Fiorenza, Samuele (2025) New strategies based on Microfluidics, PAT, and Machine Learning to ameliorate the design of process development for biopharmaceuticals. [Tesi di dottorato]

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Abstract

Biopharmaceuticals have revolutionized the treatment of complex diseases by offering highly specific and effective therapeutic options. Despite this, their inherent structural complexity and fragility pose significant challenges throughout their entire lifecycle. Ensuring product stability and efficacy requires an in-depth understanding of degradation mechanisms and the development of innovative tools and methodologies to overcome these issues. This thesis addresses the need for robust and efficient strategies to improve both biopharmaceutical formulation and process development. The work focuses on integrating advanced approaches, including microfluidics, Process Analytical Technology (PAT) frameworks, and machine learning, to enhance the stability and quality of therapeutic products while potentially accelerating their bench-to-bedside transition. The contributions of this thesis are multifaceted. First, it introduces a PAT tool based on Near-Infrared Spectroscopy (NIRS) and machine learning for rapid, non-destructive at-line evaluation of residual moisture in lyophilized biopharmaceuticals, an important critical quality attribute affecting product stability. The developed machine learning model showcases high accuracy and adaptability across different formulations, addressing the limitations of traditional methods like Karl-Fischer titration. Second, the thesis presents a modular microfluidic platform designed to study biopharmaceutical stability under thermal, mechanical, and combined stress conditions. The proposed platform provides high-throughput, automated, and reliable alternatives to traditional stability studies, improving the formulation development process. Moreover, the application of machine learning extends to nanoparticle-based formulations, offering models for optimizing nanoparticle delivery efficiency (NDE) tailored to specific pathological conditions. Finally, the thesis explores the role of microfluidics in the manipulation of lipid bilayer systems, advancing the secretion and functionalization of extracellular vesicles for nanomedicine-based therapeutic applications. By integrating these advanced tools and methodologies, this work contributes to overcome key scientific, technological, and industrial barriers in biopharmaceutical development. The proposed strategies align with demands of modern medicine, facilitating the production of stable, effective, and patient-centric biopharmaceuticals.

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