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Similarly, despite the useful focusing of the scope of the applicability of the guideline on “causes for concern” and “significant change” of existing medicinal products, it left unclear what was considered to constitute a “significant cause for concern” or a “significant change.”

Did a “cause for concern” exist if an existing impurity in an existing medicine had known genotoxicity (but the medicine concerned had been safely used for many years)? Did a “cause for concern” exist if an existing impurity in an existing medicine had a structural alert for potential genotoxicity but there was no known toxicological findings associated with the impurity?

Did a manufacturing change bring significant new risks if the same route of manufacture was scaled up or conducted at a different site? Did a manufacturing change bring significant cause for concern if process changes were conducted to optimize manufacture that instituted a change in manufacturing chemistry but not a change in the specification of the active substance? What about a change in manufacture of a starting material for active substance manufacture?

Such topics and a lack of clear, specific guidance in the published text left the guideline open to considerable degrees of interpretation and with it the possibility for inconsistent implementation. As a consequence of this uncertainty, a considerable increase in queries linked to existing products was triggered, many asking for a full evaluation of the MI risk, sometimes triggered by even simple variations not linked to the manufacturing process.

So, one can see that even with elements of the guideline that were viewed as “positive,” like the TTC concept and the risk‐based application to existing products, there were elements of detail that seemed to bring a need for further clarity to support consistent implementation. And of course, there were other aspects of the published guideline that were less well received or were simply not considered in the guideline as it was first published. These too are worthy of consideration.