not indicate what actually was done at some point in time when that specific revision was in effect.
• Of course a change requires validation to make sure the change does what it should and doesn't do what it shouldn't (no unintended consequences) and a document(s) revision if controlled/CGMP as all changes should be.  E.g., every statement in para 1b above would need to be verified or validated (tested/proved) that the requirement(s) were each met / achieved. Even the statement "It is known" is not true of itself and  also needs what it refers to, to be proved / verified to truly be "known".
• Changes should be accomplished before validation, which includes the subsequent change in the revision level of any impacted documentation by said change, the point I made in the webinar and the whole point of this discussion, as the question being resolved is "what is it you're validating, and why validate something that is being changed, before the change occurs, waste of time and money and resulting in a meaningless validation.".

- JEL@jelincoln.com  03/03/2026