Application of Arrhenius Kinetics to Acceleration of Controlled Extraction Studies

Pharmaceutical drug products are packaged in containers so that they can be manufactured, distributed, and stored. During these events in a drug product's life cycle, the drug product and its packaging could interact, resulting in substances leaching from the plastic and accumulating in the drug product. As the leached substances could adversely impact a key quality attribute of the drug product, drug products must be tested to establish which leachables are present and in what quantities.Because a drug product's lifetime can be long, it is common practice to accelerate leaching by using temperatures higher than clinical use conditions. While use of accelerated conditions is a well-accepted practice, there are questions with respect to the means by which the degree of acceleration can be calculated and justified. In this manuscript, experimental data from 10 case studies are used to evaluate commonly utilized, Arrhenius-based approaches to acceleration, and recommendations are made in terms of the proper approaches to be used for concentration and duration extrapolations. Specifically, when accumulation levels are projected from a clinical to an elevated temperature, the Arrhenius model formulated by ASTM for the accelerated aging of medical devices using a Q10 value of 1.5 most frequently provides the best fit to experimental leaching data. Alternatively, when contact durations are projected from a clinical to an elevated temperature, the Arrhenius model reflected in the empirically derived "factor 10 rule," developed for and applied to food contact packaging, most frequently provides the best fit to experimental leaching data.LAY ABSTRACT: Pharmaceutical drug products are packaged in containers so that they can be manufactured, distributed, and stored. During these events in a drug product's life cycle, the drug product and the plastic systems may interact, resulting in substances leaching from the plastic and accumulating in the drug product. As the leached substances could adversely impact a key quality attribute of the drug product, drug products must be tested to establish what leachables are present and in what quantities.Because a drug product's lifetime can be long, it is common practice to accelerate leaching by using temperatures higher than clinical use conditions. While use of accelerated conditions is a well-accepted practice, there are questions with respect to the means by which the degree of acceleration can be calculated and justified. In this manuscript, experimental data from 10 case studies are used to evaluate commonly utilized approaches to acceleration, and recommendations are made in terms of the proper approaches to be used for concentration and duration extrapolations.