Study of extractables and leachables of non‐polyvinyl chloride soft infusion bags from different batches by analytical assessment threshold screening

Abstract

AbstractThis study utilized ultra‐high‐performance liquid chromatography combined with quadrupole time‐of‐flight mass spectrometry and gas chromatography–mass spectrometry techniques to analyze multiple batches of non‐polyvinyl chloride (PVC) soft bags exposed to three extractants. Based on an established library of relative response factors for more than 30 different polymer additives, analytical evaluation thresholds for large volume injectables were determined, and 30 extractables were screened and (semi‐)quantitatively analyzed. To identify variations in extractables between batches, multivariate statistical methods such as principal component analysis, heat map analysis, and hierarchical cluster analysis were employed. Additionally, a comprehensive risk assessment of extractables and a biosafety assessment of leachables were conducted. The results of the study revealed that the concentrations of two extractables exceeded the established safety threshold. Moreover, one of these extractables was deemed to pose a mutagenic risk based on the consistent findings of two (Q)SAR software tools. Notably, certain extractables exhibited discrepancies in their content between batches, with particular emphasis on 1,3‐bis(3,5‐di‐tert‐butyl‐4‐hydroxybenzyl)‐1,3,5‐triazinane‐2,4,6‐trione. This discrepancy led to inconsistencies in risk levels across batches. However, the levels of leachables detected in the non‐PVC soft bags were found to be within the safety threshold, and cytotoxicity assessments consistently yielded negative results for leachables. Consequently, this study provides valuable data for conducting batch stability investigations concerning extractables in large volume parenteral drug delivery containers and other forms of pharmaceutical packaging.