Oliva Alexis, Fariña José, Llabrés Matías
Departamento Ingeniería Química y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de La Laguna, La Laguna, Tenerife, Spain.
Drug Dev Ind Pharm. 2003 May;29(5):513-21. doi: 10.1081/ddc-120018640.
The design of a stability study is intended to establish a shelf-life based on testing a limited number of batches of a drug product, which is applicable to all future batches of the drug product manufactured under similar circumstances. In the FDA guidelines for stability testing of new drug products, the matrix design is suggested as the alternative statistical design to the full testing approach. In the last few years, the matrix design has received increasing attention from pharmaceutical companies in order to reduce the cost of stability studies. For this, the full and matrix stability test plans were used on three batches of human insulin pharmaceutical preparation stored under a kinetic mean temperature of 22.7 degrees C for 3 years. The statistical method was suggested by Ruberg and Stegeman (Biometrics, 1991, 47, 1059-1069) and Llabrés et al. (Int. J. Pharm. 2000, 204, 61-68), and was used for comparing batches, and the maximum allowable difference in slopes between batches was used as criteria for estimating a common shelf-life. The results obtained show the conservative nature of the matrix approach, although the difference between the matrix and full shelf-life was less than 1 month. The effect of the matrix method on shelf-life was also studied. The results showed that the model for estimating the shelf-life varied as a function of the permutation used, after testing for both slope and intercept poolability at alpha = 0.25. The batches should be pooled for both full testing and matrix design since the critical significance level required to obtain a power of 0.80 was achieved when the maximum allowable difference in slopes between batches was 1%/month, according to Ruberg and Stegeman. In contrast, when the proposed method by Llabrés et al. was used, the results varied in function of the maximum allowable difference in slopes.
稳定性研究的设计旨在通过对有限批次的药品进行测试来确定有效期，该有效期适用于在类似条件下生产的该药品的所有未来批次。在美国食品药品监督管理局（FDA）关于新药产品稳定性测试的指南中，矩阵设计被建议作为全测试方法的替代统计设计。在过去几年中，矩阵设计为降低稳定性研究成本而受到制药公司越来越多的关注。为此，对三批人胰岛素药物制剂在22.7摄氏度的动力学平均温度下储存3年，采用了全稳定性测试计划和矩阵稳定性测试计划。统计方法由鲁伯格（Ruberg）和斯特格曼（Stegeman）（《生物统计学》，1991年，47卷，1059 - 1069页）以及利亚夫雷斯（Llabrés）等人（《国际药学杂志》，2000年，204卷，61 - 68页）提出，并用于比较批次，批次之间斜率的最大允许差异用作估计通用有效期的标准。所获得的结果显示了矩阵方法的保守性，尽管矩阵有效期与全有效期之间的差异小于1个月。还研究了矩阵方法对有效期的影响。结果表明，在α = 0.25时对斜率和截距合并性进行测试后，估计有效期的模型随所用排列的函数而变化。对于全测试和矩阵设计，批次都应合并，因为根据鲁伯格和斯特格曼的说法，当批次之间斜率的最大允许差异为1%/月时，可达到获得0.80检验效能所需的临界显著性水平。相比之下，当使用利亚夫雷斯等人提出的方法时，结果随斜率的最大允许差异的函数而变化。
