(654f) A Holistic Predictive Materials Science Tetrahedron (MST) Approach in Long-Acting Injectable Suspensions Development

One of the approaches for manufacturing long acting injectable (LAI) suspensions is by wet bead milling, which reduces the particle size of API crystals in a liquid vehicle via grinding. A common failure mode observed during this “top-down” high energy process is long milling time to get to target particle size distribution. In order to avoid this failure mode, APIs with appropriate mechanical and physicochemical properties are needed to render the final suspension product in a feasible time. An early evaluation of the suitability of API is necessary to prevent delays in project timelines and accelerate the project progress. However, this may not be possible without an in-depth materials science tetrahedron (MST) approach, which connects the structure, properties, processing, and performance of an API. The MST approach leverages materials structure analysis and materials sparing tests, not only does it enable process development in a shorter time but also using less API and fewer experiments. Materials structure analysis and characterization reveal the properties of the material leading to choose the suitable form of the crystal earlier in the product development. Linking structures and properties to the process renders an appropriate manufacturing step and help establishing a robust control strategy at scale-up for consistent performance. In this study, compaction-based techniques and relevant analyses were used to measure the properties of APIs and correlate those to APIs’ milling time as observed experimentally. Compaction simulator was used as a material sparing tool to develop a novel method of measuring Young’s modulus at the bulk powder level. Bulk Young’s modulus results explained the differences observed in the milling time span between different assets. Although the parameters directly impacting milling time were different some of the runs, a clear consistency was observed between the API’s Young’s Modulus and the time needed to achieve target size distribution, showing that Young’s Modulus at bulk powder level is a good predictor for milling time. At all levels of drug product development, particularly during late-stage large-scale manufacturing, milling time span should be feasible to accommodate plants’ operational capability, prevent bioburden risks, and other lengthy process time-related concerns. This mechanical characteristic can also be used to monitor lot to lot variability. In summary, the interdependency between crystal structure, properties, processing, and performance was studied. It is demonstrated that a systematic implementation of the MST approach would give us insight into the feasibility of wet bead milling unit operation at larger scales as well as expedite product development with limited amount of API and in compressed timelines.