Formal Method Validation

The development and optimization process can improve a method, but validation does not. Validation is the final proof that regulations and expectations are met.
Feb 02, 2008

When developing a new method for a new biopharmaceutical product, optimizing an existing method for an existing product, or when changing a release method for a licensed product, many development and validation elements should be considered.1–4 Analytical method validation (AMV) follows analytical method development (AMD).5

Table 1. Summary of minimum AMD/AMV requirements for a new method based on ICH Q2(R1)
The AMV report should formally verify that the method is valid (from a quality and product-release perspective) and validated (from a compliance perspective). The AMV protocol contains a summary of AMD results for the new method, and, for changed methods, historical data (AMV and release data) generated using the current method. It also provides current or expected in-process and product specifications, which determine whether the new method is suitable for comparing product quality attributes to specifications.

Portions of the AMD data that are summarized in the AMV protocol may not need to be repeated during validation as long as the AMD data were generated under GMP conditions. Therefore, AMV should not be used to modify or change critical assay elements (for example, statistical data reduction). We must be careful not to invalidate the AMD data that was used to establish robustness, system suitability, and possibly other performance characteristics.6 The formal AMV process should ideally only be a confirmation of test method performance that can be considered the least significant overall task from an operational perspective because we are usually only confirming but not improving anything in this process. The AMV process is often the most important task from a compliance perspective (inspections and submissions) and needs to be executed well mostly for this reason.6

Table 1 lists all International Conference on Harmonization (ICH) characteristics that may apply to a particular test procedure, including the corresponding minimum requirements, reported results, and acceptance criteria. Some AMD and AMV elements were added to the required ICH characteristics. In practice, more data may need to be generated. For example, three spike levels may not be sufficient to evaluate accuracy and repeatability precision over the valid assay range. Several critical elements of the AMV protocol are discussed in more detail below.