PH-mediated drug-drug interactions (DDI) is a prevalent DDI in drug development, especially for weak base compounds with highly pH-dependent solubility. FDA has released a guidance on the evaluation of pH-mediated DDI assessments using in vitro testing and clinical studies. Currently, there is no common practice of ways of testing across the academia and industry. The development of biopredictive method and physiologically-based biopharmaceutics modeling (PBBM) approaches to assess acid-reducing agent (ARA)-DDI have been proven with accurate prediction and could decrease drug development burden, inform clinical design and potentially waive clinical studies. Formulation strategies and careful clinical design could help mitigate the pH-mediated DDI to avoid more clinical studies and label restrictions, ultimately benefiting the patient. In this review paper, a detailed introduction on biorelevant dissolution testing, preclinical and clinical study requirement and PBPK modeling approaches to assess ARA-DDI are described. An improved decision tree for pH-mediated DDI is proposed. Potential mitigations including clinical or formulation strategies are discussed.

Subcutaneous administration has become an increasingly important route for delivering protein therapeutics, driven by patient convenience and the growing use of self-administration devices. However, conventional subcutaneous injection systems are typically limited to injection volumes of approximately 1–2 mL, posing significant formulation challenges for protein drugs requiring high therapeutic doses. Monoclonal antibodies (mAbs), for example, often require concentrations exceeding 100 mg/mL to enable subcutaneous delivery, which introduces challenges related to limited solubility, elevated viscosity, and an increased risk of physical and chemical instability. Therefore, high-concentration protein suspensions have emerged as a promising formulation strategy to overcome these limitations and enable subcutaneous administration of high-dose proteins. In such systems, therapeutic protein solid particles are suspended in vehicles in which they are insoluble, giving rise to unique considerations related to particle properties, protein stability, and suspension behaviors such as viscosity, injectability, and sedimentation. Accordingly, multiple particle production approaches have been explored to enable the development of ultra-high-concentration protein suspensions (>200 mg/mL). This review article aims to provide a comprehensive overview of particle formation techniques and the relationships between key particle properties and suspension performance attributes relevant to the development of high-concentration protein suspensions for injectable applications, as well as future directions in this field.