Analytical Enabling Capabilities, Analytical Research and Development, Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, NJ, 07033, USA.
Device Development, Pharmaceutical Sciences & Clinical Supply Merck & Co., Inc., 126 E Lincoln Ave, Rahway, NJ,07065, USA.
J Pharm Sci. 2023 Aug;112(8):2203-2211. doi: 10.1016/j.xphs.2023.05.017. Epub 2023 May 25.
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.
预充式注射器（PFS）作为一种主要的注射药物容器，具有许多优势，例如快速给药时间、易于自我给药以及减少给药错误。尽管 PFS 可以为患者带来诸多益处，但玻璃筒上涂覆的硅油已显示出向药物产品中的迁移，这可能会影响颗粒形成和注射器功能。由于硅油的存在，健康当局已敦促产品开发人员更好地了解药物产品在 PFS 中形成颗粒的易感性。在市场上，各种 PFS 供应商提供了多种注射器来源。由于当前供应链短缺以及对商业产品的采购偏好，在开发过程中 PFS 的来源可能会发生变化。此外，健康当局要求建立双重来源。因此，了解不同的注射器来源和配方成分如何影响药物产品质量至关重要。在这里，我们执行了几项设计实验（DOE），重点研究了注射器来源、表面活性剂、蛋白质类型、压力等因素引起的硅油迁移风险。我们利用共振质量测量（RMM）和微流成像（MFI）来表征硅油和蛋白质颗粒在微米和亚微米范围内的分布，以及 ICP-MS 来定量硅含量。在稳定性研究中还监测了蛋白质聚集和 PFS 功能。结果表明，硅油迁移受注射器来源、硅化工艺和表面活性剂（类型和浓度）的影响更大。随着蛋白质浓度和储存温度的升高，所有注射器来源的断裂力和挤出力都显著增加。研究发现蛋白质稳定性受其分子特性的影响，而受硅油存在的影响较小，这与其他文献中的推断相同。本文详细的评估可以彻底优化选择主要容器密封，并降低硅油对药物产品稳定性的影响。
