Fan Zhewen, Zhang Lanju
a PNC Bank , Pittsburgh , Pennsylvania , USA.
J Biopharm Stat. 2015;25(2):307-16. doi: 10.1080/10543406.2014.972743.
One of the most challenging aspects of the pharmaceutical development is the demonstration and estimation of chemical stability. It is imperative that pharmaceutical products be stable for two or more years. Long-term stability studies are required to support such shelf life claim at registration. However, during drug development to facilitate formulation and dosage form selection, an accelerated stability study with stressed storage condition is preferred to quickly obtain a good prediction of shelf life under ambient storage conditions. Such a prediction typically uses Arrhenius equation that describes relationship between degradation rate and temperature (and humidity). Existing methods usually rely on the assumption of normality of the errors. In addition, shelf life projection is usually based on confidence band of a regression line. However, the coverage probability of a method is often overlooked or under-reported. In this paper, we introduce two nonparametric bootstrap procedures for shelf life estimation based on accelerated stability testing, and compare them with a one-stage nonlinear Arrhenius prediction model. Our simulation results demonstrate that one-stage nonlinear Arrhenius method has significant lower coverage than nominal levels. Our bootstrap method gave better coverage and led to a shelf life prediction closer to that based on long-term stability data.
药物研发中最具挑战性的方面之一是化学稳定性的论证和评估。药品必须稳定两年或更长时间，这至关重要。注册时需要进行长期稳定性研究来支持此类保质期声明。然而，在药物研发过程中，为便于制剂和剂型选择，在加速储存条件下进行加速稳定性研究更可取，以便快速获得在环境储存条件下保质期的良好预测。这种预测通常使用描述降解速率与温度（和湿度）之间关系的阿伦尼乌斯方程。现有方法通常依赖于误差正态性的假设。此外，保质期预测通常基于回归线的置信带。然而，一种方法的覆盖概率常常被忽视或报告不足。在本文中，我们介绍了两种基于加速稳定性测试的保质期估计的非参数自助法程序，并将它们与单阶段非线性阿伦尼乌斯预测模型进行比较。我们的模拟结果表明，单阶段非线性阿伦尼乌斯方法的覆盖范围明显低于标称水平。我们的自助法给出了更好的覆盖范围，并得出了更接近基于长期稳定性数据的保质期预测。
