FDA Warning Letter Highlights the Importance of Analytical Methods Validation and System Suitability Tests

The U.S. Food and Drug Administration (FDA) inspected the drug manufacturing facility, BBC Group Limited, located in China, from March 22 to March 26, 2021. During the inspection, significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals were found. One of the points raised concerns the validation of analytical test methods.

Regulatory Requirements and Definition of Validation

ICH Q2 (R1) "Validation of analytical procedures: text and methodology" presents a discussion of the characteristics that should be considered during the validation of analytical procedures. General principles and approaches that FDA considers appropriate elements of method validation can be found in the FDA's guidance document "Analytical Procedures and Methods Validation for Drugs and Biologics".

Validation can be defined as follows:

• ICH: “The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose.”
• FDA: “Analytical method validation is the process of demonstrating that an analytical procedure is suitable for its intended purpose.”
• USP: “Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications.”

Not Adequately Validated Test Methods

In the Warning Letter dated August 4, 2021, the FDA criticises, among other aspects, that analytical test methods were not adequately validated, including those for the active ingredient ethanol, which the company uses to manufacture alcohol-based hand sanitizers. In the warning letter, it is stated that "specifically, no system suitability requirements were present and reference standards were not identified. Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose."

In the response to Form FDA 483, which preceded the Warning Letter, the company indicated that test methods were updated, method validation protocols established, and test method evaluation completed. However, the FDA considered the response as inadequate. The FDA missed the following relevant aspects:

• Information on the analyte reference standards used for the method validation.
• Method validation details on identity of the tested analytes, system suitability, method specificity data, preparations of the analyte stock solutions, and accuracy and precision data from spike and recovery experiments at different concentration levels.
• An assessment of drug products manufactured utilizing the deficient methods.

For further information, including the other findings made by the FDA, please read the full Warning Letter to BBC Group Limited published on the FDA website.