(550g) Navigating API Particle Morphology Challenges to Streamline Continuous Drug Product Manufacturing

In the pioneering work “On the Equilibrium of Heterogeneous Substances”, Prof. J.W. Gibbs, provided, for the first time, a description of the general rules determining the morphology of a growing crystal stating that: “The shape of a crystal or the form of a crystal is determined by the mode of growth”, while he, already notes that “ In many cases, the shape of a particle is intimately connected with its function or utility in a particular application or process."

Nowadays, 150 years after the publication of Gibbs’ seminal work, the reconciliation of crystallisation, a process with dual purification and particle engineering function, with downstream, drug product manufacturing processes, becomes increasingly important, in the biopharmaceutical industry. The need for continuous and dry drug product (DP) processing gets momentum, thanks to business and scientific considerations. The hitherto published literature, along with the accumulated experience within the community, highlights that having Active Pharmaceutical Ingredient (API) particles with the right particle characteristics is paramount for the development of any continuous dry DP process operation.

Targeting the desired particle morphology, with an industrially relevant way, stands as out as a conundrum in the pharmaceutical crystallisation community. A growing number of APIs appears to exhibit persistent needle behaviour. Identifying early on, during the development of an API, the potential morphologies, the API can assume, and the available particle morphology levers emerges as a critical capability for API isolation process development and de-risking.

UCB’s crystallisation development workflow addresses this challenge, through the CrystalGrower platform. The deployment of this in-silico tool allowed us to screen the morphologies of our APIs at different crystal growth conditions (solvents, temperatures, supersaturation profiles). As the main input is only the crystal structure of the API, this tool can be deployed early in the development workflow. This is quite groundbreaking, it allows the project team to decide, from the Ph I of the clinical development, the most suitable particle engineering strategy, identify crystallisation solvents of particular interest for particle morphology control and even to predict whether secondary particle modifications are necessary to tailor the particle properties. In this framework, the particle morphology toolbox synergises with other tools from the crystallisation development workflow, such as the solubility prediction app and miniaturised screening platforms, such as the Crystalline. The results to be presented come from two on-going therapeutic projects demonstrating the flexibility gained by the introduction of a robust particle morphology prediction framework.