The aim of validating any process is to ensure that it achieves its intended purpose with adequate accuracy and precision. The purpose of analytical procedures or methods is to measure certain attributes of the test article, whether a drug substance or a final product. This may include, among others, measuring the content (assay) or the amounts of certain undesirable components like related substances, degradation products, or residual solvents. Regulatory authorities and auditors are increasingly focusing on ensuring that all analytical methods used within the pharmaceutical industry are validated and that validation work complies with general GMP rules similar to any other process within the industry. In other words, validating analytical methods should follow structured, predefined procedures from start to finish. In this article, we discuss auditing analytical method validation as a critical industry process. And answer the question, what do auditors look for when reviewing this process?
Validation master document
Auditors will initially examine the presence of master documents that describe analytical method validation as a process. This document (or documents) should adhere to general GMP rules; and provides guidance to responsible personnel about the required analytical validation studies and the acceptance criteria as per ICH guidelines. The major sections of such document(s) should cover the following key points;
- An overview of the validation studies conducted and their significance, and the acceptance criteria for each, which should be aligned with ICH guidelines and other general chapters from various compendia.
- Another section describes the process of generating validation protocols, the types of validation studies to be included based on of method validated, and who is responsible for approving the protocol.
- During validation work, a section deals with Out of Limit (OoL) results. It should provide details about how to investigate the root cause behind such results, the impact on the validation work, and document such results in the final report.
Analytical method validation is conducted per documented methodology, and any results should comply with predefined acceptance criteria. Both the methodology and acceptance criteria are mentioned in protocols that should be approved before validation work.
Validation protocols attract auditors’ attention which is critical to the validation process. They initially examine the rationale behind using the chosen analytical technique for the intended purpose, which should be mentioned in the protocol. For instance, the choice of HPLC, rather than simple TLC, for the quantitative determination of related substances is backed by the ability of the technique to separate complex mixtures. Then, they ensure the adequacy of the validation studies included within the protocol to prove the suitability of the method for its purpose. For example, the validation of the HPLC method for assay tests must consist of validation experiments that demonstrate the specificity, accuracy, precision, linearity of response, and robustness of the method towards changes in the testing environment. For each of these studies, enough data points or measurements should be performed to comply with ICH guidelines. And any required calculations or statistical analysis that is carried out on these results should be mentioned in the protocol.
The working analytes’ concentration levels at which the validation studies are conducted must be in alignment with the limit of impurities to be tested or the purpose of the method. For instance, if the assay procedure is used for testing the dissolution of tablets or capsules, then the range of validation studies must cover the expected range of results from the such test, i.e., from 0 to 120% of the labeled claim. Finally, the acceptance criteria and the justification for them should be clearly defined in the protocol.
Validation analytical work
Generally, any validation-related work should adhere to broad GMP/GDP rules and other site procedures relevant to the testing technique. They will also examine the adherence of the work conducted to the methodology stated in the protocol and how any Out of Limit (OOL) results was captured, investigated, and documented. Auditors may specifically request examples of validation-related OoL results to examine how they were investigated to identify the root cause and the impact on the validation work, as well as the final methodology. Any Out of Limit results and their relevant investigations should be addressed as per Validation Master documents.
Auditors will examine the agreement of the validation report relevant to the protocol. They will ensure that all results of validation studies specified in the protocol are documented in the final report and in addition to any statistical analysis conducted on these results, such as regression analysis for proof of linearity or standard deviation and confidence intervals for determining the precision.
The final report should also include a section for discussing any OoL(s) results and any investigation work conducted for these results. It should also show a detailed explanation of the root cause found, and the impact of the OoL on the intended purpose of the method should be stated in the report.
For instance, the need for an acceptable linear relationship between the test response and the analyte concentration may lead to a change in the purpose of the analytical method to become a semi-quantitative or a limit test. Where the presence of significant matrix interference may lead to adopting a standard addition procedure rather than relying on external standards for measurement. Auditors will carefully examine the scientific rationale behind these changes.
Finally, the validation report should include the final methodology culminating from the results and findings of the validation work. In addition to the method should consist of details about any solutions or preparations that need to be employed during routine analysis to assure the performance of the method, such as resolution and/or sensitivity solutions for chromatographic methods. This is in addition to any instructions identified during the validation work, which would improve the outcome of the method or prevent failure of method performance criteria such as reproducibility or resolution.
Auditors adopt a comprehensive approach when auditing the process of analytical method validation rather than focusing on the final report. Instead, they aim to ensure that the entire process follows GMP rules and a defined system that will capture any deviations so that validated methods can serve their purpose accurately and efficiently.