Evaluating Current Practices in Shelf Life Estimation.

The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) methods for determining the supported shelf life of a drug product, described in ICH guidance documents Q1A and Q1E, are evaluated in this paper. To support this evaluation, an industry data set is used which is comprised of 26 individual stability batches of a common drug product where most batches are measured over a 24 month storage period. Using randomly sampled sets of 3 or 6 batches from the industry data set, the current ICH methods are assessed from three perspectives. First, the distributional properties of the supported shelf lives are summarized and compared to the distributional properties of the true shelf lives associated with the industry data set, assuming the industry data set represents a finite population of drug product batches for discussion purposes. Second, the results of the ICH "poolability" tests for model selection are summarized and the separate shelf life distributions from the possible alternative models are compared. Finally, the ICH methods are evaluated in terms of their ability to manage risk. Shelf life estimates that are too long result in an unacceptable percentage of nonconforming batches at expiry while those that are too short put the manufacturer at risk of possibly having to prematurely discard safe and efficacious drug product. Based on the analysis of the industry data set, the ICH-recommended approach did not produce supported shelf lives that effectively managed risk. Alternative approaches are required.

On the shelf life of pharmaceutical products.

This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of "product" on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf life-a Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute.