Rational Design of Stable Protein Formulations

by Carpenter, John F.; Manning, Mark C.

• ISBN13: 9780306467417
• ISBN10: 0306467410
• Format: Hardcover
• Copyright: 2002-04-01
• Publisher: Plenum Pub Corp

Summary

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.

Table of Contents

Practical Approaches to Protein Formulation Development
Byeong S. Chang
Susan Hershenson
Introduction	1	(2)
Preparation for Formulation Development	3	(1)
Resource Requirements for Formulation Development	3	(1)
Useful Information for Designing Formulations	4	(1)
Preformulation Development	4	(6)
Characterization of Protein Pharmaceuticals	5	(1)
Accelerated Stability Studies	5	(1)
Development of Analytical Methods	6	(1)
Evaluation of the Significance of Problems	7	(3)
Formulation Development	10	(8)
Formulation Options for Protein Pharmaceuticals	10	(3)
Typical Protein Stability Problems: Causes and Solutions	13	(1)
Optimization of Formulation Variables	13	(2)
Necessary Studies for Formulation Development	15	(2)
Strategies to Overcome Difficult Formulation Problems	17	(1)
Formulation in Commercial Product Development	18	(2)
Critical Formulation Decisions During Pharmaceutical Development	18	(1)
Formulation for Early Preclinical and Clinical Studies	19	(1)
Commercial Formulation	19	(1)
Regulatory Issues in Formulation Development	20	(2)
Appenix: List of Regulatory Documents	22	(1)
References	23	(4)
Recombinant Production of Native Proteins from
Escherichia coli Tsutomu Arakawa
Tiansheng Li
Linda O. Narhi
Introduction	27	(1)
Distribution of Expressed Proteins	28	(4)
Cell Washing and Lysis	32	(2)
Purification of Soluble, Folded Proteins	34	(1)
Purification and Refolding of Soluble, Misfolded Proteins	35	(1)
Purification and Refolding of Proteins from Inclusion Bodies	36	(2)
Washing and Solubilization of Inclusion Bodies	36	(1)
Purification of Expressed Proteins from Inclusion Bodies	36	(2)
Refolding Mechanism	38	(10)
Disulfide Bond Formation	41	(1)
Removal of Denaturant	41	(3)
Effects of Tag Sequences	44	(1)
Effects of Excipients	44	(3)
Response Surface Methodology	47	(1)
High Pressur Disaggregation and Refolding	48	(1)
Methods to Analyze Folded Structures	48	(3)
Bioactivity	49	(1)
Binding to Receptors	49	(1)
Dilsulfide Bond Analysis	50	(1)
Spectroscopy	50	(1)
Conformational Stability	51	(1)
Limited Proteolysis	51	(1)
References	51	(10)
Physical Stabilization of Proteins in Aqueous Solution
Brent S. Kendrick
Tiansheng Li
Byeong S. Chang
Introduction	61	(1)
Overview of Physical Stability	62	(3)
Thermodynamic Control of Protein Stability	62	(1)
Kinetic Control of Protein Stability	63	(2)
Interactions of Excipients with Proteins	65	(5)
Preferentially Excluded Cosolvents	66	(1)
Buffers/Salts	67	(1)
Specific Binding of Ligands	68	(1)
Protein Self-Stabilization	69	(1)
Physical Factors Affecting Protein Stability	70	(3)
Temperature	70	(1)
Freeze-Thawing	71	(1)
Agitation and Exposure to Denaturing Interfaces	71	(1)
Pressure	72	(1)
Conclusions	73	(1)
Appendix: Derivation of the Wyman Linkage Function and Application to the Timasheff Preferential Exclusion Mechanism	73	(5)
References	78	(7)
Effects of Conformation on the Chemical Stability of Pharmaceutically Relevant Polypeptides
Jeffrey D. Meyer
Bert Ho
Mark C. Manning
Introduction	85	(1)
Relationship Between Structure and Deamidation Rates	86	(6)
Primary Structure Effects	87	(2)
Secondary Structure Effects	89	(2)
Tertiary Structure Effects	91	(1)
Summary of Structure Effects on Demidation	92	(1)
Role of Structure in Protein Oxidation	92	(9)
Types of Oxidation Processes	93	(2)
Effects of Oxidation of Surface and Buried Methionines on Protein Structure	95	(1)
Limiting Solvent Accessibility of Residues	96	(1)
Conformational Control of Oxidation in Aqueous Solution	97	(2)
Structural Control of Oxidation in Lyophilized Products	99	(1)
Summary of Structural Control of Oxidation	100	(1)
Summary	101	(1)
References	101	(8)
Rational Design of Stable Lyophilized Formulations: Theory and Practce
John F. Carpenter
Beyong S. Chang
William Garzon-Rodriguez
Theodore W. Randolph
Introduction	109	(2)
Minimal Criteria for a Successful Lyophilized Formulation	111	(6)
Inhibition of Lyophilization-Induced Protein Unfolding	112	(1)
Storage at Temperatures Below Formulation Glass Transition Temperature	113	(1)
The Water Content is Relatively Low	114	(1)
A Strong, Elegant Cake Structure is Obtained	114	(2)
Steps Taken to Minimize Specific Routes of Protein Chemical Degradation	116	(1)
Rational Design of Stable Lyophiilized Formulations	117	(10)
Choice of Buffer	118	(1)
Specific Ligands/pH that Optimizes Thermodynamic Stability of Protein	119	(1)
Trehalose or Sucrose to Inhibit Protein Unfolding and Provide Glassy Matrix	120	(6)
Bulking Agent (e.g., Mannitol, Glycine or Hydroxyethyl Starch)	126	(1)
Nonionic Surfactant to Inhibit Aggregation	127	(1)
Acknowledgments	127	(1)
References	127	(8)
Spray-Drying of Proteins
Geoffrey Lee
Introduction: Why Spray-Dry a Protein?	135	(1)
Developments in the Last 10 Years	136	(3)
The Practice of Spray-Drying Proteins	139	(17)
Type of Equipment	139	(1)
Spray-Drying Conditions	140	(7)
Influence of Formulation	147	(1)
Pure Proteins	147	(2)
Formulated Systems	149	(2)
Use of Added Surface Active Substances	151	(5)
Concluding Remarks	156	(1)
References	156	(3)
Surfactant-Protein Interactions
Theodore W. Randolph
LaToya S. Jones
Introduction	159	(2)
Proteins and Surfactants at Surfaces	161	(5)
Protein-Surfactant Interactions in Solution	166	(1)
Surfactant Effects on Protein Assembly State	167	(2)
Surfactant Effects on Proteins During Freezing, Freeze-Drying and Reconstitution	169	(1)
Enzymatic Degradation of Non-Ionic Surfactants	170	(1)
Recommendations for Protein Formulation	170	(1)
References	171	(6)
High Throughput Formulation: Strategies for Rapid Development of Stable Protein Products
Rajiv Nayar
Mark C. Manning
Introduction	177	(2)
Overall Structure of the HTF Approach	179	(2)
Role of an Established Decision Tree for Formulation Design	181	(8)
Constraints on a Pharmaceutically Acceptable Protein Formulation	182	(1)
Proper Choice of Dosage Form	183	(2)
Preformulation Studies	185	(1)
Proper Choice of Excipients	186	(2)
Estimates of Resources Needed for Formulation Development	188	(1)
Use of Software and Databases to Assist in the HTF Process	189	(2)
Essential Analytical Methods	191	(2)
Stability Protocols	193	(1)
Unified Strategy for HTF	194	(1)
References	195	(4)
Index	199