What’s the difference between method verification and method validation?
Although trivial, but often people confuse between the GMP relevant terms method verification and method validation. These two terms are closely related but are not the same. In this small article, we will try to clear the doubts through proper explanations and suitable examples. Let’s take this step by step:
Method Verification
The United States Pharmacopoeia (USP) explains method verification as a measure by which a compendial method can be tested for its suitability under actual conditions of use. A laboratory that employs a compendial method for testing a specific sample is required to perform method verification. Hence, method verification is directly related to the particular laboratory conducting that specific test on a definite sample type.
Elaborating, if e.g. a contract lab has verified a compendial method for a distinct sample but a new order to test a new sample is submitted to the lab, it is required to re-perform the method verification for the new sample. Similarly, if a method has been successfully verified by a certain laboratory but the same sample is sent to a different laboratory for fresh analytical testing applying the same method, the new laboratory must verify the method in the current location for the same sample already previously analyzed by the other lab. As method verification is related to methods listed in pharmacopoeias, it is performed on established analytical methods known to work. All compendial methods have already been validated and extensively tested in international round-robin tests. But as not every existing drug could have been tested, these compendial methods are not applicable to all test substances without a prior check. Thus, this “check” is the method verification to be performed for the specific sample of interest. A short overview about some regulatory requirements can be found here.
An example is pyrogen / endotoxin testing. Instead of using a LAL or a rabbit pyrogen test, the in vitro Monocyte activation test (MAT), included in the European pharmacopoeia as chapter 2.6.30, can be applied. For this test, whole human blood (cryoblood or fresh blood), PBMCs or a cell line (Mono Mac 6) can be used. Thus, already due to the choice of the test system, the method must be verified in that lab that wants to perform the test for the specific drug of its client to be analyzed.
Method Validation
Validation of a method is a process that confirms the suitability of the method for its intended analytical use. Method validation belongs to “in-house” methods developed by the lab itself, not to general tests listed in any pharmacopoeia = non-compendial methods. The Guideline “Validation of Analytical Procedures: Text and Methodology” (ICH Q2(R1)) published by International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use clearly defines the criteria a method must fulfill to be considered as validated. The parameters for validation are trueness, linearity, specificity, precision, robustness, limit of detection / quantification and range. Depending on the intended use of the test (identification, purity, assay), the parameters differ. Some more explanations can also be found in this article. A method is first developed keeping its use in mind, potentially qualified when indicated, and later on validated for its acceptance to be used as a routine test in a pharmaceutical lab as a reliable method, shown to be suitable.
Like for method verification, re-validation is also applicable to method validation. Example: If an in-house developed chromatography method is employed to validate a certain monoclonal antibody in lab 1 but is sent to a lab 2 for a second analysis, then lab 2 must re-validate the chromatographic method used by lab 1 to analyze the antibody. Similarly, if a lab has successfully established an analytical method for the analysis of a monoclonal antibody but is asked to analyze another class of monoclonal antibodies, even if structurally similar, the lab must re-asses the validation of the established method. Which aspects of method validation have to be taken into account for the the different methods and how method validations are performed practically can be found in our Journal Club articles for an identification method, a content determination, a proof of potency and a purity test.
And again, specifically, where is the difference now?
A few words to put the difference between method validation and method verification in a nutshell: compendial methods are verified while in house developed methods are validated. For method verification, in general you’ve got to follow the appropriate pharmacopeial requirements and might add some further parameters to look at which you consider necessary, while for in house developed methods you’ve got to perform all validation parameters set by the ICH Q2(R1) guideline and other regulatory requirements if appropriate. In most cases method validations are more extensive.