In analytical chemistry, validation, verification, and transfer are distinct processes that ensure an analytical method is reliable, accurate, and applicable under different conditions.
Firstly, The International Council for Harmonisation (ICH) Guideline Q2(R2) “Validation of Analytical Procedures” summarizes the principles and practices for analytical method validation, including an overview of the required validation parameters per analytical test method type. Q2(R2) replaces Q2(R1) (EU effective date: 14 June 2024) and is designed to be read together with ICH Q14 “Analytical Procedure Development”.
The objective of validating a newly developed analytical method is to demonstrate that it is suitable for its intended purpose. It is a comprehensive process involving the determination of performance characteristics.
Typical validation parameters are:
- Specificity: Can the analyte be detected in the presence of other substances?
- Range: Is the method able to produce results that are proportional to the concentration of the analyte over a specified range? E.g., the Detection Limit (DL) – What is the lowest amount of analyte that can be detected? – and the Quantification Limit (QL) – What is the lowest amount of analyte that can be accurately quantified?
- Accuracy: Do the experimentally obtained values correspond to the expected true values?
- Precision (Repeatability, Intermediate Precision & Reproducibility): Are results consistent under the same conditions over a short interval (repeatability), within one laboratory on different days, with different operators or equipment (intermediate precision), and between different laboratories (reproducibility)?
- Robustness: To what extent do the results remain unaffected by small, deliberate variations in method parameters (e.g., temperature, pH, flow rate)?
The experimental design of a validation should be described in an analytical method validation protocol, including pre-set validation acceptance criteria for each chosen validation parameter. After executing the validation study, the data is reported in an analytical method validation report, including observations and/or deviations.
Furthermore, revalidation may be necessary in the following circumstances:
- Changes in the synthesis of the drug substance
- Changes in the composition of the finished product
- Changes in the analytical procedure
The extent of revalidation (full or partial) depends on the nature and impact of the change.
Secondly, when implementing an established and validated analytical method in a quality control laboratory, method verification is needed to ensure that the method performs as expected in routine use under actual working conditions. Verification refers to the process of confirming that a validated method is being correctly applied in a specific setting or by a particular operator. This may be achieved by carrying out system suitability tests, controlling sensitivity at the reporting thresholds, controlling the completeness of a reaction step before the actual determination can be performed, verifying the precision of the methods, etc. Key aspects of method verification are:
- Confirming proper implementation: To ensure that the method is applied consistently and accurately by operators in the lab.
- Checking equipment and conditions: To verify that the instruments, reagents, and environment are suitable for the method.
- Routine performance checks: To monitor the ongoing performance in real life.
Typical verifications performed in quality control laboratories include the verification of legacy compendial test methods, which are established and validated methods described in pharmacopoeial monographs and used throughout the world.
Thirdly, for newly developed and previously validated test methods, the receiving laboratory may demonstrate that it can run the method by carrying out a method transfer exercise where results are compared to show equivalence between the laboratory that has established the method (the transferring site) and the laboratory that wants to implement the validated method (the receiving site).
In summary, validation ensures a method’s overall suitability, verification confirms it works as intended under actual conditions of use, and transfer ensures its consistent performance across different settings. In all cases, a short note explaining the rationale for the chosen validation/verification/transfer approach (depending on the complexity of the analysis required) should be provided in the internal method validation/verification/transfer documentation, whereby deviations from the ICH Q2(R2) guideline shall be justified.
