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ICH Q2(R2) Validation of Analytical Procedures
10 January 2024
We have been having a critical look at a recently upgraded validation guideline and thought it might be helpful to share some thoughts.
ICH Q2(R2) is a revised guideline on validation of analytical procedures which when compared to the preceding version, covers a more diverse set of analytical methods, such as spectroscopic or spectrometry data, multivariate statistical analyses, and biotechnological products. It also aligns the content with Q14, a relatively new (03/2023) guideline on strategies for analytical procedure development.
Some of the key changes in Q2(R2) compared to Q2(R1) are:
- It provides a general framework for the principles of analytical procedure validation applicable to products mostly in the scope of Q6A (New
Drug Substances and New Drug Products: Chemical Substances) and Q6B (Biotechnological/Biological Products). - It incorporates guidance for validation of non-chromatographic analytical procedures and includes a discussion of statistical aspects in
validation. - It clarifies the definitions and terminology of validation tests, methodology and evaluation, such as specificity/selectivity, range, response,
linearity, accuracy, precision etc. - It has introduced small but quite significant changes to the reportable ranges for various parameters. As an example, for accuracy of drug
product the original requirement was to report over a range between 80% and 120% of the test concentration, based on the declared
content. In this latest revision a choice is given;
o Continue as per original document
o Change the range to 80% of lower specified limit and 120% upper limit.
- The revision updates the examples and references to reflect the current state of the art and best practices in analytical procedure validation.
Comments:
1. Why is there no revision history? It would be extremely helpful to see a summary of all changes from the last edition without the need to compare documents side by side. This is normal practice under document change control.
2. With respect to reportable ranges:
- · Low end of reportable range
o 80% of declared content or 80% or lower specification acceptance criterion.
o There are no indications where either should be used.
- High end of reportable range
o 120% of declared content or 120% or higher specification acceptance criterion.
o There are no indications where either should be used.
Essentially, we see little advantage to be gained by broadening the scope of the limits to include the lower and upper specification. It offers little in practical terms, complicates an existing satisfactory convention and in theory at least, creates valid practical issues. As an illustration, consider a product which is a solution of a poorly aqueous soluble drug at 50 mg/ml. Whilst most commonly the upper limit would be 52.5 mg/ml (105% w/v), there are instances where it can be 55 mg/ml (110% w/v). This would mean two validation options:
a) continue as previously and validate upper range 60 mg/ml (120% declared content) or,
b) follow alternative approach and validate at 66mg/ml (120% upper limit).
There may not seem much of a difference but what if the drugs solubility lies between the two values? Similar concerns apply to high end reporting for dissolution testing – 130% declared content.
3. Acceptance Criteria
- Would be nice to have – no regulatory authority could question how the acceptance criteria were derived. It might be reasonable to expect a validation guideline to include guidance on what is acceptable and appropriate acceptance criteria.
4. Will VICH update GL2? Possibly, maybe? Best guess – eventually!
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