ICH Q2(R2) and ICH Q14: What's new?
It has been 5 years since ICH published the concept paper and business plan for the revision of ICH Q2 and the development of ICH Q14. Just before Christmas 2023, revision 2 of ICH Q2 and the new guidance ICH Q14 were published. So what are the main points to consider for future analytical validations?
1. The publication of ICH Q14
Although we tend to talk about the update of ICH Q2 and how we need to adjust our validation studies, the biggest update is actually the accompanying publication of ICH Q14. This guideline describes science- and risk-based approaches for developing and maintaining analytical procedures suitable for the assessment of the quality of drug substances and drug products. Validation according to ICH Q2 is only a part of this lifecycle and ICH Q14 and ICH Q2 complement each other. Therefore, the way you design your analytical lifecycle approach and the knowledge you gather during analytical development will influence the design of the validation study.
In addition, ICH Q14 also provides information on the submission of analytical procedure development and related lifecycle information in the Common Technical Document (CTD) format. The tools described in ICH Q14 can provide opportunities for more efficient regulatory approaches to analytical post-approval changes. Again, to benefit from these tools, the analytical validations need to be in line with the analytical lifecycle approach described in ICH Q14.
2. Reportable range and working range
According to revision 1 of ICH Q2, the range of the method needs to be validated. However, what is the range of the method? Is it the range of the calibration curve or of the reportable result? In many (more complex) analytical procedures, there is a difference between the range of the reportable result and the measuring range of an instrument. In revision 2, this difference is acknowledged and definitions are provided for the reportable range and the working range:
The reportable range of an analytical procedure includes all values from the lowest to the highest reportable result for which there is a suitable level of precision and accuracy. Typically, the reportable range is given in the same unit as presented in the specification.
A working range corresponds to the lowest and the highest level of the quality attribute to be measured (e.g., content or purity) as presented to the analytical instrument and for which the analytical procedure provides reliable results.
Although the discrimination between reportable and working range may sound like semantics, this has consequences on how to analyze the validation parameters, as indicated in point 3.
3. Validation tests
As a result of the concept of the reportable range, the validation tests are also grouped differently. According to revision 1, the validation characteristics were: accuracy, precision, specificity, detection limit, quantitation limit, linearity, and range.
Revision 2 lists the following validation tests: specificity, range (response and lower range limit), accuracy, and precision (repeatability and intermediate precision). The response (suitability of the calibration model, which can be linearity) and the determination of detection and quantitation limits, should now be analyzed as part of the range assessment. In addition, in revision 2 more guidance is given on the different types of ranges and how to use this to design your validation strategy.
4. Changes per validation test
As mentioned above, ICH Q2 revision 2 lists the following validation tests: specificity, range (response and lower range limit), accuracy, and precision (repeatability and intermediate precision).
In general, the validation tests are described in more detail and with more examples for various analytical techniques to gain a better understanding of the validation tests. Nevertheless, the analytical approaches are very similar or the same as described in revision 1. It should be noted though, that the introduction of reportable and working ranges may lead to differences in the execution of the validation. For example, if you have always determined linearity of the reportable range, you will now also need to assess the response model for the calibration curve.
Some key differences per validation test are:
Information added :
Use of selectivity
More extensive description of approaches to be used
Option (in some cases) of technical inherent justification
The use of reportable range and working range is described
As part of the range, the lower limits and the calibration model need to be assessed.
Information on how to analyze different calibration models is provided
c) Accuracy and Precision:
The precision and accuracy results need to be reported with their confidence intervals
The definition for reproducibility has been changed to include the precision when performing analytical procedures at multiple sites
The possibility of a combined approach for accuracy and precision has been added
Information for multivariate analytical procedures has been added.
5. Additional information in ICH Q2 revision 2
Historically, ICH Q2 revision 1 was the result of the combination of ICH Q2A and ICH Q2B. ICH Q2A identified the validation parameters needed for a variety of analytical methods and discussed the characteristics that must be considered during the validation of the analytical procedures which are included as part of registration applications. ICH Q2B included the actual experimental data required, along with the statistical interpretation, for the validation of analytical procedures.
Revision 2 of ICH Q2 is a more elaborate document that also includes information about types of validation, documentation of validation studies, use of prior knowledge, demonstration of stability‑indicating properties, and considerations for multivariate analytical procedures. In addition, the guideline contains examples of approaches to analytical procedure validation for a selection of technologies.
In conclusion, although the changes per validation parameter may be limited, the publication of ICH Q14 emphasizes again that validation is more than a tick‑box exercise. Validation is part of the analytical procedure lifecycle as described in ICH Q14. Therefore, the question is not only whether your analytical validation strategies are in line with ICH Q2 revision 2, but also whether your analytical development and lifecycle strategies are in line with ICH Q14.
More information and references
This information is based on the step 4 documents published by the ICH (ICH Official website : ICH):
Validation of Analytical Procedures (Q2(R2))
Analytical Procedure Development (Q14)
Quality RA offers a course providing detailed discussion of the differences between revision 1 and 2 of ICH Q2 and the content of ICH Q14. (CLICK HERE)