Inhaltsangabe1 Practical Approaches to Protein Formulation Development.- Preparation for Formulation Development.- Resource Requirements for Formulation Development.- Useful Information for Designing Formulations.- Preformulation Development.- Characterization of Protein Pharmaceuticals.- Accelerated Stability Studies.- Development of Analytical Methods.- Evaluation of the Significance of Problems.- Formulation Development.- Formulation Options for Protein Pharmaceuticals.- Typical Protein Stability Problems: Causes and Solutions.- Optimization of Formulation Variables.- Necessary Studies for Formulation Development.- Strategies to Overcome Difficult Formulation Problems.- Formulation in Commercial Product Development.- Critical Formulation Decisions During Pharmaceutical Development.- Formulation for Early Preclinical and Clinical Studies.- Commercial Formulation.- Regulatory Issues in Formulation Development.- Appendix: List of Regulatory Documents.- References.- 2 Recombinant Production of Native Proteins from Escherichia coli.- Distribution of Expressed Proteins.- Cell Washing and Lysis.- Purification of Soluble, Folded Proteins.- Purification and Refolding of Soluble, Misfolded Proteins.- Purification and Refolding of Proteins from Inclusion Bodies.- Washing and Solubilization of Inclusion Bodies.- Purification of Expressed Proteins from Inclusion Bodies.- Refolding Mechanism.- Disulfide Bond Formation.- Removal of Denaturant.- Effects of Tag Sequences.- Effects of Excipients.- Response Surface Methodology.- High Pressure Disaggregation and Refolding.- Methods to Analyze Folded Structures.- Bioactivity.- Binding to Receptors.- Dilsulfide Bond Analysis.- Spectroscopy.- Conformational Stability.- Limited Proteolysis.- References.- 3 Physical Stabilization of Proteins in Aqueous Solution.- Overview of Physical Stability.- Thermodynamic Control of Protein Stability.- Kinetic Control of Protein Stability.- Interactions of Excipients with Proteins.- Preferentially Excluded Cosolvents.- Buffers/Salts.- Specific Binding of Ligands.- Protein Self-Stabilization.- Physical Factors Affecting Protein Stability.- Temperature.- Freeze-Thawing.- Agitation and Exposure to Denaturing Interfaces.- Pressure.- Conclusions.- Appendix: Derivation of the Wyman Linkage Function and Application to the Timasheff Preferential Exclusion Mechanism.- References.- 4 Effects of Conformation on the Chemical Stability of Pharmaceutically Relevant Polypeptides.- Relationship Between Structure and Deamidation Rates.- Primary Structure Effects.- Secondary Structure Effects.- Tertiary Structure Effects.- Summary of Structure Effects on Deamidation.- Role of Structure in Protein Oxidation.- Types of Oxidation Processes.- Effects of Oxidation of Surface and Buried Methionines on Protein Structure.- Limiting Solvent Accessibility of Residues.- Conformational Control of Oxidation in Aqueous Solution.- Structural Control of Oxidation in Lyophilized Products.- Summary of Structural Control of Oxidation.- Summary.- References.- 5 Rational Design of Stable Lyophilized Protein Formulations: Theory and Practice.- Minimal Criteria for a Successful Lyophilized Formulation.- Inhibition of Lyophilization-Induced Protein Unfolding.- Storage at Temperatures Below Formulation Glass Transition Temperature.- The Water Content is Relatively Low.- A Strong, Elegant Cake Structure is Obtained.- Steps Taken to Minimize Specific Routes of Protein Chemical Degradation.- Rational Design of Stable Lyophiilized Formulations.- Choice of Buffer.- Specific Ligands/pH that Optimizes Thermodynamic Stability of Protein.- Trehalose or Sucrose to Inhibit Protein Unfolding and Provide Glassy Matrix.- Bulking Agent (e.g., Mannitol, Glycine or Hydroxyethyl Starch).- Nonionic Surfactant to Inhibit Aggregation.- Acknowledgments.- References.- 6 Spray-Drying of Proteins.- Introduction: Why Spray-Dry a Protein?.- Developments in the Last 10 Years.- The Practice of Spray-Drying Proteins.- Type of Equipment.- Spray-