Unraveling the complexity of amorphous solid as direct ingredient for conventional oral solid dosage form: The story of Elagolix Sodium.

Conventional solid oral dosage form development is not typically challenged by reliance on an amorphous drug substance as a direct ingredient in the drug product, as this may result in product development hurdles arising from process design and scale-up, control of physical quality attributes, drug product processability and stability. Here, we present the Chemistry, Manufacturing and Controls development journey behind the successful commercialization of an amorphous drug substance, Elagolix Sodium, a first-in-class, orally active gonadotropin-releasing hormone antagonist. The reason behind the lack of crystalline state was assessed via Molecular Dynamics (MD) at the molecular and inter-molecular level, revealing barriers for nucleation due to prevalence of intra-molecular hydrogen bond, repulsive interactions between active pharmaceutical ingredient (API) molecules and strong solvation effects. To provide a foundational basis for the design of the API manufacturing process, we modeled the solvent-induced plasticization behavior experimentally and computationally via MD for insights into molecular mobility. In addition, we applied material science tetrahedron concepts to link API porosity to drug product tablet compressibility. Finally, we designed the API isolation process, incorporating computational fluid dynamics modeling in the design of an impinging jet mixer for precipitation and solvent-dependent glass transition relationships in the cake wash, blow-down and drying process, to enable the consistent manufacture of a porous, non-sintered amorphous API powder that is suitable for robust drug product manufacturing.

Control Strategies for Drug Product Continuous Direct Compression-State of Control, Product Collection Strategies, and Startup/Shutdown Operations for the Production of Clinical Trial Materials and Commercial Products.

Continuous manufacturing (CM) has emerged in the pharmaceutical industry as a paradigm shift with significant advantages related to cost, efficiency, flexibility, and higher assurance of quality. The inherent differences from batch processes justify examining the CM control strategy more holistically. This article describes the current thinking for the control and implementation of CM, using the example of a direct compression process and taking into consideration the ICH Q10 definition of "state of control" and process validation requirements. Statistical process control using control charts, sources of variation, process capability, and process performance is explained as a useful concept that can help assess the impact of variation within a batch and indicates if a process is in state of control. The potential for time-variant nature of startup and shutdown with CM is discussed to assure product quality while minimizing waste as well as different options for detection and isolation of non-conforming materials due to process upsets. While different levels of control are possible with CM, an appropriate balance between process control and end product testing is needed depending on the level of process understanding at the different stages of development from the production of clinical supplies through commercialization.