(172f) Advancements of Accelerated Stability Studies and Modeling through Use of Nonlinear Kinetics and Bootstrapping

“ASAP Studies” are accelerated stability studies, which use modelling in order to predict the stability of compounds, blends and products at long term storage conditions.  The ASAP approach provides significant benefits in science based decision making throughout drug substance and drug product development.

  ASAP Studies are used throughout the pharmaceutical industry and have had significant exposure to regulatory agencies across the globe.  The concept is proposed as an improvement on current working practices for assigning retest periods for intermediates and starting materials.  Traditionally, materials are stored at 50/amb for 1 month in order to assign a 6 month retest period. In contrast, ASAP experiments are typically carried out over 2-3 weeks at temperatures up to 80°C and relative humidities up to 90%. The study can often be completed, including data analysis in the space of 3 working weeks, and the information gathered and learning made in this time period can rival years of traditional analysis.  The speed of the studies allows an earlier assessment of risk to quality enabling appropriate risk mitigation strategies to be implemented in a timely manner. 

  The modeling has been fully automated using JMP scripting in GSK’s ASAP development.   The scientific foundation is based upon Arrhenius kinetic equations that can be linear or nonlinear in time, and can be based upon water vapor pressure or liquid water activity (relative humidity).  A variety of kinetic models are evaluated, and the best model is chosen based upon both Bayesian Information criteria and an automated assessment of kinetic model parameters fitting within acceptable ranges.   Confidence intervals are estimated based upon a bootstrapping approach.       

  Moisture vapour transmission rate (MVTR) models are applied on top of the resulting kinetic models in order to simulate different packaging types, and use of desiccant.  The kinetic models are integrated with the prediction of packaging humidity over time to create a long term prediction of impurities and other phenomena.  Control strategies can be developed by evaluating the effect of packaging and desiccant.

  The resulting models have been shown to be useful for not only prediction of drug product impurities in long term storage, but other physical phenomena as well such as solvate loss, salt disproportionation and subsequent crystallization of a free acid in a drug product, increased disintegration time of a rapid release tablet, and increased dissolution time of a stick pack product.