Vaccine Development and Manufacturing E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Wiley Series on Biotechnology
• Sprache: Englisch

Seitenzahl: 879

Veröffentlichungsjahr: 2014

Beschreibung

Vaccine Manufacturing and Production is an invaluable reference on how to produce a vaccine - from beginning to end - addressing all classes of vaccines from a processing, production, and regulatory viewpoint. It will provide comprehensive information on the various fields involved in the production of vaccines, from fermentation, purification, formulation, to regulatory filing and facility designs. In recent years, there have been tremendous advances in all aspects of vaccine manufacturing. Improved technology and growth media have been developed for the production of cell culture with high cell density or fermentation. Vaccine Manufacturing and Production will serve as a reference on all aspects of vaccine production by providing an in-depth description of the available technologies for making different types of vaccines and the current thinking in facility designs and supply issues. This book will provide insight to the issues scientists face when producing a vaccine, the steps that are involved, and will serve as a reference tool regarding state-of-the-art vaccine manufacturing technologies and facility set-up.

Highlights include:

• Comprehensive coverage of vaccine production : from a process point of view- fermentation to purification to formulation developments; from a production point of view - from facility design to manufacturing; and from a regulatory point of view - requirements from government agencies
• Authors from different major pharmaceutical and biotechnology companies
• Describes the challenges and issues involved in vaccine production and manufacturing of the different classes of vaccines, an area not covered by other books currently on the market

Leseprobe

Table of Contents

Cover

Series

Title Page

Copyright

Acknowledgments

Preface

Contributors

Chapter 1: History of Vaccine Process Development

1.1 Introduction

1.2 Vaccines Bioprocess Evolution

1.3 Live Attenuated and Inactivated Virus Vaccines

1.4 Live or Whole-Killed Bacterial Vaccines

1.5 Classical Subunit Vaccines

1.6 Recombinant Subunit Vaccines

1.7 Conjugate Vaccines

1.8 Downstream Processing

1.9 Vaccines for the Developing World: Large Volume, Low Cost, and Thermostable

1.10 Summary

Acknowledgments

References

Chapter 2: The Production of Plasmid DNA Vaccine in Escherichia coli: A Novel Bacterial-Based Vaccine Production Platform

