The ICH guideline Q2(R1) (Validation of Analytical Procedures) has remained in its current guise since 2005 but is now generally considered to be somewhat lacking in certain areas, especially with regards to modern analytical procedures (Near IR and NMR), multivariate models, and hyphenated techniques such as CE-MS, CE-ICP-MS, LC-NMR, GC-MS, LC-MS.
Over the past few years this document has been reworked, with ICH Q2(R2) recently having concluded its public consultation period. A look at the revised discussion document shows that, whilst its focus has been kept much the same, sections have been expanded upon and bolstered in various places to align with ICH Q14 (Analytical Procedure Development) and to include information on the above-mentioned missing procedures. There is therefore a need to consider how this document revision may impact qualification/validation procedures.
Recently, my colleagues wrote an article covering the requirement to demonstrate that structural characterization methods for biosimilars are fit-for-purpose with regards to the considerations of qualification or validation (read this article here). The article detailed how BioPharmaSpec uses the ICH Q2(R1) guideline as the foundation of our method qualification process. In essence this will not change through the publication of the ICH Q2(R2) guidance.
In many areas the new document remains unchanged from ICH Q2(R1) and is true to the principles given in that guidance. However, there are some areas that have been developed and serve to give clarification to what is expected.
As an example, the document now has useful annexes which cover a variety of methods from Binding Assays to Quantitative LC/MS. This is of course not an exhaustive list but does serve to provide useful guidance for how to handle a variety of scenarios. These examples clarify expectations for the various aspects of a qualification/validation study, something that was lacking in Q2(R1).
One point of note is that within Q2(R2) there is clear guidance for measurements of robustness and the expected parameters that one should be testing under that heading. As a reminder, robustness of an analytical procedure is a measure of its capacity to meet the expected performance requirements during normal use. Robustness is therefore the testing of a system’s response to change by deliberate variations of methodological parameters and assessing the capacity of the system to remain unaffected by those changes. This serves to assess how critical certain parameters are to variation, which may well be expected to happen naturally with time through the actions of different users.
As developers of analytical methods, we need to keep an open mind about what changes may occur over time and through different operators, and how we can ensure we have considered the impact of these changes during the development stage.
At BioPharmaSpec, our preference is that robustness be tested during the method development stage which can be, and in most cases is, performed ahead of method qualification or validation.
If we look at Quantitative LC/MS methods for example, then the parameters listed in Q2(R2) that should be considered include:
However, one could argue that LC column temperature, mobile phase composition and column ageshould also be included and may play a bigger part in session-to-session variability than some of the examples listed. This demonstrates that we must continue to use scientific justification as to which method parameters are tested and considered higher or lower impact.
It is interesting to see the idea of orthogonality being brought into the qualification/validation arena. ICH Q2(R2) states that orthogonality can be used as a mechanism for verifying specificity and also within impurity analysis. The application of orthogonality in analytical testing is very important and serves to support conclusions from two or more separate methods that can analyze a particular parameter using two different procedures. This is something Independent Consultant Fiona M Greer, BSc (Hons), MSc, PhD recently discussed in more depth in this article and BioPharmaSpec colleagues blogged about here). In the revised guideline it is made clear that any applied orthogonal procedure must itself be well characterized.
The draft ICH Q2(R2) guideline is a welcome evolution of Q2(R1) and, in aligning with ICH Q14 with a view to the documents being combined in the future, brings in new methods of process and procedure. Stage 3 -Public Consultation has recently ended and multiple comments were received from the scientific community whose combined voices of experience will serve to bring this document in line with current thinking. It is anticipated that the Working Group developing these guidelines will meet in November 2022 to review the comments received and decide revision directions.
Please contact our scientists if you would like to discuss appropriate characterization strategies for your biopharmaceutical.
