Formulating the Interplay of Protein and Device for Combination Drug Product

This presentation addresses the challenges of developing high-concentration biologics for subcutaneous (SC) injection using prefilled syringes. We will begin by discussing formulation strategies aimed at pushing the boundaries of achieving higher protein concentrations with lower viscosity. This will include examples of suspension formulations that go beyond conventional sterile aqueous drug products. While these devices offer patient-centric benefits, they introduce mechanical and chemical stressors that can compromise protein stability. Factors such as silicone oil release from lubrication coatings and zinc ion migration from rigid needle shields can lead to protein aggregation, increased subvisible particles, and device-related issues like needle clogging, ultimately affecting product performance and patient safety. We will discuss how advanced techniques, including Raman imaging and machine learning, are employed to identify the chemical nature of protein aggregates and provide insights into aggregation mechanisms. Imaging methods such as neutron radiography, synchrotron-based X-ray tomography, and X-ray fluorescence will be highlighted to visualize key dynamics during SC injection, including pressure distribution, air gap morphology, and in situ zinc migration through syringes and stainless-steel needles. We will report the disruptive interaction between formulation components and Zn that potentially induce protein gelation, drying and subdequetnt drying in the needle. These insights help uncover the mechanisms behind needle clogging. Additionally, we introduce the Reciprocal Injection Device (RID), an innovative tool designed to simulate injection stresses and investigate interactions between proteins, excipients, and device interfaces (e.g., silicone oil, metals, and air gaps). RID supports the optimization of formulation design by mitigating risks associated with protein instability. By integrating advanced characterization tools with formulation strategies, we emphasize a comprehensive, data-driven approach to improving the stability and reliability of biologic-device combination products.