A Holistic Approach for Fill volume Variability Evaluation and Control with Statistical Tool.

Quanmin Chen, Qingqing She, Zhaowei Jin, Mingyang Hei, Chunmeng Sun, Jiasheng Tu, Jeremy Guo
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Abstract

Vial and syringe filling by peristaltic pump has been widely implemented by contract manufacturing organizations and biopharmaceutical companies. Fill volume is commonly considered as critical quality attribute related in aseptic filling process and the variation needs to be well controlled to guarantee the safety, efficacy and consistency of drug products. However, the criteria for justifying the filling variation and underlying mechanisms that affect the variability are not fully revealed quantitatively in the literatures. This study selected filling accuracy, filling process capability and filling precision as three criteria for evaluating the filling process performance with four statistical indexes: Relative Error Mean, Critical Control Limit (Cpk ≥ 1.33), Relative Standard Deviation and Relative Moving Range Mean. The impact of liquid properties, pump tubing sizes and pump settings on above indexes were investigated using a bench-top system with a peristatic pump and a high-precision balance. The results showed that the viscosity, target fill volume, pump tubing size, pump speed, acceleration/deceleration rate and suck-back had statistical significance on the fill volume variability. Definitive Screening Design was further applied to clarify and visualize the priorities and interaction impact of above factors on fill volume variability. Stepwise approach for fill volume variability optimization and control based on predictive models was established and verified for drug product solution with viscosity between 1-23 cp and target fill volume between 0.2-2.0 mL.

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利用统计工具评估和控制填充量变异性的整体方法。
合同生产组织和生物制药公司已广泛采用蠕动泵进行小瓶和注射器灌装。灌装量通常被认为是无菌灌装过程中的关键质量属性,需要对其变化进行良好控制,以保证药物产品的安全性、有效性和一致性。然而,灌装变异的合理性标准和影响变异的潜在机制并未在文献中得到充分的定量揭示。本研究选择了灌装准确度、灌装工艺能力和灌装精度作为评价灌装工艺性能的三个标准,并采用了四个统计指标:相对误差均值、临界控制限(Cpk ≥ 1.33)、相对标准偏差和相对移动范围均值。使用配备蠕动泵和高精度天平的台式系统研究了液体特性、泵管尺寸和泵设置对上述指标的影响。结果表明,粘度、目标填充量、泵管尺寸、泵速、加速/减速率和回吸对填充量的变化具有统计学意义。我们还进一步采用了确定性筛选设计,以明确和直观地显示上述因素对填充体积变化的优先影响和交互影响。针对粘度在 1-23 cp 之间、目标填充体积在 0.2-2.0 mL 之间的药物产品溶液,建立并验证了基于预测模型的填充体积变化优化和控制的逐步方法。
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来源期刊
CiteScore
1.90
自引率
0.00%
发文量
34
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