A comprehensive introduction to the art and science used by the biochemist and process engineer in the design and optimization of large-scale protein-purification processes. Covers the basics of proteins' properties, the unit operations involved in protein purification as well as important related issues of process design, integration with upstream operations, cost and timing to market. Includes an abundance of figures and tables.

Scott M. Wheelwright is the author of Protein Purification: Design and Scale up of Downstream Processing, published by Wiley.

Nomenclature

xv

Process Design and Competitive Advantage

1

(9)

Sources of Competitive Advantage

2

(1)

Product Specifications

3

(1)

First to Market

3

(1)

Quality

4

(1)

Process Costs

5

(2)

Further Design Considerations

7

(1)

Overview of Book

8

(2)

Strategies for Process Design

10

(16)

Definitions and Bases for Design

10

(2)

Design Methods

12

(2)

Evolutionary Synthesis

14

(2)

Selection of Purification Steps

16

(3)

Process Synthesis

19

(7)

List of Heuristics

25

(1)

Protein Characteristics

26

(15)

General Behavior

26

(4)

Bases for Separation

30

(1)

Solubility

31

(4)

Stability

35

(1)

Buffers

36

(5)

Molal Surface Tension

39

(1)

Dissociation Constants of Buffer Agents

40

(1)

Analytical Methods

41

(11)

Characterization

42

(1)

Material Balance

42

(2)

Reproducibility

44

(1)

Comparisons

45

(7)

Tests for Protein Determination

46

(1)

Tests for Specific Protein Determination

46

(6)

Impact of Upstream Operations

52

(8)

Upstream Influences

54

(1)

Differences Between Upstream and Downstream Unit Operations

54

(2)

Synergistic Opportunities

56

(4)

Cell Disruption

60

(13)

Quantitation

61

(1)

Nonmechanical Disruption

62

(1)

Ultrasonics

63

(1)

High-pressure Homogenization

64

(3)

Mechanical Grinding

67

(6)

Vendors of Large-scale Disruption Equipment

72

(1)

Centrifugation

73

(14)

Design Principles

74

(6)

Flow-through Centrifuges

80

(2)

Disk-type Rotor

80

(2)

Tube-type Rotor

82

(1)

Chamber-type Rotor

82

(1)

Isopycnic Sedimentation and Ultracentrifugation

82

(2)

Fixed-volume Centrifuges

84

(3)

Nomograph for Computing Relative Centrifugal Force

85

(1)

Manufacturers of Centrifuges

86

(1)

Precipitation and Extraction

87

(12)

Precipitation

88

(4)

Liquid--Liquid Extraction

92

(7)

Aqueous Partitioning

92

(2)

Reversed Micelles

94

(2)

Other Partitioning Systems

96

(3)

Filtration

99

(28)

Microfiltration

102

(4)

Depth Filters

103

(1)

Membrane Microfilters

104

(2)

Ultrafiltration

106

(11)

Flux

107

(6)

Fouling

113

(1)

Materials

114

(1)

Configurations

115

(2)

Bubble-point Testing

117

(1)

Cleaning and Sanitizing

118

(1)

Applications

119

(2)

Concentration

119

(1)

Fractionation

120

(1)

Diafiltration

120

(1)

Scale up

121

(2)

Other Membrane Processes

123

(4)

Vendors of Filters, Membranes, and Associated Equipment

126

(1)

General Chromatography

127

(27)

General Theory

128

(9)

Equilibrium Models

130

(2)

Rate Models

132

(1)

Statistical Models

133

(2)

Measures of Resolution

135

(2)

Resolution

137

(5)

Fluid Phase

137

(3)

Sample

140

(1)

Solid Phase

141

(1)

Practical Operation

142

(4)

Equipment

146

(3)

Scale up

149

(5)

Vendors of Preparative Chromatography Equipment

152

(2)

Ion Exchange Chromatography

154

(18)

Mechanism

154

(4)

Ionic Nature of Proteins

155

(1)

Isotherms and the Law of Mass Action

156

(2)

Matrices

158

(4)

Shrinking and Swelling

160

(1)

Strong and Weak Exchangers

160

(1)

Charge Groups

161

(1)

Capacity

162

(1)

Operation and Application

162

(4)

Batch Mode

163

(1)

Elution

164

(1)

Additional Considerations for Resolution

165

(1)

Optimization and Scale up

166

(6)

Mode of Operation

167

(1)

Resin-Buffer-Elution Scheme

167

(2)

Aspect Ratio

169

(1)

Scale up

170

(2)

Hydrophobic Interaction Chromatography and Reversed Phase Chromatography

172

(12)

Mechanism

173

(2)

Matrices

175

(2)

Operation and Application

177

(4)

Hydrophobic Interaction

177

(1)

Reversed Phase

178

(3)

Optimization and Scale up

181

(3)

Affinity Chromatography

184

(10)

Mechanism

184

(4)

Affinity Ligands

185

(2)

Coupling Chemistries

187

(1)

Matrices

188

(2)

Operation and Application

190

(1)

Optimization and Scale up

191

(1)

Other Affinity Methods

192

(2)

Gel Filtration Chromatography

194

(10)

Mechanism

195

(2)

Matrices

197

(2)

Operation and Application

199

(2)

Optimization and Scale up

201

(3)

Large-Scale Examples

204

(19)

Somatotropin (Bovine Growth Hormone)

205

(2)

Recombinant Human Leukocyte Interferon (rIFNαA)

207

(3)

L-Leucine Dehydrogenase

210

(3)

Tissue Plasminogen Activator (TPA)

213

(3)

Other Examples

216

(3)

Monoclonal Antibodies

217

(1)

Insulin

217

(1)

Protein A

217

(1)

Enterotoxin B

218

(1)

Summary

219

(4)

Index

223

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