Comparing designs for stability studies and shelf life estimation for drug product with multiple components

For every drug product on the market, the United States Food and Drug Administration (FDA) requires that the expiration dating period must be indicated in immediate container label. The stability studies are usually conducted to characterize the degradation of the drug product and establish the drug expiration dating period. In this thesis, several practical issues that are commonly encountered in design and analysis of stability studies are examined. Firstly, the performances of two reduced stability designs, bracketing and matrixing designs, are compared in terms of their powers for detection of a scientifically meaningful difference between the rate of stability loss (i.e., slope) and the precision of the estimated drug expiration dating. It is shown that the bracketing design is better than matrixing design for the usually encountered ranges of the unknown parameters in study. Secondly, the distributions of shelf lives among FDA's full sampling plan, bracketing design, and matrixing design for a drug product with either one or two ingredients (components) are examined. It is concluded that both reduced designs, bracketing and matrixing, have no difference in distribution of drug shelf life to the FDA's sampling plan. In recent years, statistical methods for estimation of expiration date of drug products with a single active ingredient are well established. In practice many drug products contain more than one active ingredient. There is no discussion regarding the statistical method for determining the expiration dating period for dug products with multiple active ingredients in both the ICH and the FDA stability guidelines. A typical approach is to consider the minimum of expiration dating periods of individual ingredients as the labeled expiration dating period of the drug product. However, this approach is not only too conservative but also lacks statistical or scientific justification. In addition, the minimum approach may lead to a relatively short expiration dating of little practical interest. The third goal of this thesis is to propose a method for determination of a single shelf life for multiple ingredients, which was derived by minimizing the variability associated with each ingredient for a better statistical justification.