Impact of sample heterogeneity on the evaluation of uncertainty from sampling and analytical steps in pharmaceutical analysis

Measurement uncertainty is a critical factor in the reliability of pharmaceutical analyses, since it directly affects batch acceptance and regulatory compliance. While analytical uncertainty has been extensively studied, uncertainty arising from sampling remains less explored. This study aims to address this gap by evaluating the contributions of sampling and analytical uncertainties to the overall uncertainty for acetaminophen tablets and oral solution. The duplicate method and analysis of variance (ANOVA) were used to assess the uncertainty from sampling and analytical steps. Ten different batches of acetaminophen tablets and oral solution were analyzed, and the combined uncertainties were calculated. For tablets, uncertainty from sampling accounted for 89 % of the overall uncertainty, highlighting the critical role of sample heterogeneity. In contrast, for oral solutions, analytical uncertainty dominated (90 % of the total), reflecting the homogeneous nature of the solution. Considering the uncertainty from sampling can be important to ensure a reduced risk of false acceptance or false rejection, particularly for heterogeneous dosage forms. In conclusion, incorporating sampling uncertainty into uncertainty budgets can significantly improve decision-making in pharmaceutical quality control.