Extractables Screening of Polypropylene Resins Used in Pharmaceutical Packaging for Safety Hazards

Abstract

Pharmaceutical products are packaged in containers so that they can be manufactured, distributed, and used. Because extractables from such containers are precursors of leachable impurities in the product, extractables represent potential hazards to user safety. Polypropylene resins are frequently used as materials of construction for packaging of liquid parenteral drug products. Thus, extractables profiling of polypropylene resins may be an effective means of hazard identification associated with the resin's safe use. Twenty-one polypropylene resins were extracted using aqueous and organic extraction solvents, and the resulting extracts were screened for extractables using appropriate general chemistry, chromatographic, and spectroscopic methodologies. The resulting extractables profiles were toxicologically reviewed by a defined process to identify potential hazards given a specified therapeutic application involving long-term use of a large-volume aqueous parenteral drug product. The organic extractables profiles of individual polypropylene resins were variable in terms of the individual extractable identified and their extracted levels, consistent with high variability in polypropylene resin formulations and pharmaceutical product manufacturing. However, the profiles were similar in terms of the groups of extractables measured. Thus, for example, all the resins had extractables associated with antioxidants, as all the resins contained antioxidants but the specific extractables for a given resin depended on the specific antioxidants present in that resin. Few of the targeted extractable elements were present in the extracts at measurable levels, although most resins had measurable levels of extracted aluminum, silicon, and alkali and alkaline earths. A worst-case extractables profile (all the extractables measured in individual resins at their highest levels) was toxicologically reviewed considering an aqueous large-volume parenteral drug product. This review established certain extractables as potential hazards whose actual toxicological safety risk assessment would require more rigorous data and a more rigorous process than those used for hazard identification.

LAY ABSTRACT: Packages used to contain aqueous parenteral drug products may be made of polypropylene. During storage, extractables from the polypropylene may leach out of the container and accumulate in the drug product, where they could affect product quality and/or safety. In this study, 21 polypropylene resins were characterized with respect to their organic and elemental extractables profiles. A worst-case extractables profile (highest level of all the extractables identified) was toxicologically assessed to establish potentially hazardous extractables. Certain extractables were established as potential hazards whose actual toxicological safety risk assessment would require more rigorous data and a more rigorous process than those used for hazard identification.