Chapter 1. Fundamental Structures and Behaviors of Proteins (Jennifer S. Laurence and C. Russell Middaugh).
1.1 The Problem of Protein Aggregation.
1.2 Parallels to Protein Folding.
1.3 Views of Protein Stability and Aggregation.
1.4 Models of Aggregation.
1.5 Models of Protein Folding.
1.6 Influences of Chemical Alteration on Aggregation.
1.7 Approaches to Predicting Aggregation.
1.8 Conclusions.
1.9 References.
Chapter 2. Protein Aggregation Pathways, Kinetics, and Thermodynamics (Yi Li and Christopher J. Roberts).
2.1 Introduction.
2.2 Native and Non-Native Aggregation Pathway(s).
2.3 Thermodynamics of Reversible Self-Association.
2.4 Aggregation Kinetics and Distinguishing Kinetic Pathways.
2.5 Chemical Modifications.
2.6 Effects of Cosolvents or Cosolutes.
2.7 Nomenclature.
2.8 Appendix - Derivation of "32 for a van der Waals Mixture.
2.9 Acknowledgements.
2.10 References.
Chapter 3. Identification and Impact of Aggregation Prone Regions in Proteins and Therapeutic Monoclonal Antibodies (Sandeep Kumar, Xiaoling Wang, and Satish K. Singh).
3.1 Introduction.
3.2 Energy Landscapes, Protein Folding and Aggregation.
3.3 Prediction of Aggregation Prone Regions in Proteins and Biotherapeutics.
3.4 Conclusions and Future Directions.
3.5 Acknowledgments .
3.6 Abbreviations.
3.7 References.
Chapter 4. External Factors Affecting Protein Aggregation (Wei Wang, Ning Li, and Stan Speaker).
4.1 Introduction.
4.2 Protein Aggregation Pathways.
4.3 Effects of Temperature.
4.4 Effects of Solution Conditions and Composition on Protein Aggregation.
4.5 Effects of Processing Steps on Protein Aggregation.
4.6 Effects of Solid-State Conditions and Composition on Protein Aggregation.
4.7 Summary.
4.8 Acknowledgements.
4.9 References.
Chapter 5. Experimental Detection and Characterization of Protein Aggregates (Vikas K. Sharma and Devendra S. Kalonia).
5.1 Introduction.
5.2 Aggregate Classification.
5.3 Analytical Tools for Characterization of Aggregates.
5.4 Summary.
5.5 References.
Chapter 6. Approaches to Control Protein Aggregation during Bulk Production (Linda O. Narhi, Yijia Jiang, Rohini Deshpande, Sohye Kang, and Joseph Shultz).
6.1 Introduction.
6.2 Candidate selection.
6.3 Protein aggregation and cell culture.
6.4 Protein aggregation and purification.
6.5 Summary.
6.6 References.
Chapter 7. Protein Aggregation and Particle Formation: Effects of Formulation, Interfaces and Drug Product Manufacturing Operations (Hanns-Christian Mahler, Stefan Fischer, Theodore W. Randolph, and John F. Carpenter).
7.1 Introduction.
7.2 Roles of Conformational and Colloidal Stability in Reducing Rates of Aggregation.
7.3 Effects of Interfaces on Protein Aggregation.
7.4 Critical processing steps during drug product manufacturing of biopharmaceuticals.
7.5 Particles in parenteral products and visible inspection.
7.6 Summary and Outlook.
7.7 References.
Chapter 8. Approaches to Managing Protein Aggregation in Product Development (Wei Wang and Nicholas W. Warne).
8.1 Introduction.
8.2 Approaches in Formulation Development.
8.3 Protection of Proteins in Various Processing Steps.
8.4 Aggregation Control by Structural Modifications.
8.5 Summary.
8.6 References.
Chapter 9. Case Studies Involving Protein Aggregation (Rahul S. Rajan, Tiansheng Li, and Tsutomu Arakawa).
9.1 Introduction.
9.2 Case study 1. Aggregation in the liquid state: the role of osmolytes in stabilizing Keratinocyte Growth Factor (KGF) towards aggregation.
9.3 Case Study 2: Aggregation in the liquid state: heterogeneity and non-linearity in IgG2 aggregation during long term storage.
9.4 Case Study 3: Aggregation in the frozen state: the role of excipient crystallization.
9.5. Case Studies 4&5: Aggregation in the lyophilized state: role of residual moisture and mechanisms of excipient stabilization.
9.6 Case study 6: Protein particulation due to nucleation by foreign material in fill/finish manufacturing operations.
9.7 Overall Discussion.
9.8 Acknowledgements.
9.9 References.
Chapter 10. Aggregation and Immunogenicity of Therapeutic Proteins (Vasco Filipe, Andrea Hawe, Huub Schellekens, and Wim Jiskoot).
10.1 Introduction.
10.2 Immunogenicity of therapeutic proteins.
10.3 Immune mechanisms related to protein immunogenicity.
10.4 Aggregates and Immunogenicity.
10.5 Conclusions.
10.6 References.
Chapter 11. Regulatory Perspective on Aggregates as Product Quality Attribute (Wendy C. Weinberg, Linan Ha, Susan L. Kirshner, and Daniela I. Verthelyi).
11.1 Introduction.
11.2 An overview of the regulatory process.
11.3 Product aggregates and safety concerns.
11.4 The assessment of aggregates: regulatory approaches to controlling product aggregation.
11.5 Future challenges.
11.6 Summary.
11.7 Acknowledgements.
11.8 References.
