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Current trends in market for high dose therapeutic proteins require concentrated liquid formulations for patient convenience, in home subcutaneous administration, to cut manufacturing costs and to improve product marketability. Protein-protein interactions in these solutions need to be characterized to prepare these solutions with desired viscosity and physical stability during storage. The nature and consequences of protein-protein interactions in concentrated protein solutions is reviewed. An ultrasonic shear rheometer based on impedance analysis of piezoelectric quartz crystals was developed for rheological analysis and viscosity measurement of liquids at small sample volumes. Solution viscosities of aqueous solutions of sucrose, urea, PEG-400, glucose, and ethylene glycol were measured at 25°C. The measured viscosities were reproducible and consistent with the literature values. Characterization of viscoelastic fluids was conducted and storage modulus (G') and loss modulus (G") were measured. Bovine serum albumin solutions were analyzed in order to establish the utility of the developed ultrasonic rheometer for studying subtle differences in protein solution rheology as a function of solution conditions. Results of high-frequency rheology analysis were consistent with the structural information reported for the protein in the literature. Rheological analysis and biophysical characterization conducted on a model monoclonal antibody, IgG2, between pH 4.0 to 9.0 and ionic strengths between 4 mM and 300 mM demonstrated the significant role of protein-protein interactions in governing the solution behavior of protein in concentrated solutions. Results from these studies indicated that solution G' could serve as a parameter for assessing protein-protein interactions in high protein concentration solutions. Its validity for this purpose was confirmed by static and dynamic light scattering measurements under relatively dilute solution conditions. The measured second virial coefficient (B 22) and interaction parameter (kD) were found to be consistent with the solution G' measurements. Extent of aggregate formation after storing the IgG2 solutions at 25°C and 37°C for three months was higher for the solution conditions exhibiting sharper increase in solution G' with protein concentration and for which B22 and kD were lower. The results demonstrated the utility of ultrasonic G' measurements for characterizing protein-protein interactions and for predicting favorable solution conditions for formulating high protein concentration solution formulations.
Leading scientists offer detailed profiles of ten protein drugs currently in development. The case histories of these important new compounds are described from the perspective of their formulation, characterization, and stability. This ready reference also features recent data and an abundance of previously unpublished information. The in-depth coverage includes a highly useful compendium of degradation sites occurring in over 70 proteins. An invaluable aid in the rapid identification of potential `hot spots' in proteins, this accessible compilation allows for inspection of the protein's primary structure and preparation of a hydroflex plot.
This book describes how to address the analysis of aggregates and particles in protein pharmaceuticals, provides a comprehensive overview of current methods and integrated approaches used to quantify and characterize aggregates and particles, and discusses regulatory requirements. Analytical methods covered in the book include separation, light scattering, microscopy, and spectroscopy.
The rapid advances in recombinant DNA technology and the increasing availability of peptides and proteins with therapeutic potential are a challenge for pharmaceutical scientists who have to formulate these compounds as drug products. Pharmaceutical Formulation Development of Peptides and Proteins, Second Edition discusses the development of therapeutic peptides and proteins, from the production of active compounds via basic pre-formulation and formulation to the registration of the final product. Providing integrated solutions, this book discusses: The synthesis of peptides and the biotechnological production of proteins through recombinant DNA technology The physicochemical characteristics and stability of peptides and proteins The formulation of proteins as suspensions, solutions, and (mostly freeze-dried) solids The opportunities and challenges of non-parenteral delivery of peptides and proteins Risk factors, specifically the development of an unwanted immune response A simulation approach to describe the fate of peptides and proteins upon administration to a biological system The documentation required to register a protein-based drug Scientists in the pharmaceutical industry and academia as well as postgraduate students in pharmaceutical science will find this a valuable resource.
Overall, the results in here demonstrate: (i) the effects of solution environment in mediating protein-protein interactions, (ii) how that can be studied within the framework of preferential interactions, (iii) the viability of coupling experimental measurements and computer simulations at low c2 to predict high-c2 interactions and better understand the effect of solution formulations at the microscopic level, and (iv) how more detailed CG models can be used to both capture the anisotropic surface charge distribution of proteins as well as the unfolding and aggregation propensities of polypeptides. The approaches can be generalized to other proteins of interest outside those studied here.
Recombinant proteins and polypeptides continue to be the most important class of biotechnology-derived agents in today's pharmaceutical industry. Over the past few years, our fundamental understanding of how proteins degrade and how stabilizing agents work has made it possible to approach formulation of protein pharmaceuticals from a much more rational point of view. This book describes the current level of understanding of protein instability and the strategies for stabilizing proteins under a variety of stressful conditions.
A real-world guide to the production and manufacturing of biopharmaceuticals While much has been written about the science of biopharmaceuticals, there is a need for practical, up-to-date information on key issues at all stages of developing and manufacturing commercially viable biopharmaceutical drug products. This book helps fill the gap in the field, examining all areas of biopharmaceuticals manufacturing, from development and formulation to production and packaging. Written by a group of experts from industry and academia, the book focuses on real-world methods for maintaining product integrity throughout the commercialization process, clearly explaining the fundamentals and essential pathways for all development stages. Coverage includes: Research and early development phase–appropriate approaches for ensuring product stability Development of commercially viable formulations for liquid and lyophilized dosage forms Optimal storage, packaging, and shipping methods Case studies relating to therapeutic monoclonal antibodies, recombinant proteins, and plasma fractions Useful analysis of successful and failed products Formulation and Process Development Strategies for Manufacturing Biopharma-ceuticals is an essential resource for scientists and engineers in the pharmaceutical and biotech industries, for government and regulatory agencies, and for anyone with an interest in the latest developments in the field.
Development of Vaccines: From Discovery to Clinical Testing outlines the critical steps, and analytical tools and techniques, needed to take a vaccine from discovery through a successful clinical trial. Contributions from leading experts in the critical areas of vaccine expression, purification, formulation, pre-clinical testing and regulatory submissions make this book an authoritative collection of issues, challenges and solutions for progressing a biologic drug formulation from its early stage of discovery into its final clinical testing. A section with details and real-life experiences of toxicology testing and regulatory filing for vaccines is also included.
Parenteral Medications is an authoritative, comprehensive reference work on the formulation and manufacturing of parenteral dosage forms, effectively balancing theoretical considerations with practical aspects of their development. Previously published as a three-volume set, all volumes have been combined into one comprehensive publication that addresses the plethora of changes in the science and considerable advances in the technology associated with these products and routes of administration. Key Features: Provides a comprehensive reference work on the formulation and manufacturing of parenteral dosage forms Addresses changes in the science and advances in the technology associated with parenteral medications and routes of administration Includes 13 new chapters and updated chapters throughout Contains the contributors of leading researchers in the field of parenteral medications Uses full color detailed illustrations, enhancing the learning process The fourth edition not only reflects enhanced content in all the chapters but also highlights the rapidly advancing formulation, processing, manufacturing parenteral technology including advanced delivery and cell therapies. The book is divided into seven sectionss: Section 1 - Parenteral Drug Administration and Delivery Devices; Section 2 - Formulation Design and Development; Section 3 - Specialized Drug Delivery Systems; Section 4 - Primary Packaging and Container Closure Integrity; Section 5 - Facility Design and Environmental Control; Section 6 - Sterilization and Pharmaceutical Processing; Section 7 - Quality Testing and Regulatory Requirements