PLGA/PLA-Based Long-Acting Injectable Depot Microspheres in Clinical Use: Production and Characterization Overview for Protein/Peptide Delivery.

Over the past few decades, long acting injectable (LAI) depots of polylactide-co-glycolide (PLGA) or polylactic acid (PLA) based microspheres have been developed for controlled drug delivery to reduce dosing frequency and to improve the therapeutic effects. Biopharmaceuticals such as proteins and peptides are encapsulated in the microspheres to increase their bioavailability and provide a long release period (days or months) with constant drug plasma concentration. The biodegradable and biocompatible properties of PLGA/PLA polymers, including but not limited to molecular weight, end group, lactide to glycolide ratio, and minor manufacturing changes, could greatly affect the quality attributes of microsphere formulations such as release profile, size, encapsulation efficiency, and bioactivity of biopharmaceuticals. Besides, the encapsulated proteins/peptides are susceptible to harsh processing conditions associated with microsphere fabrication methods, including exposure to organic solvent, shear stress, and temperature fluctuations. The protein/peptide containing LAI microspheres in clinical use is typically prepared by double emulsion, coacervation, and spray drying techniques. The purpose of this review is to provide an overview of the formulation attributes and conventional manufacturing techniques of LAI microspheres that are currently in clinical use for protein/peptides. Furthermore, the physicochemical characteristics of the microsphere formulations are deliberated.

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.