Abstract
Pharmaceutical stability studies are conducted to estimate the shelf life, i.e. the period during which the drug product maintains its identity and stability. In the evaluation of process, regression curve is fitted on the data obtained during the study and the shelf life is determined using the fitted curve. The evaluation process suggested by ICH considers only the case of the true relationship between the measured attribute and time being linear. However, no method is suggested for the practitioner to decide if the linear model is appropriate for their dataset. This is a major problem, as a falsely selected model may distort the estimated shelf life to a great extent, resulting in unreliable quality control. The difficulty of model misspecification detection in stability studies is that very few observations are available. The conventional methods applied for model verification might not be appropriate or efficient due to the small sample size. In this paper, this problem is addressed and some developed methods are proposed to detect model misspecification. The methods can be applied for any process where the regression estimation is performed on independent small samples. Besides stability studies, frequently performed construction of single calibration curves for an analytical measurement is another case where the methods may be applied. It is shown that our methods are statistically appropriate and some of them have high efficiency in the detection of model misspecification when applied in simulated situations which resemble pre-approval and post-approval stability studies.
Highlights
According to the definition of FDA (U.S Food and Drug Administration), shelf life is the period during which a drug product remains suitable for the intended use
It is shown that our methods are statistically appropriate and some of them have high efficiency in the detection of model misspecification when applied in simulated situations which resemble pre-approval and postapproval stability studies
7 Conclusion Pharmaceutical guide Q1E lacks statistical support regarding the detection of model misspecification
Summary
According to the definition of FDA (U.S Food and Drug Administration), shelf life is the period during which a drug product remains suitable for the intended use The length of this period determined during registration of the drug product is referred to as claimed shelf life. It is required for the products from the on-going manufacturing process to have a period of shelf life the same or longer than that of the claimed shelf life. If this requirement is not fulfilled, a deviation procedure must be initialized by the producer company and the root cause is to be found. The ICH Q1A Guide [1] considers pre-approval stability studies only, but the general principles can be and convenient to be applied for on-going stability studies as well
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