Safety Study of Extractables of Non-Polyvinyl Chloride Soft Infusion Bags from Different Batches by Analytical Assessment Threshold Screening

The safety studies of large-volume parenteral (LVP) containers still have many challenges because of the low concentration of migrating substances, the presence of degradation products, and the paucity of available toxicity data. Among all the problems, the stability of different batches is of great importance because it may lead to variations in extractables, posing a potential risk to the patients. In this paper, extractables from different batches of non-polyvinyl chloride (PVC) soft bags exposed to three extractants were analyzed by ultra high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Principal component analysis, heatmap, and hierarchical cluster analysis were employed to observe the differences in extractables among the batches. Finally, risk assessment and in vitro cytotoxicity tests were carried out for compatibility evaluation. The results show that 28 extractables were efficiently screened out and semi-quantified with the analytical evaluation threshold (AET) developed from 25 diverse polymer additives. Among them, the concentrations of 2 extractables exceeded the safety thresholds, indicating the need for further studies on the leachables to verify their compatibility with drugs. In addition, there was no significant difference in the concentrations of most extractables among batches, however, there were batch-to-batch differences in the levels of some extractables. In particular, 1,3-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-1,3,5-triazinane-2,4,6-trione which was only present in three batches exceeded the safety threshold. This study offers technical assistance for the stability study of extractables in batches and their safety assessments in LVP containers and other pharmaceutical packaging.