Protein Instability at Interfaces During Drug Product Development: Fundamental Understanding, Evaluation, and Mitigation

Proteins are exposed to interfacial stresses during drug product development, which can lead to denaturation and aggregation. This book covers the fundamental aspects of protein interfaces and the quantification of interfacial behaviors, and introduces the industrial aspects of protein instabilities at interfaces. It is intended for scientists in the pharmaceutical and biotech industry and academia in surface science, pharmaceutical, and medicinal chemistry.

Format: Paperback / softback
Length: 338 pages
Publication date: 13 February 2022
Publisher: Springer Nature Switzerland AG

Proteins encounter diverse interfacial stresses throughout the drug product development process. They undergo exposure to air-liquid, liquid-solid, and occasionally liquid-liquid interfaces throughout the entire development cycle, spanning from the manufacturing of drug substances to storage and drug delivery. Unlike small molecule drugs, proteins often exhibit instability at interfaces, leading to denaturation and aggregation upon adsorption, resulting in reduced efficacy and potential immunogenicity.

This comprehensive book delves into both the fundamental principles of proteins at interfaces and the quantification of their interfacial behaviors. Moreover, it introduces the industrial aspects of protein instabilities at interfaces, encompassing processes that introduce new interfaces, evaluation of interfacial instabilities, and mitigation strategies. The intended audience for this book encompasses scientists working in the pharmaceutical and biotech industries, as well as faculty and students from academia specializing in surface science, pharmaceutical, and medicinal chemistry.

Proteins, as essential macromolecules, play pivotal roles in various biological processes and therapeutic applications. However, their behavior at interfaces is a significant challenge due to their complex nature and diverse interactions. At interfaces, proteins can undergo conformational changes, denaturation, and aggregation, leading to changes in their functional properties and stability. These interfacial phenomena can have a profound impact on the efficacy and safety of protein-based drugs.

One of the primary challenges associated with protein stability at interfaces is the presence of water. Water molecules can interact with protein residues, disrupting their secondary and tertiary structures and leading to protein denaturation. Additionally, the hydrophobic nature of many protein surfaces can attract water molecules, further exacerbating the instability of proteins at interfaces.

Another factor that contributes to protein instability at interfaces is the presence of charged or polar groups. These groups can interact with the charged or polar surfaces of the interface, leading to electrostatic repulsion and the formation of unstable complexes. Additionally, the presence of charged or polar groups can disrupt the hydrophobic interactions that stabilize protein structures, further promoting protein instability.

In addition to these interfacial factors, the manufacturing process can also introduce new interfaces into protein-based drugs. For example, during the purification of proteins, they may be subjected to different buffer conditions, ionic strengths, and pH values, which can introduce new interfaces and disrupt the stability of the protein. Similarly, during drug formulation, proteins may be mixed with excipients, such as polymers or sugars, which can introduce new interfaces and alter the stability of the protein-excipient complex.

Evaluation of interfacial instabilities is crucial for the successful development of protein-based drugs. Various techniques, such as surface tension measurements, fluorescence spectroscopy, and X-ray diffraction, can be used to study the behavior of proteins at interfaces. These techniques can provide insights into the conformational changes, denaturation, and aggregation of proteins at interfaces, as well as the interactions between proteins and the interface.

Mitigation strategies are also essential for addressing protein instability at interfaces. One approach is to modify the protein structure to enhance its stability at the interface. This can involve introducing mutations or modifying the protein's surface properties to reduce the attraction of water or other interfacial molecules. Additionally, the use of excipients or additives can be used to stabilize the protein-excipient complex, reducing the likelihood of protein denaturation or aggregation.

In conclusion, proteins encounter diverse interfacial stresses during drug product development. These stresses can lead to protein instability, which can have significant implications for the efficacy and safety of protein-based drugs. This book provides a comprehensive overview of the fundamental aspects of proteins at interfaces and the quantification of their interfacial behaviors. It also introduces the industrial aspects of protein instabilities at interfaces, including processes that introduce new interfaces, evaluation of interfacial instabilities, and mitigation strategies. By understanding the challenges associated with protein stability at interfaces and implementing effective mitigation strategies, scientists can develop more stable and effective protein-based drugs for various therapeutic applications.

Weight: 534g
Dimension: 235 x 155 (mm)
ISBN-13: 9783030571795
Edition number: 1st ed. 2021