MEASUREMENT UNCERTAINTY EVALUATION FROM ANALYTICAL PROCEDURES VALIDATION DATA

• Grant number: 24/22682-0
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal Investigator: Felipe Rebello Lourenço
• Grantee: Felipe Rebello Lourenço
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Decision-making regarding the quality of pharmaceuticals is typically based on measurements taken from a sample of the drug batch using validated analytical methods. Despite efforts to ensure the reliability of these measurements, including the validation of analytical methods, there will always be some degree of uncertainty associated with the measured value. Measurement uncertainty can be assessed using the bottom-up approach (a detailed and labor-intensive evaluation of uncertainty in each analytical stage) or the top-down approach (a pragmatic and simplified evaluation, usually based on analytical method validation data). Despite the advantages of the top-down approach, the final uncertainty assessment obtained may be overestimated (due to significantly different recovery from the expected value) or underestimated (as sampling uncertainty can be significant and is usually not assessed during analytical method validation), which can affect decision-making regarding conformity (or non-conformity). This project aims to propose improvements in the top-down measurement uncertainty assessment, including: 1) evaluating the impact of the analytical method validation protocol on uncertainty assessment and the contribution of accuracy and precision components; 2) proposing a measurement uncertainty model with an asymmetric confidence interval as an alternative to current models; 3) proposing an analytical method validation protocol that includes the sampling stage and evaluating its impact on measurement uncertainty; 4) proposing procedures for evaluating correlations between measured values due to shared method validation and sampling stages; 5) proposing procedures for defining asymmetric guard bands (univariate and multivariate), including sampling uncertainty; and 6) propose a protocol for the validation of analytical methods in the context of the AQbD. Chromatographic (HPLC), spectrophotometric (UV-Vis), dissolution tests, particulate matter tests in injectables, microbial count tests, among other methods applicable to the analysis of solid, semi-solid, liquid, sterile, and non-sterile pharmaceutical forms, will be the focus of the study. The expected results from this project have the potential to generate academic, social, economic, environmental, and health impacts, and are aligned with various sustainable development goals (SDGs) of the United Nations 2030 agenda. (AU)