Lyophilization of Small-Molecule Injectables: an Industry Perspective on Formulation Development, Process Optimization, Scale-Up Challenges, and Drug Product Quality Attributes

Lyophilization is a pivotal manufacturing process to obtain a stable drug product that is unstable as a ready-to-use formulation. Some formulations may require the addition of drug-specific excipients such as stabilizers, buffers, and bulking agents to support the cake appearance and ensure long-term stability of the drug product. Optimization of the lyophilization process parameters at each stage including freezing and primary and secondary drying is important because these parameters can have a direct impact on the process efficiency (shortened cycle time) and product performance (cake appearance and homogeneous moisture content). Several parameters of the formulation, including properties of the active pharmaceutical ingredient, excipients, solvent system, and container closure, determine the success of lyophilization. Development, scale-up, and transfer of the lyophilization cycle are challenging; hence, a comprehensive understanding of the critical parameters related to the formulation, lyophilization process, and lyophilizer design allows designing a quality drug product. One approach for a successful transfer of the lyophilization cycle between the laboratory and commercial-scale lyophilizer is using vial heat transfer coefficient and ice slab test to establish a maximum sublimation rate. This review provides a general overview of the lyophilization process and discusses several key considerations and product development aspects of formulation, process optimization, container closure system, scale-up principles, and drug product quality attributes from the industrial viewpoint. Grapical abstract.