(M1030-08-54) ASAPprime®: A Fast-Track Insight to the Stability of Tablets Impacted by Coating

Purpose: ASAPprime® (accelerated stability assessment program) is increasingly used to justify shelf-life assignments without having to wait months for ICH stability testing and results. ASAPprime® utilises modelling of experimental data from high stress conditions to predict shelf-life of products in very short time periods. In most cases, this is approximately 2 weeks.[1] In this case study, API X was formulated in tablets of multiple dose strengths for First in Human (FIH) studies for an oncology indication. Excipient compatibility (EC) studies performed over a 4 week period as a part of formulation development revealed some interaction between API and coating agent. API purity dropped by about 10% for samples stored at 60 °C/75%RH and about 1.5% for samples stored at 60 °C/Ambient RH. It was hypothesised that these observations were largely due to the fact that API and excipient are intimately mixed during excipient compatibility which would not be the case when coating was applied as a thin coat on the tablets. The drug product required coloured coatings of the dose strengths for ease of identification. To test the above hypothesis, tablets were coated and underwent an ASAPprime® study to establish shelf life and storage conditions of the coated and uncoated (core) tablets in an accelerated timeline.

Methods: The ASAPprime® study design was generated using ASAPdesign®, inputting physicochemical data and known stability data of the API. The resulting design was a set-up of 9 storage conditions (range 50-80 °C, 0-79% RH), up to 14 days. The study was performed on tablets: 0.5 mg dose, 100 mg tablet, 0.5% w/w blend, coated (3% weight) and uncoated (core) tablets. Tablets were placed in open vials exposed to saturated salt solutions to generate the desired relative humidity within sealed containers. Tablets were analysed by HPLC to quantify impurities at the designated timepoints. The %area of Impurity A (IMP A) was recorded and imported into ASAPprime® software V6.0.3 for modelling. Values of %area of IMP A >1.5% were excluded from the model, along with conditions which showed either no conversion or excessively high conversion. Target Isoconversion (degradation) was as per the analytical specification: 0.5% area for IMP A. Once a suitable model was established, shelf-life predictions were generated in the desired packaging configuration using ASAPprime® databases for excipients and packaging materials.

Results: The percentage (%) area of IMP A for all storage conditions and timepoints was entered into ASAPprime® software with default model fit parameters. The model linearity and suitability for both coated and uncoated tablets was acceptable. Using the model outputs, IMP A stability was modelled for the tablets in the proposed packaging configuration (HDPE bottles, 1 g silica desiccant) at ICH stability conditions to generate shelf-life predictions. Obtained model parameters and shelf-life predictions are detailed in Table 1. There was a clear difference between the predicted stability of coated and uncoated tablets on long term ICH stability. At 25 °C/60% RH conditions, coated tablets had a 0.44% chance of passing the specification (≤0.5% area of IMP A) at 3 years, whereas uncoated tablets were expected to pass (100%) at the same condition. However, on refrigerated storage, both coated and uncoated tablets were predicted to be acceptably stable. As coated tablets were preferred for clinical use, in order to achieve >2-year shelf life, storage under refrigerated (2-8 °C) condition for the coated tablets was recommended. This data output was achieved within 3 weeks from ASAPprime® study initiation and was used to support IND submission.

Conclusion: The ASAPprime® study clearly demonstrated that coating had a notable impact on the stability of the tablets. This impact was greater than expected and hypothesised at the point of EC studies. Despite their lower stability than the uncoated tablets, coated tablets were still viable with appropriate storage conditions, determined by the model outputs. The study demonstrated the importance of excipient compatibility studies as part of the formulation development process and highlighted the potential impact of inclusion of excipients with sub-optimal EC results into a clinical formulation. Furthermore, the rapid design, set up, analysis and modelling of the ASAPprime® study enabled generation of stability data for a successful IND submission significantly faster than the traditional ICH stability studies.

References: FreeThink Technologies, Inc., “ASAPprime® and ASAPdesign™,” Brandford, 2025

Table 1 - Arrhenius parameters and shelf-life predictions resulting from the ASAPprime model