(M1230-01-07) Does Elastomer QbD Approach Benefit the E&L Risk Profile for Drug Compatibility? A Comparative Leachables Simulation Study at 12M for Stoppers

Purpose: Ensuring that a drug product is safe and effective includes selecting a container closure system that will not significantly interact with the drug nor contribute adversely to the patient. West developed a lyophilization stopper using Quality by Design (QbD) principles, which entails carefully selecting and characterizing raw material ingredients and processing steps to reduce the risk associated with leachables from the container closure. This poster summarizes the fit-for-purpose drug lyophilization simulation 12-month leachables data and demonstrates how extractables translate to leachables for the stopper developed utilizing QbD, as well as two comparator stoppers comprised of different elastomer formulations. Information is included which outlines the impact of QbD and raw material selection in early development on volatile, semi-volatile, and non-volatile extractable and leachable data, as well as the test methodology and study controls.

Methods: Long term stability testing was performed on West's leading chlorobutyl (4432), bromobutyl (4023), and newly developed chlorobutyl (4040) lyo stoppers assembled with a 20mL American Blowback (ABB) tubular glass vial and simulated lyophilized drug product. The stoppers contain a film on the top of the stopper to prevent sticking to the lyo shelves, as well as a B2-Coating on the drug contact side. All components were steam sterilized for 60 minutes at 121°C and provided in ready-to-use, or RU, format. A single test method could not provide a full extractable and leachable profile for non-volatile, semi-volatile, and volatile compounds. In order to understand the leachable profile, three screening qualitative methods were used to analyze the extracted samples: LC/DAD/MS, GC/MS direct injection, and GC/MS headspace. This poster presents the data from the reconstituted cakes and assembled vial with the cake from the 0, 1, 6, and 12 month time points where compounds were found above the detection limit. More information will be provided regarding the simulated lyo cake, test structure, and controls.

Results: The results quantifying the non-volatile, semi-volatile, and volatile leachables compounds that were detected over time show trends for each stopper configuration. GC/MS HS analysis results comparing volatile leachables from the 4040 lyo stopper to the comparator chlorobutyl and bromobutyl stoppers are captured in Figure X. Non-volatile and semi-volatile compounds detected through GC/MS DI and LC/MS will also be presented. The graphs show the importance of evaluating multiple time points over the shelf-life of a drug product, as different chemical species migrate at different times and varying levels after assembly.

Conclusion: This fit-for-purpose simulation study exemplifies what happens under real world conditions. Fewer leachable compounds were detected, and at reduced concentrations, in the lyo cakes when using the 4040/stoppers compared to the the 4432 chlorobutyl and 4023 bromobutyl formulations tested after storage at 25°C/60% RH for 12M. Because of the lowest risk E&L profile, the 4040 stopper provides users with a broad drug compatibility option which aids in the stability of their product. The results of this study were as expected and reinforce that deliberate raw material selection and QbD approach reduces risk from an E&L perspective.

Figure X: Volatile Leachable Profile Over Time