A Tolerance-based Approach for Validating Analytical Methods Using Design of Experiments
Open Access DepositedThe ISO 15288-2015 technical processes of verification and validation are essential to ensuring systems are built correctly (the "verification") and the right systems are built (the "validation"). While it is intuitive to think of systems as physical objects that can be easily measured with classical tools such as physical checking, testing, and demonstration, many modern systems are microscopic or molecular in nature, and measuring and assessing them poses huge difficulties. However, even molecular-scale systems, such as complex pharmaceuticals, must be rigorously tested because changes in formulation or function can lead to significant risks for the end-users. The increased importance of precision, particularly with the development of molecular-scale engineering and manufacturing, has driven the systems engineering community to develop robust verification and validation techniques for molecular level systems. These established systems engineering methodologies are applied here in this research to the pharmaceutical industry, filling gaps in published analytical method validation methodologies. A tolerance-based, Design of Experiments (DOE) approach, proven successful in the field of engineering in the past, is used and adapted here to pharmaceutical analytical method validation. This strategy enhances reliability by fully addressing variability and robustness, imposing strict tolerance limits for acceptance, and significantly expanding the efficiency and coverage of pharmaceutical validation testing. The study demonstrates this integrated approach on a analytical method validation use case and demonstrates its applicability and potential for general biopharmaceutical industry adoption. Statistically reliable analytical method validation is essential in pharmaceutical manufacturing for generating accurate and reproducible results, thereby ensuring regulatory compliance, meeting quality assurance requirements, and maintaining consistent product development. Unfortunately, the standard traditional methods of validation do not account for the variation in the data compared to the assay range or specification limit. This could lead to an inconclusive judgment regarding the alternative's applicability for its intended purpose, especially for lower concentrations of active pharmaceutical ingredients (APIs), excipients, or impurities within a drug product. This study aims at overcoming the current limitations by implementing a tolerance-based DOE approach to analytical method validation and provides evidence of the technique's efficacy in validating the analytical method for polyethyleneimine (PEI) and sodium butyrate (NaBu), impurities of viral vector drug products. The method emphasizes the variation around the allowable tolerance margin or design margin instead of the average, leading to optimal experimental designs with the least number of samples analyzed. To validate the analytical method, high-performance liquid chromatography (HPLC) was implemented to determine the accuracy, repeatability, and intermediate precision of low-concentration components. Through validating the analytical method with the traditional validation approach, the method derived by the tolerance-based DOE approach measured the variability more accurately and was able to clarify errant interpretations for selected parameters, which are commonly skewed by average-based calculations. This framework not only ensures the method's fitness-for-use by correctly assessing the variability around the allowable tolerance limits but also assists in making more informed decisions and strengthens the overall quality control process toward consistently producing safe and effective pharmaceutical products. The tolerance-based DOE approach demonstrates significant advancements in this area with regard to low-concentration analysis.
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