Mary E. Krause - Protein instability at interfaces during drug product development : fundamental understanding, evaluation, and mitigation

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Over the last two decades, the landscape of medicine has changed significantly, as biologic therapeutics have played an increasingly pivotal role in disease treatment. The recent emergence of protein-based immuno-oncological therapeutics has altered the treatment pathway for many cancer patients, providing new hope in various diseases with high mortality rates. The discovery and development of biological therapies for many diseases, such as cancer and diabetes, have been the focus of numerous international pharmaceutical and biotechnological companies, and the development of biologics frequently outpaces that of small molecule drugs. Unlike small molecule drug candidates, the therapeutic function of proteins relies not only on the primary structure (sequence) but also on the precisely folded higher order structure. Disruption of these higher order structures could result in the loss of therapeutic functions and, thus, the loss of efficacy. Therefore, during the manufacturing and formulation of biologics, the preservation of the often-fragile higher order structure of proteins is critical. Because proteins are typically surface-active, they tend to adsorb to interfaces, potentially leading to changes in conformation and denaturation. During the development and manufacturing of biologics, proteins are subjected to interfacial stresses that are present from the early-stage isolation of drug substances through eventual storage and clinical administration.

When discussing the scope of this book, we understood that the breadth of topics relevant to the scalable production and distribution of biologic drug products was wide-ranging. As a consequence, this book examines the fundamental understanding of the interfacial behavior of proteins as well as the applications of interfacial stresses in drug development. Contributions from both academicians and industrialists are folded together to illustrate how the interfacial behavior of these complex drug products can be effectively modeled and how existing protocols in industry can be used to mitigate unwanted aggregation and precipitation. Taken together, the collected sections define the impact of these interfacial stresses in the pharmaceutical development and manufacturing of biologics for an audience that should include graduate students who are hoping to enter this field and professionals who want a deeper understanding of the role of interfaces in drug development. Additionally, we believe that the publication of this book will catalyze additional research in this area.

We thank our authors for taking their precious time to contribute this book. Additionally, we are indebted to all the reviewers of the various chapters, including Atul Bhangale, Danny Chow, Daan Crommelin, Bart Demeule, Frank Etzler, Archana Jaiswal, Cavan Kalonia, Ajit Narang, Bjorn Peters, Ronak Shah, and Joseph Zasadzinski. Finally, we are grateful to the staff of Springer for their professional expertise and guidance.