Biophysical Methods for Biotherapeutics Discovery and Development Applications

With a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development.

? Helps formulation and analytical scientists in pharma and biotech better understand and use biophysical methods
? Chapters organized according to the sequential nature of the drug development process
? Helps formulation, analytical, and bioanalytical scientists in pharma and biotech better understand and usestrengths and limitations of biophysical methods
? Explains how to use biophysical methods, the information obtained, and what needs to be presented in a regulatory filing, assess impact on quality and immunogenicity
? With a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development.

Preface vii

About the Editor ix

Contributors xi

Section 1 Early Discovery Stages and Biotherapeutic Candidate Selection

1 Biophysical Methods Applied in Early Discovery of a Biotherapeutic: Case Study of an EGFR-IGF1R Bispecific Adnectin 3
Michael L. Doyle, James W. Bryson, Virginie Lafont, Zheng Lin, Paul E. Morin, Lumelle A. Schneeweis, Aaron P. Yamniuk, and Joseph Yanchunas Jr.

2 X-Ray Crystallography for Biotherapeutics 25
Glen Spraggon

3 Solubility and Early Assessment of Stability for Protein Therapeutics 65
Sheng-Jiun Wu, Gary L. Gilliland, and Yiqing Feng

Section 2 First-in-Human and up to Proof-of-Concept Clinical Trials

4 Biophysical and Structural Characterization Needed Prior to Proof of Concept 95
Angela W. Blake-Haskins, Yen-Huei Lin, Zhuchun Wu, Melissa D. Perkins, and Thomas M. Spitznagel

5 Nucleation, Aggregation, and Conformational Distortion 125
Christopher J. Roberts

6 Utilization of Chemical Labeling and Mass Spectrometry for the Biophysical Characterization of Biopharmaceuticals 151
Justin B. Sperry and Lisa M. Jones

7 Application of Biophysical and High-Throughput Methods in the Preformulation of Therapeutic Proteins—Facts and Fictions 173
Ahmad M. Abdul-Fattah and Hanns-Christian Mahler

8 Bioanalytical Methods and Immunogenicity Assays 207
Bonita Rup, Corinna Krinos-Fiorotti, Boris Gorovits, and Hendrik Neubert

9 Structures and Dynamics of Proteins Probed by UV Resonance Raman Spectroscopy 243
Brian S. Leigh, Diana E. Schlamadinger, and Judy E. Kim

10 Freezing- and Drying-Induced Micro- and Nano-Heterogeneity in Biological Solutions 269
Alptekin Aksan, Vishard Ragoonanan, and Carol Hirschmugl

Section 3 Phase III and Commercial Development

11 Late-Stage Product Characterization: Applications in Formulation, Process, and Manufacturing Development 287
Christine P. Chan and Li Shi

12 Biophysical Analyses Suitable for Chemistry, Manufacturing, and Control Sections of the Biologic License Application (BLA) 317
Zahra Shahrokh, Nazila Salamat-Miller, and John J. Thomas

Index 355

TAPAN K. DAS is the Director of the Mass Spectrometry and Biophysics Center of Excellence in the Analytical Development and Testing group at Bristol-Myers Squibb. He is responsible for biophysical and analytical development for biotherapeutics structure-function characterization, analytical comparability, protein particulate analysis, and support for commercial biotherapeutics products. Dr. Das is also the Chair of the Biotechnology Section of Ameri an Association of Pharmaceutical Scientists.