2.1 Introduction:

E. coli

in Vaccine Production

2.2 Brief Overview of DNA Vaccines: Mechanisms and Methods of Vaccinations

2.3 Current Status of DNA Vaccines

2.4 Required Physical Properties of Plasmid DNA Vaccines

2.5 Choice of

E. coli

Host Strain

2.6 Factors Influencing Plasmid Stability

2.7 Transformation, Selection of Producing Clones, and Cell Banking

2.8 Production Process

2.9 Requirements for Clinical Supplies

2.10 Conclusions

References

Chapter 3: Fungal Expression Systems for Vaccine Production

3.1 Introduction

3.2 Hepatitis B Vaccines

3.3 Human Papillomavirus Vaccine

3.4 Malaria Vaccine Candidates

3.5 HIV Vaccine Candidates

3.6 Veterinary Vaccines

3.7 Perspectives

3.8 Concluding Remarks

Acknowledgments

References

Chapter 4: Novel Expression Systems for Vaccine Production

4.1 Introduction

4.2 Subunit Vaccines

4.3 Expression Systems

4.4 Novel Expression Systems

4.5 Production of Recombinant Proteins in Plants

4.6 Launch Vector System

4.7 Conclusions

References

Chapter 5: Viral Vaccines Purification

5.1 Introduction

5.2 Process Tasks

5.3 Conclusions and Outlook

Acknowledgments

Nomenclature

Abbreviations

References

Chapter 6: Protein Subunit Vaccine Purification

6.1 Introduction

6.2 Purification Technologies—Applications in Protein Subunit Vaccine Purification

6.3 Purification Process Development and Scale-Up for Protein Subunit Vaccine

6.4 Process Definition Studies

6.5 Process Economy and Automation

6.6 Application of Process Analytical Technology in Protein Purification

6.7 Downstream Purification—An Outlook

References

Chapter 7: Conjugate Vaccine Production Technology

7.1 Conjugate Vaccine Production Technology

7.2 Preparation of Antigen and Carrier Protein

7.3 Polysaccharide Size

7.4 Activation and Coupling of Polysaccharide and Carrier Protein

7.5 Characterization of the Conjugate

7.6 Future Directions

References

Chapter 8: Stabilization and Formulation of Vaccines

8.1 Introduction

8.2 An Example of a Modern Vaccine Characterization Strategy

8.3 A Comprehensive Approach to Vaccine Formulation in Practice

8.4 Conclusions

References

Chapter 9: Lyophilization In Vaccine Processes

9.1 Introduction

9.2 Formulation

9.3 Filling

9.4 Lyophilization

9.5 Equipment

9.6 Conclusions

References

Chapter 10: Strategies for Heat-Stable Vaccines

10.1 Introduction: Importance of Stable Vaccines

10.2 Stability of Current Vaccines

10.3 Vaccine Stabilization Strategies

10.4 Future of Vaccine Stabilization

References

Chapter 11: Production And Characterization Of Aluminum-Containing Adjuvants

11.1 Structure

11.2 Properties

11.3 Production

11.4 Characterization

11.5 Summary

References

Chapter 12: The Biologics License Application (BLA) in Common Technical Document (CTD) Format

12.1 Introduction

12.2 Organization of the Biologics Licensing Application

12.3 Hints for Preparing the Biological Licensing Application

References

Chapter 13: The Original New Drug Application (Investigational New Drug)

13.1 Introduction

13.2 Format for Submitting an IND

13.3 Detailed Discussion of Information Required in the Chemistry Manufacturing and Control Sections

13.4 General Overview of Information Required in the Regional, Nonclinical, and Clinical Items

References

Chapter 14: Facility Design for Vaccine Manufacturing—Regulatory, Business, and Technical Considerations and a Risk-Based Design Approach

14.1 Introduction

14.2 Regulatory Considerations

14.3 The Business Context

14.4 Vaccine Manufacturing Facility—Overview

14.5 Expectations for Design of Vaccine Facilities

14.6 Risk-Based Principles for Design of Vaccine Facilities

14.7 Conclusions

References

Chapter 15: Vaccine Production Economics

15.1 Introduction

15.2 Vaccine Manufacturing, History, and Drivers

15.3 The Importance of Capital in Biologic Manufacturing

15.4 Process Design and Optimization

15.5 Process Development Knowledge Management—Capturing the Data

15.6 Modeling Approaches

15.7 Cost Models in Practice

15.8 Conclusions

Acknowledgments

References

Index

End User License Agreement

Pages

ix

x

xi

xii

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

437

438

439

440

Guide

Cover

Table of Contents

Preface

Chapter 1: History of Vaccine Process Development

List of Illustrations

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 4.1

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.6

Figure 5.5

Figure 5.7

Figure 5.8

Figure 5.9

Figure 5.10

Figure 5.11

Figure 5.12

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 7.1

Figure 7.2

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 8.6

Figure 9.1

Figure 9.2

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 11.6

Figure 11.7

Figure 11.8

Figure 11.10

Figure 11.11

Figure 11.12

Figure 11.13

Figure 11.14

Figure 14.1

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 15.5

Figure 15.6

List of Tables

Table 2.1

Table 2.2

Table 4.1

Table 5.1

Table 5.2

Table 5.3

Table 5.4

Table 5.6

Table 5.7

Table 6.1

Table 6.2

Table 6.3

Table 6.4

Table 6.5

Table 6.6

Table 6.7

Table 8

Table 7.1

Table 7.2

Table 9.1

Table 9.2

Table 9.3

Table 10.1

Table 10.2

Table 11.1

Table 11.2

Table 14.1

Table 14.2

Table 14.3

Table 15.1

Table 15.2

Table 15.3

Table 15.4

Vaccine Development and Manufacturing

Edited by

EMILY P. WEN

RONALD ELLIS

NARAHARI S. PUJAR

Wiley Series in Biotechnology and Bioengineering

Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Vaccine development and manufacturing / edited by Emily P. Wen, Ronald Ellis, Narahari S. Pujar.

pages cm. – (Wiley series in biotechnology and bioengineering)

Includes index.

ISBN 978-0-470-26194-1 (cloth)

1. Vaccines–Laboratory manuals. I. Wen, Emily P. II. Ellis, Ronald III. Pujar, Narahari S.

QR189.V2512 2015

615.3'72–dc23

2015028866

Acknowledgments

During the preparation of this book, one of our authors, Dr. Stanley Lawrence Hem passed away on 23 January 2011. Dr. Hem led a distinguished career at Purdue for more than forty years where he was a gifted and dedicated teacher. He was a recognized leader in vaccine adjuvants and he served as the major professor for 40 Ph.D. students. Also, CTJ would like to acknowledge with gratitude the many helpful discussions and exchanges that Stan provided over the past 20 years.

