An analytical method which is used in pharmaceutical analysis should always be validated to ensure that the results generated are trustworthy. These results may be used to make critical decisions during the drug development process relating to issues such as safety of the drug, the synthetic route and the manufacturing process. However performing formal validation studies as per ICH guidelines requires considerable resources. In the early stages of the development of a drug the investment required for formal validation may not be desirable due to a number of reasons including:
- The development and optimisation of the analytical methods is ongoing.
- The development of the synthetic route for the drug substance is ongoing.
- The development of the formulation of the drug product is ongoing.
- The drug may not progress into later stages of development.
The ICH guidelines apply to ‘validation of the analytical procedures included as part of registration applications submitted within the EC, Japan and USA’ , and thus do not formally apply to the early phases of drug development. The guidelines from the FDA regarding INDs for phase 2 and phase 3 studies  require ‘appropriate’ validation data for methods which are not from a pharmacopoeia or official reference standard.
The consequence of this is that it is common for pharmaceutical companies to use a phased approach to analytical method validation studies. Validation performed for early phase drugs tends to be less extensive than that performed for late stage drugs. However the objective of validation still applies, i.e. to demonstrate that a method is suitable for its intended purpose.
The following list provides suggestions for validation of early phase drugs:
- A formal validation protocol is not yet mandatory. Internal guidelines, or a standard operating procedure (SOP), may be used to summarise the general validation requirements. This may be referenced rather than producing time consuming documentation.
- The extent of testing and the number of replications may be reduced.
- Wider acceptance criteria may be adequate in early phases of development.
- Specificity and evaluation of the quantitation limit are the primary characteristics to ensure that assay and impurity methods meet their intended purposes of potency and safety.
- A second method to evaluate accuracy is unlikely to exist in the early phase of development, therefore accuracy may be inferred from the results of precision, linearity and specificity.
- For precision testing synthetic mixtures of drug substance and placebo may be used, rather than authentic samples, thus enabling the combination of accuracy, precision and potentially linearity at the same time.
- Formal intermediate precision experiments are not yet needed but if different laboratories need to operate the method then the handover will require suitable validation.
- The evaluation of the detection limit for impurity methods may be delayed.
- Formal robustness testing is not yet required. Robustness studies associated with method development are likely to be ongoing at this stage.
- The validation report may be presented in a simplified tabular format, together with the conclusions. This type of summary report fulfils the expectations of the regulatory authorities, e.g. phase 2 and phase 3 INDs.
Further information regarding validation of analytical methods by phase of development is available from Bloch in ‘‘Method Validation in Pharmaceutical Analysis. A guide to Best Practice’  and also from Boudreau et al. in a paper developed from a PhRMA 2003 workshop .
1. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Topic Q2 (R1): Validation of Analytical Procedures: Text and Methodology, 2005, http://www.ich.org/.
2. Guidance for Industry: INDs for Phase 2 and Phase 3 Studies, Chemistry, Manufacturing, and Controls information, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2003.
3. M. Bloch, ‘Validation During Drug Product Development – Considerations as a Function of the Stage of Drug Development’, in ‘Method Validation in Pharmaceutical Analysis, a Guide to Best Practice’, Eds. J. Ermer, J. H. Miller, Wiley, 2005, p243-264.
4. S. P. Boudreau, J. S. McElvain, L. D. Martin, T. Dowling, S. M. Fields, Pharm. Technol., 28 (11), 54-66, 2004, ‘Method Validation by Phase of Development – An Acceptable Analytical Practice’.
This blog post is an excerpt from 'Validation of Analytical Methods for Pharmaceutical Analysis' by Oona McPolin, available to purchase through the MTS website.