Formation and degradation process of in situ forming implants - Attributes and impact on performance

In situ forming implants (ISFIs) are long-acting drug delivery systems that solidify upon administration to enable sustained release of therapeutics. They are administered by a minimally invasive injection, have adjustable release duration up to six-months or longer, enable localized delivery, and are easier to manufacture compared with other modalities of long-acting injectables (LAIs). Despite clinical successes with several FDA-approved products in the last three decades, ISFIs remain challenging to develop due to complexity of the formulation and fundamental understanding of drug release mechanism. This review summarizes the status of ISFI technology and highlights advances in technical understanding with a focus on translation to drug products. It provides the first review on the formation and degradation processes of ISFIs, including the interplay of solvent exchange, polymer attributes, and drug physicochemical properties in shaping burst release, diffusion-driven release, and degradation-mediated release phases. Beyond the discussion of attributes, the morphology and inner structure change along with the implant formation and degradation is first reviewed. We summarize characterization tools-such as electron microscopy, MRI, CT, ultrasound, and spectroscopy-that provide mechanistic insights into implant morphology, microenvironmental changes, and drug deposition. Emphasis is placed on how these mechanistic understanding can inform critical quality attributes, improve in vitro-in vivo correlations, and support the development of drug products. Collectively, the knowledge presented will be instructive to understand the formation and degradation process of ISFI, further facilitating the development of ISFI products.