Preface

The advent of vaccine development has increased lifespan and improved quality of life. Measles was once an epidemic in the United States, with more than 55,000 cases and 120 deaths as recently as 1989–1991. Today, it is no longer circulating in the United States with the introduction of the measles vaccine. Rubella is no longer endemic in the United States; however in the 1960s, many people witnessed firsthand the terrible effects of the rubella virus. During an epidemic between 1964 and 1965, about 20,000 infants were born with deafness, blindness, heart disease, mental retardation, or other birth defects because the rubella virus infected their pregnant mothers. The same is true for other diseases such as polio, hepatitis A and B, peumococcal, and invasive Hib diseases, whereas the introduction of vaccines greatly diminishes the disease incidence, morbidity, and mortality.

Vaccines work by presenting a foreign antigen to the immune system in order to evoke an immune response. A vaccine can be in the form of inactivated virus particles, attenuated virus, virus-like particles, subunit vaccine, DNA vaccine, and recombinant particles. Vaccine containing inactivated virus particles is grown in culture, purified, and then killed with heat, formaldehyde, or other methods. The inactivated virus particles cannot replicate, but the intact particle can elicit an immune response. Attenuated vaccines contain low virulent particles, whereas virus-like particle vaccines are derived from the structural proteins of a virus and lack viral nucleic acids for reproduction. A subunit vaccine, as the name suggests, consists only a part of a virulent strain, such as polysaccharides on the surface of bacterial cells.

Since the introduction of penicillin, antibiotics have been effective against most bacterial diseases. However, with an increase in antibiotic resistance and newer bacterial diseases, antibiotics have shown diminished efficacy, and vaccines are needed for prevention of diseases. New-generation vaccines are also being developed not only to prevent diseases, but also to cure ailments such as cancer. The development of a vaccine is a complex process, requiring multiple clinical trials to demonstrate the product's safety, efficacy, purity, potency, and consistency in manufacturing. Unlike the manufacturing of small molecules, vaccines are usually derived from highly variable living sources and cannot be easily characterized or analyzed completely. Changes in manufacturing process can have a large impact on the final vaccine product and may require additional clinical testing. The same can be said of generic vaccines because the production process generally defined the product, and regulators still require follow-on biologics and vaccines to complete a new filing and perform clinical trials. The production process of vaccines thus plays an important role in defining the end product.

The process of vaccine production comprises fermentation, purification, formulation, and analytics. In recent years, there have been tremendous advances in all aspects of vaccine manufacturing. Improved technology and growth media have been developed for the production of cell culture with high cell density or fermentation. Advances in expression systems help lower some manufacturing costs and minimize problems seen in older manufacturing processes, such as contamination frequently observed in the manufacturing of influenza vaccines. Improvements in large-scale purification equipment have enabled the efficient processing of large biomasses. Novel adjuvants discovered in the past few years have shown great promises in human clinical trials by helping to elicit stronger immune response and provide long-lasting memory effects. New concepts in facility designs have allowed for multiple use of the same facility.

This book is written with the aim to provide comprehensive information on the various fields involved in the production of vaccines, from fermentation, purification, and formulation to regulatory filing and facility designs. The book can be divided into five sections. First is a review of the history of vaccines development (Chapter 1). The second section comprises new advances in fermentation technology, such as the use of recombinant DNA technology (Chapter 2), different fungal expression systems (Chapter 3), and novel expression systems using host plant systems (Chapter 4). The third section focuses on different purification technology on viral vaccines, protein subunit vaccines, and conjugate vaccines (Chapters 5–7). The next section discusses advances in formulation technology, starting with a general summary on how to stabilize a vaccine via formulation (Chapter 8), followed by specifics such as freeze drying, production of heat-stable vaccine, and the use of aluminum-containing adjuvants (Chapters 9–11). The last section covers other topics that are very important in vaccine production, including regulatory filing, facility design, and production economics (Chapters 12–15).

We hope this book will be useful to a broad cross section of biotechnology professionals, medical and biomedical scientists, health care professional, and anyone who is interested in the making of vaccines.

