What is Analytical Method Validation?

The FDA’s 1987 Process Validation Guidelines define analytical method validation as “the process of establishing documented evidence which provides a high degree of assurance that a specific process such as an analytical test method, will consistently produce a product supported by assay results meeting its predetermined specifications and quality attributes (i.e., accuracy, precision, etc.)”

To fully grasp this concept, we need to define “test method” and “validation” separately. The CDER’s 2001 Guidance for Industry on Bioanalytical Method Validation defines a method as “a comprehensive description of all procedures used in sample analysis.” Validation, conversely, is a documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria. Essentially, validation demonstrates that any procedure, process, equipment, material, activity, or system actually achieves the expected results, adhering to the principles of Good Manufacturing Practice (GMP).

A crucial related term is “specification,” which refers to a list of acceptance criteria, such as numerical limits, ranges, or other criteria, for the described test method. Specifications establish the criteria a material must meet to be considered acceptable for its intended use. Conformance to specification means the material will meet the listed acceptance criteria when tested according to the listed analytical procedures. These specifications typically apply to starting materials, components, bulk products, and finished products, but can also apply to critical manufacturing steps where failing to meet acceptance criteria would result in defective products. Analytical method validation ensures that the test method is robust enough to provide evidence of whether a product meets or fails to meet these predetermined specifications.

Test Method Validation: An Interchangeable Term

Test method validation is generally synonymous with analytical method validation; the terms are often used interchangeably. Like analytical methods, test method validation is the process of establishing that the performance characteristics of the test method—such as precision, accuracy, specificity, linearity, limit of detection (LOD), limit of quantitation (LOQ), and robustness—meet the requirements for the intended applications.

Why is Analytical Validation Necessary?

Manufacturers of medicinal products or medical devices must demonstrate to local regulatory authorities that their therapeutic goods are safe, pure, effective, and traceable. This requires sufficient evidence for product registration. A GMP regulatory requirement is to provide evidence that the analytical methods used to analyze products are validated. This means the methods consistently generate accurate and precise results. A well-planned analytical method validation process generates a high level of confidence in product quality.

Prerequisites for Analytical Method Validation

Several prerequisites must be in place before starting the validation process:

• Instrument Qualification: All laboratory instruments must be qualified.
• Documentation: A well-developed documentation process is essential.
• Reference Standards: Reliable and stable reference standards must be available.
• Trained Analysts: Analysts must be trained and qualified.
• Method Robustness: The test method must be robust to potential variations.
• Validation Protocol: A well-documented method validation protocol and reporting system are necessary.

Types of Analytical Procedures Requiring Validation

Test methods used to determine product quality attributes and the efficacy of processes that directly or indirectly impact product quality require validation. This includes:

• Identity Tests: For active pharmaceutical ingredients (APIs).
• Impurity/Degradant Measurements: Qualitative and quantitative.
• Limit Tests: For impurities/degradants.
• Quantitative Assays: Of APIs or drug product active materials.
• Physical Characteristics Tests: E.g., dissolution rate.