Rational Design of Stable Protein Formulations: Theory and Practice / Edition 1

Rational Design of Stable Protein Formulations: Theory and Practice / Edition 1

Pub. Date:
Springer US


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Rational Design of Stable Protein Formulations: Theory and Practice / Edition 1

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.

Product Details

ISBN-13: 9780306467417
Publisher: Springer US
Publication date: 04/30/2002
Series: Pharmaceutical Biotechnology , #13
Edition description: 2002
Pages: 206
Product dimensions: 6.10(w) x 9.25(h) x 0.02(d)

Table of Contents

Chapter 1Practical Approaches to Protein Formulation Development
Preparation for Formulation Development3
Resource Requirements for Formulation Development3
Useful Information for Designing Formulations4
Preformulation Development4
Characterization of Protein Pharmaceuticals5
Accelerated Stability Studies5
Developmentof Analytical Methods6
Evaluation of the Significance of Problems7
Formulation Development10
Formulation Options for Protein Pharmaceuticals10
Typical Protein Stability Problems: Causes and Solutions13
Optimization of Formulation Variables13
Necessary Studies for Formulation Development15
Strategies to Overcome Difficult Formulation Problems17
Formulation in Commercial Product Development18
Critical Formulation Decisions During Pharmaceutical Development18
Formulation for Early Preclinical and Clinical Studies19
Commercial Formulation19
Regulatory Issues in Formulation Development20
AppendixList of Regulatory Documents22
Chapter 2Recombinant Production of Native Proteins from Escherichia coli
Distribution of Expressed Proteins28
Cell Washing and Lysis32
Purification of Soluble, Folded Proteins34
Purification and Refolding of Soluble, Misfolded Proteins35
Purification and Refolding of Proteins from Inclusion Bodies36
Washing and Solubilization of Inclusion Bodies36
Purification of Expressed Proteins from Inclusion Bodies36
Refolding Mechanism38
Disulfide Bond Formation41
Removal of Denaturant41
Effects of Tag Sequences44
Effects of Excipients44
Response Surface Methodology47
High Pressure Disaggregation and Refolding48
Methods to Analyze Folded Structures48
Binding to Receptors49
Dilsulfide Bond Analysis50
Conformational Stability51
Limited Proteolysis51
Chapter 3Physical Stabilization of Proteins in Aqueous Solution
Overview of Physical Stability62
Thermodynamic Control of Protein Stability62
Kinetic Control of Protein Stability63
Interactions of Excipients with Proteins65
Preferentially Excluded Cosolvents66
Specific Binding of Ligands68
Protein Self-Stabilization69
Physical Factors Affecting Protein Stability70
Agitation and Exposure to Denaturing Interfaces71
AppendixDerivation of the Wyman Linkage Function and Application to the Timasheff Preferential Exclusion Mechanism73
Chapter 4Effects of Conformation on the Chemical Stability of Pharmaceutically Relevant Polypeptides
Relationship Between Structure and Deamidation Rates86
Primary Structure Effects87
Secondary Structure Effects89
Tertiary Structure Effects91
Summary of Structure Effects on Deamidation92
Role of Structure in Protein Oxidation92
Types of Oxidation Processes93
Effects of Oxidation of Surface and Buried Methionines on Protein Structure95
Limiting Solvent Accessibility of Residues96
Conformational Control of Oxidation in Aqueous Solution97
Structural Control of Oxidation in Lyophilized Products99
Summary of Structural Control of Oxidation100
Chapter 5Rational Design of Stable Lyophilized Protein Formulations: Theory and Practice
Minimal Criteria for a Successful Lyophilized Formulation111
Inhibition of Lyophilization-Induced Protein Unfolding112
Storage at Temperatures Below Formulation Glass Transition Temperature113
The Water Content is Relatively Low114
A Strong, Elegant Cake Structure is Obtained114
Steps Taken to Minimzie Specific Routes of Protein Chemical Degradation116
Rational Design of Stable Lyophiilized Formulations117
Choice of Buffer118
Specific Ligands/pH that Optimizes Thermodynamic Stability of Protein119
Trehalose or Sucrose to Inhibit Protein Unfolding and Provide Glassy Matrix120
Bulking Agent (e.g., Mannitol, Glycine or Hydroxyethyl Starch)126
Nonionic Surfactant to Inhibit Aggregation127
Chapter 6Spray-Drying of Proteins
Introduction: Why Spray-Dry a Protein?135
Developments in the Last 10 Years136
The Practice of Spray-Drying Proteins139
Type of Equipment139
Spray-Drying Conditions140
Influence of Formulation147
Pure Proteins147
Formulated Systems149
Use of Added Surface Active Substances151
Concluding Remarks156
Chapter 7Surfactant-Protein Interactions
Proteins and Surfactants at Surfaces161
Protein-Surfactant Interactions in Solution166
Surfactant Effects on Protein Assembly State167
Surfactant Effects on Proteins During Freezing, Freeze-Drying and Reconstitution169
Enzymatic Degradation of Non-Ionic Surfactants170
Recommendations for Protein Formulation170
Chapter 8High Throughout Formulation: Strategies for Rapid Development of Stable Protein Products
Overall Structure of the HTF Approach179
Role of an Established Decision Tree for Formulation Design181
Constraints on a Pharmaceutically Acceptable Protein Formulation182
Proper Choice of Dosage Form183
Preformulation Studies185
Proper Choice of Excipients186
Estimates of Resources Needed for Formulation Development188
Use of Software and Databases to Assist in the HTF Process189
Essential Analytical Methods191
Stability Protocols193
Unified Strategy for HTF194

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