EMILY P. WEN

RONALD ELLIS

NARAHARI S. PUJAR

Contributors

Michel Chartrain

, Merck & Co., Inc., Kenilworth, NJ, USA

Sudha Chennasamudram

, Laboratory of Bacterial Polysaccharides, Office of Vaccine Research and Review, Center for Biologics Evaluations and Research, Bethesda, MD, USA

Tony D'Amore

, Sanofi Pasteur, Toronto, Ontario, Canada

Anand Ekambaram

, Merck & Co., Inc., West Point, PA, USA

Stanley L. Hem

, Purdue University, West Lafayette, IN, USA

Zbigniew Janowicz

, Dynavax Europe/Rhein Biotech GmbH, Düsseldorf, Germany

Volker Jenzelewski

, Dynavax Europe/Rhein Biotech GmbH, Düsseldorf, Germany

Cliff T. Johnston

, Purdue University, West Lafayette, IN, USA

Peter Latham

, Latham Biopharm Group, Maynard, MA, USA

David Lechuga-Ballesteros

, Aridis Pharmaceuticals LLC, San Jose, CA, USA

Ann L. Lee

, Genentech, South San Francisco, CA, USA

Karl Melber

, Dynavax Europe/Rhein Biotech GmbH, Düsseldorf, Germany

C. Russell Middaugh

, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA

Satoshi Ohtake

, Aridis Pharmaceuticals LLC, San Jose, CA, USA

Eric J. Patzer

, Aridis Pharmaceuticals LLC, San Jose, CA, USA

Bret R. Phillips

, Merck & Co., Inc. West Point, PA, USA

Timothy S. Priddy

, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA

Narahari S. Pujar

, Merck & Co., Inc. West Point, PA, USA

Shailaja Rabindran

, US Department of Agriculture Animal and Plant Health Inspection Service, Riverdale, MD, USA

Udo Reichl

, Max Planck Institute for Dynamics of Complex Technical Systems, Bioprocess Engineering, Magdeburg, Germany; Otto-von-Guericke University, Magdeburg, Germany

R.S. Robin Robinett

, Merck & Co., Inc., West Point, PA, USA

Sangeetha L. Sagar

, Merck & Co., Inc. West Point, PA, USA

Ranjit Sarpal

, Amgen, Thousand Oaks, CA, USA

Abraham Shamir

, Shamir Biologics LLC, Ft. Washington PA, USA

Andrew Sinclair

, Biopharm Services US, Maynard, MA, USA.

Vu Truong-Le

, Aridis Pharmaceuticals LLC, San Jose, CA, USA

Willie F. Vann

, Laboratory of Bacterial Polysaccharides, Office of Vaccine Research and Review, Center for Biologics Evaluations and Research, Bethesda, MD, USA

Alexis Wasserman

, Merck & Co., Inc. West Point, PA, USA

Roland Weyhenmeyer

, Dynavax Europe/Rhein Biotech GmbH, Düsseldorf, Germany

Yan-ping Yang

, Sanofi Pasteur, Toronto, Ontario, Canada

Vidadi Yusibov

, Fraunhofer USA Center for Molecular Biotechnology, Newark, DE, USA

Bernd Kalbfuss-Zimmermann

, Novartis Pharma AG, Basel, Switzerland

Chapter 1History of Vaccine Process Development

NARAHARI S. PUJARAND SANGEETHA L. SAGAR

Merck & Co., Inc. West Point, PA, USA

ANN L. LEE*

Genentech, South San Francisco, CA, USA

1.1 Introduction

The goal of vaccine process development is to develop a manufacturing process that can consistently produce a vaccine that is safe and efficacious. During vaccine discovery, the etiologic agent is identified, the immunogen, adjuvant (if applicable), and administration regimens are developed in animal models such that the vaccine candidate produces a prophylactic immune response that is safe and effective. A requirement of the manufacturing process is to preserve the immunological properties innate to the molecular/biological architecture defined in vaccine discovery and enable production of the vaccine in increasingly larger quantities for use in human clinical studies and later commercial supplies. These activities of vaccine discovery and process development must be well integrated, require collaborative efforts and iterative refinements. The safety and efficacy of the vaccine gets proven though phases of clinical studies with increasing number of subjects. The final process developed and used to produce the vaccine for pivotal clinical trials becomes the manufacturing process which is licensed by regulatory authorities for full-scale production to supply the market.

Unlike for many other pharmaceutical drugs, the manufacturing process used to produce the vaccine is still frequently tied to the definition of the product. While many modern vaccines are highly purified biomolecules, others are complex preparations, such as live viral vaccines or multivalent conjugate vaccines, consisting of the antigen, trace levels of cellular and process residuals, excipients, as well as adjuvants. For some types of vaccines the “product-is-the-process” interdependence can be greatly alleviated by modern process and analytical technology. This approach is built upon much greater scientific understanding of the process and product characteristics which allows greater process control and performance.