In situ-forming implants (ISFIs) based on poly(lactic-co-glycolic acid) (PLGA) offer a promising platform for long-acting parenteral drug delivery, enabling minimally invasive administration without surgical implantation. However, the development and clinical translation of PLGA-based ISFIs are hindered by formulation complexity, sensitivity to aterial variability, and limited predictability of drug release, particularly during early implant formation. Although previous reviews have described formulation components and release mechanisms, a comprehensive integration of Quality by Design (QbD) principles with a focus on risk prioritization remains absent. This review examines the application of QbD to solvent-exchange PLGA-based ISFIs, with an emphasis on identifying critical material attributes (CMAs) governing implant formation, burst release, and long-term release performance. Risk-based prioritization of CMAs and the role of design of experiments are systematically discussed. Special attention is given to burst release as a major CMA affecting safety, efficacy, and translational robustness. The evidence indicates that formulation-driven CMAs, such as polymer physicochemical properties, drug characteristics, and solvent selection, exert a greater influence on ISFI performance than process-related parameters. This review provides a structured perspective to support rational formulation design, improved reproducibility, and enhanced clinical translation of PLGA-based ISFI systems.
Campos-Morales et al. (2026) studied this question.