Prefilled Syringe Injection Force Impact Assessment from Back Pressure: An Approach for Testing Syringe Injectability In Situ vs. In Vitro.

Prefilled syringes are commonly used combination products for parenteral drug and vaccine administration. The characterization of these devices is through functionality testing, such as injection and extrusion force performance. This testing is typically completed by measuring these forces in a nonrepresentative environment (i.e., dispensed in-air) or route of administration conditions. Although injection tissue may not always be feasible or accessible for use, questions from the health authorities make it increasingly important to understand the impact of tissue back pressure on device functionality. Particularly for injectables containing larger volumes and higher viscosities, which can widely impact injection and user experience. This work evaluates a comprehensive, safe, and cost-effective in situ testing model to characterize extrusion force while accounting for the variable range of opposing forces (i.e., back pressure) experienced by the user during injection into live tissue with a novel test configuration. Due to the variability of back pressure presented by human tissue for both subcutaneous and intramuscular injections, tissue back pressure was simulated (0 psi-13.1 psi) using a controlled, pressurized injection system. Testing was conducted across different syringe sizes (2.25 mL, 1.5 mL, and 1.0 mL) and types (Luer lock and stake needle) with two simulated drug product viscosities product (1 cP and 20 cP). Extrusion force was measured using a Texture Analyzer mechanical testing instrument with crosshead speeds of 100 mm/min and 200 mm/min. The results demonstrated that there is a contribution of increasing back pressure on extrusion force across all syringe types, viscosities, and injection speeds that can be predicted using the proposed empirical model. Moreover, this work demonstrated that the factors that largely influence the average and maximum extrusion force during injection are syringe and needle geometries, viscosity, and back pressure. This understanding of the device usability may aid in the development of more robust prefilled syringe designs to minimize use-related risks.

Variables Impacting Silicone Oil Migration and Biologics in Prefilled Syringes.

Prefilled syringes (PFS) as a primary container for parenteral drug products offer significant advantages, such as fast delivery time, ease of self-administration and fewer dosing errors. Despite the benefits that PFS can provide to patients, the silicone oil pre-coated on the glass barrels has shown migration into the drug product, which can impact particle formation and syringe functionality. Health authorities have urged product developers to better understand the susceptibility of drug products to particle formation in PFS due to silicone oil. In the market, there are multiple syringe sources provided by various PFS suppliers. Due to current supply chain shortages and procurement preferences for commercial products, the PFS source may change in the middle of development. Additionally, health authorities require establishing source duality. Therefore, it is crucial to understand how different syringe sources and formulation compositions impact the drug product quality. Here, several design of experiments (DOE) are executed that focus on the risk of silicone oil migration induced by syringe sources, surfactants, protein types, stress, etc. We utilized Resonant Mass Measurement (RMM) and Micro Flow Imaging (MFI) to characterize silicone oil and proteinaceous particle distribution in both micron and submicron size ranges, as well as ICP-MS to quantify silicon content. The protein aggregation and PFS functionality were also monitored in the stability study. The results show that silicone oil migration is impacted more by syringe source, siliconization process and surfactant (type & concentration). The break loose force and extrusion force across all syringe sources increase significantly as protein concentration and storage temperature increase. Protein stability is found to be impacted by its molecular properties and is less impacted by the presence of silicone oil, which is the same inference drawn in other literatures. A detailed evaluation described in this paper enables a thorough and optimal selection of primary container closure and de-risks the impact of silicone oil on drug product stability.