The use of alternate methods, especially for USP methods, some of which are rather old, has long been a question that both the industry and the FDA have contemplated. Alternate methods can be easier to use and, in some instances, more accurate and reliable. But how can you demonstrate that an alternate method is indeed equivalent to an existing method?
USP General Chapter Section 6 for Testing Practices and Procedures states, under Adjustments to Solutions, that:
“Proportionately larger or smaller quantities than the specified weights and volumes of assay or test substances and Reference Standards may be taken, provided the measurement is made with at least equivalent accuracy.”
This leads to the question of “how do I determine equivalency?” Under the same USP chapter, there is reference to alternative methods:
“…alternative method or procedure must be fully validated and must produce comparable results to the compendial method or procedure within allowable limits established on a case-by-case basis”
The July 2015 FDA Guidance “Analytical Procedures and Method Validation for Drugs and Biologics” has a section dedicated to method comparability studies where guidance is provided on what data is needed (when filing an alternative method) to demonstrate that the new method is equivalent or superior (to the alternative method). Statistical analysis should be employed for method comparison purposes and USP Chapter <1010>, Analytical Data – Interpretation and Treatment, provides consideration for such tools where the focus of equivalency assessment is the methods’ precision and accuracy variances.
If the methods’ equivalency statistical data determines that the methods are not equivalent, then it is critical to assess the cause for such non-equivalency as this may be due the superiority of the new method. Such an outcome is expected as this is likely to be the motivation for developing the new method.
When revising a method, the change must be validated to establish suitability of the new method’s conditions, but a protocol-driven comparability study is also necessary to determine the impact to data from the old to new method.
If you have any questions in relation to analytical method validation and method comparison, please contact Paul Mason, Ph.D. at p.mason@staging.lachmanconsultants.flywheelsites.com.
