As of June 14th 2024, the ICH guideline Q2(R2) and the complementary Q14 guideline (1,2) have been implemented, providing expanded clarity to the guidelines that have been in place for over 20 years. This revision brings in much needed updates referencing technological advancements that have occurred in the intervening years.
The aspects of validation we are familiar with are covered in the updated guidelines including:
And whilst they have been expanded upon, the principles remain fundamentally unchanged from the previous iteration.
One change from the Q2(R1) to Q2(R2) which has large implications is the definition and consideration of robustness; where previously it was only concerned with small, but deliberate changes to the method parameters, the new guidelines require testing to show reliability in response to deliberate variation of the parameters as well as stability of the sample and reagents.
This seemingly innocuous change to the phrasing opens up a much wider consideration as to what robustness studies to perform and how far explorations into method robustness should go. ICH Q2(R2) and Q14 do provide some guidance on when to perform and what to investigate for robustness and point out that this area should be investigated during method development studies. Examples of parameters to consider for robustness investigations are given ICH Q2(R2) Annex 2, though this is by no means an exhaustive list, nor is it intended that all points made are mandatory for investigation of those methods shown.
What is expected, quite understandably, is that the robustness of a method will be evaluated during the development phase, prior to method validation or qualification. Prior knowledge of both the product and the applicable method will allow a relevant and risk-based approach to inform the selection of parameters to investigate. For example:
One should also carefully consider any aspects of the method which have human input. This may be considered the highest risk contribution to variation, with human error creeping in through a variety of means. For example:
This is just a handful of examples and it is easy to get lost in what should be considered higher or lower risk, but a logical and step-wise approach to identifying risks within a method should be taken. Guidance on this is provided in ICH Q9(R1) Quality Risk Management.
During the subsequent validation or qualification of any method, the data generated in the development phase can be drawn upon to cover robustness considerations of the method as part of the validation/qualification study.
It should also be borne in mind that internal method qualifications should also be performed in line with ICH guidelines, this being irrespective of whether the method is qualitative or quantitative. This is the approach we take at BioPharmaSpec and was discussed in detail in a recent article (3). This approach gives confidence that the results obtained are specific, accurate, precise and robust.
At BioPharmaSpec, we specialize in early phase method development and can help in identifying those risks that are most likely to affect any methods used to study your molecule. In this way you can identify critical parameters, investigate their impact and ultimately conclude how robust your method really is.
