Evaluation and characterization of different extraction methods for obtaining extractable and leachable materials from rubber stopper systems used in pharmaceutical products

Abstract

Bromobutyl rubber stoppers are widely used in the primary packaging systems of many different drug products. However, different additives are added to provide the existing properties of these synthetic elastomeric stoppers. The most important additives are curing agents, activators, plasticizers, fillers, antioxidants and accelerators. However, these components are not covalently bonded to the polymer chains and have the potential to leach from the rubber stopper material to the drug product during its shelf life. Therefore, since they may adversely affect the product’s safety, efficacy and stability, they should be identified and monitored through extractable studies. In addition, regulatory authorities such as the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) require the submission of Extractables and Leachables (E&L) information to examine the risks. For this purpose, E&L originating from bromobutyl rubber stoppers was examined within the scope of the study. Two different sample preparation methods were used to extract volatile, semi-volatile and non-volatile components at the highest level. The microwave assisted extraction methods, which are relatively widely used and provide faster and less solvent consumption than Soxhlet and also provide longer and continuous contact with the packaging matrix, were compared with the conventional Soxhlet extraction method. The results show that the number of components obtained by microwave assisted extraction method is higher. In addition, different solvent environments (IPA + water, pH 3.5 solution and pH 9.5 solution) were used to expose the matrix to extreme conditions to obtain non-volatile components. The extractable components obtained were identified by using the library databases of the relevant gas chromatography-Mass Spectrometry (GC–MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF) analytical devices. Elemental impurities were quantitatively determined by inductively coupled plasma mass spectrometry (ICP-MS) and evaluated within the scope of possible additives. In addition, six different drug product formulations using bromobutyl rubber stoppers in container-lid systems were investigated within the scope of leachable studies. The results show that the presented methodology is successful in the E&L analysis of different therapeutic products. Moreover, it is adaptable to the analysis of different primary packaging products to ensure product quality and patient safety, while also offering a new approach to E&L analysis for both the literature and the pharmaceutical industry.