Robustness Validation

[CHRISCHAR]

Good morning to everyone,
we are in a process of defending our CTD and we have been asked to repeat the validation of robustness of assay also to the other strengths, cause in the assay method we use different sample concentration for each strength. Our product have two APIs and three strengths. We have carried out the robustness experiments using as matrix the big strength and the maximum sample concentration. We have submit this product in many countries in Europe and never we have been asked about that. Is it rational to do the validation in all strengths or even to waive the validation? As far as I know the validation experiments of the robustness is only to validate the chromatography of the method and is not relative with the concentration of the sample.
Many thanks

[DR]

In general - If a regulatory agency has asked you to do something, you either do it, or you diplomatically point out to them that you've already done it and bring the precise location of the applicable data to their attention. When that fails, you do as they ask.

That said, method validation for multiple strengths typically involves preparing samples of every strength per method as part of intermediate precision (robustness) testing while linearity, accuracy and precision are covered by preparing a range of final sample concentrations that would cover the protocol specified window of sample concentrations (frequently 75%-125% of claim for each strength). While being correct in that not every strength has to be prepared at high and low API concentrations, one must be careful here as the sample dilutions for different strengths may not lead to 75% of the lowest strength and 125% of the highest strength preparations being the best for covering the appropriate range of final sample concentrations for which you must validate.
You have to look at anticipated final dilution concentrations for 75% and 125% of theory for each strength. The highest and lowest final concentrations are what should define your accuracy and linearity ranges.

My guess is that this is where someone went wrong, and probably not by a lot but a correction is probably still in order.

[Consumer Products Guy]

When we had "higher strengths", we used our same method just used a smaller sample size, and all was part of the same validation study.

Since a smaller sample size was used, all non-active components were of lesser concentration and had even less potential matrix interference.

[CHRISCHAR]

thank you very much for your answers,
our method is linear, precised and accurate in all the concentration range (from 50% of the lower concentration up to 150% of the higher). We use that as an argument but they didn't accept it. Is not exactly an authority, is like ''consultant'' of the local market who is experienced with the demands of this state. We will see how to manage that but I just wondering, if from a science point of view, has any meaning this demand, when you have done linearity, precision and accuracy for all the strengths.
Have a nice day