(725c) In-Depth Mechanistic Understanding of Pibrentasvir Agglomeration to Enable Successful Scale-up

Physical properties of active pharmaceutical ingredients (APIs), such as the particle size distribution (PSD) and extent of agglomeration, often impact downstream drug product processes. Strategies utilized to isolate the API, namely the crystallization, filtration, and drying unit operations, must be designed to ensure consistency in the resultant API physical properties. Development and deployment of non-traditional isolation strategies, for an API prone to agglomerate formation, is often necessary to ensure that the API meets the acceptance criteria for PSD.

In this presentation, we will describe the strategies utilized to develop the API isolation for pibrentasvir, a non-nucleoside inhibitor of the hepatitis C virus NS5A replicon. While the pibrentasvir crystallization consistently yielded non-agglomerated material, drying in the agitated filter dryer resulted in agglomerates on the order of 10 to several 100 μm, with varying degree of agglomerate strength as a result of agitation in the presence of residual solvent. In this presentation, we will discuss a mechanistic understanding of the parameters that impact the extent of agglomeration of pibrentasvir and methods for quantifying the strength of the resulting agglomerates. To address agglomeration, the use of non-traditional isolation strategies were employed to ensure significant removal of the residual solvent and prevent the formation of agglomerates through crystalline bridges. This work demonstrates a systematic approach for understanding the formation and characterization of API agglomerates and provides a novel approach to address agglomeration in an agitated filter dryer. Successful deployment of the isolation strategy enabled scale-up of the drying process to yield API that met the acceptance criteria for PSD.

All authors are employees of AbbVie and may own AbbVie stock. AbbVie and Enanta sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.