Purification Development, Genentech Inc, 1 DNA Way, South San Francisco, California, 94080, USA.
Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
Pharm Res. 2020 Oct 7;37(11):216. doi: 10.1007/s11095-020-02936-3.
Polysorbate 20 (PS20), a commonly used surfactant in biopharmaceutical formulations, can undergo hydrolytic degradation resulting in free fatty acids (FFAs) that precipitate to form particles. This work investigates the ability for silicone oil (si-oil) coated on the interior walls of prefilled syringes (PFSs) to act as a sink for FFAs and potentially delay FFA particle formation.
Myristic acid distribution coefficient was measured in a two-phase system containing si-oil and formulation buffer at a range of aqueous conditions. An empirical model was built from these data to predict distribution coefficient based on aqueous conditions. To verify the model, PS20 was degraded using model lipases side-by-side in glass vials and PFSs while monitoring sub-visible particles.
The empirical model demonstrates that the partitioning of myristic acid into si-oil is maximized at low pH and low PS20 concentration. The model predicts that the presence of si-oil at levels typical in PFSs provides at most an 8.5% increase in the total carrying capacity for myristic acid compared to a non-coated glass vial. The time to onset of FFA particles was equivalent between degradations performed in two PFS models coated with differing levels of silicone oil and in non-coated glass vials.
Herein, we demonstrate that FFAs partition from aqueous solution into si-oil. However, the extent of the partitioning effect is not large enough to delay PS20-related FFA particle formation at typical formulation conditions (pH 5.0-7.5, 0.01% - 0.1% w/v PS20) filled in typical PFSs (<1.0 mg si-oil/mL aqueous fill).
聚山梨酯 20（PS20）是生物制药制剂中常用的表面活性剂，可发生水解降解，生成游离脂肪酸（FFA）并沉淀形成颗粒。本研究考察了硅油（si-oil）涂覆于预充式注射器（PFS）内壁的能力，即作为 FFA 的收容所，并可能延迟 FFA 颗粒形成。
在包含 si-oil 和制剂缓冲液的两相体系中，测量豆蔻酸分配系数，考察在一系列水相条件下的分配系数。根据这些数据建立经验模型，基于水相条件预测分配系数。为了验证模型，采用模型脂肪酶在玻璃小瓶和 PFS 中同时降解 PS20，同时监测亚可见颗粒。
经验模型表明，在低 pH 和低 PS20 浓度下，豆蔻酸分配到 si-oil 中的分配系数最大。该模型预测，与非涂覆玻璃小瓶相比，在 PFS 中典型水平下存在 si-oil 最多可使豆蔻酸的总承载能力增加 8.5%。在两种涂覆不同水平硅油的 PFS 模型和非涂覆玻璃小瓶中进行的降解实验中，FFA 颗粒出现的时间相同。
本研究表明，FFA 从水相分配到 si-oil 中。然而，分配效应的程度不足以在典型制剂条件（pH 5.0-7.5，0.01%-0.1%w/v PS20）下延迟 PS20 相关 FFA 颗粒形成，典型 PFS 中的填充量（<1.0mg si-oil/mL 水填充量）。
