Tsae-Yun Daphne Lin | PubMed Health

PubMed2003

Overview of stability study designs.

Stability requirements for the worldwide registration of pharmaceutical products have changed dramatically in the past few years. A series of guidelines on the design, conduct, and data analysis of stability studies of pharmaceuticals have been published by the International Conference on Harmonization (ICH); however, the statistical discussion on study design is limited. In this paper, stability designs including full, bracketing, and matrixing designs will be exemplified. The statistical aspects of these stability designs will be discussed in relation to the recent ICH guidelines. The statistical and regulatory considerations on the selection of stability design will also be presented. The stability study should be well designed so the shelf life of the drug product can be estimated with a high degree of accuracy and precision. Several commonly used criteria for design comparison will be presented. Finally, a case study is presented to illustrate the potential problems of an overreduced design from the statistical and regulatory perspectives.

Chemistry, Pharmaceutical↗

PubMed2003

Shelf life determination based on equivalence assessment.

In a regular analysis of covariance (ANCOVA) approach to stability analysis, the decision for pooling data from different batches plays a key role in the determination of the shelf life of the drug product. Conventionally, the decision to pool data for the estimate of slope and intercept of common or individual regression lines is made by "no evidence to reject the null hypothesis of no difference." With typically limited observations, a significance level of much higher than 0.05 was recommended for the pooling tests in order to avoid inflation of type-I error rate of the shelf life testing. This logic of the pooling test decision making discouraged the use of replicates to improve power of testing and precision of estimation. The concept of pooling by equivalence test was originally proposed by Ruberg and Hsu in their 1990 article "Multiple comparison procedures for pooling batches in stability studies" Such a concept has evolved to pooling batches based on the shelf life equivalence test by Yoshioka et al. in their 1996 article "Power of analysis of variance for assessing batch-variation of stability data of pharmaceuticals." In this article, an approximation test of shelf life equivalence and a test of chemical value equivalence for the data pooling decision are proposed as an alternative to the conventional ANCOVA approach.

Confidence Intervals↗