Risk Mitigation of Plunger-Stopper Displacement Under Low Atmospheric Pressure by Establishing Design Space for Filling-Stoppering Process of Prefilled Syringes: A Design of Experiment (DoE) Approach

柱塞 气泡 注射器 大气压力 材料科学 体积热力学 流离失所(心理学) 活塞(光学) 复合材料 机械工程 机械 工程类 光学 物理 气象学 量子力学 心理治疗师 心理学 波前
作者
Shyam B. Mehta,Joseph P. Cook,Wei Liu,Charlene Brisbane
出处
期刊:Journal of Pharmaceutical Sciences [Elsevier BV]
卷期号:111 (7): 2038-2048 被引量:2
标识
DOI:10.1016/j.xphs.2022.01.028
摘要

There is a concern that low atmospheric pressure typically encountered during shipment could result in plunger-stopper displacement in prefilled syringes impacting sterility and container closure integrity (CCI) of drug product.1 In this work, following DoE principles we first investigated the impact of filling and stoppering operating parameters on creation of bubble height as performance parameters among others in nominal 1 mL and 2.25 mL Type I glass prefilled syringes (PFSs) with staked needle and rigid needle shield (RNS). Bubble height ranging from <2.0 mm to >15.0 mm were produced in syringes by filling water and vacuum stoppering at operating vacuum pressure ranging from 400 mbar to 950 mbar using a pilot scale filling-stoppering machine. We found that for a particular nominal fill volume in prefilled syringe, as the stoppering vacuum pressure increased, bubble height decreased resulting in plunger-stopper placed closer to the fill level. Subsequently, syringes with varying bubble size were exposed to reduced atmospheric pressure ranging from 628 Torr to 293 Torr bracketing the low pressure recommended by ASTM D4169 standard to qualify shipping containers for transportation of drug products. We found inverse linear correlation between bubble height and plunger-stopper displacement under low atmospheric pressure. However, plunger-stopper displacement increased exponentially as atmospheric pressure decreased. The results suggest that air bubble size in filled glass syringes should be minimized in order to mitigate sterility and container closure integrity (CCI) risk to drug product in prefilled syringes.
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