Contents

Preface ........................................................................

List of Acronyms ..........................................................

vii

Glossary ......................................................................

xiii

1. Introduction .........................................................

2. Regulatory Aspects ............................................

2.1

Introduction .............................................................

2.2

Key Stages in Drug Approval Process ..................

10

2.3

Example of Requirements .....................................

12

2.4

Post-Marketing Evaluation .....................................

13

2.5

Procedures for Authorizing Medicinal

Products in the European Union ............................

14

European and US Regulatory Perspectives ..........

14

3. Good Manufacturing Practice ............................

17

2.6

3.1

Introduction .............................................................

17

3.2

GMP Design Requirements ...................................

22

3.3

GMP Reviews of Design ........................................

34

4. Validation .............................................................

38

4.1

Introduction .............................................................

38

4.2

Preliminary Activities ..............................................

41

4.3

Validation Master Planning ....................................

44

4.4

Development of Qualification Protocols and

Reports ...................................................................

51

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Contents
4.5

Design Qualification (DQ) ......................................

53

4.6

Installation Qualification (IQ) ..................................

55

4.7

Operational Qualification (OQ) ..............................

56

4.8

Handover and Process Optimization .....................

58

4.9

Performance Qualification (PQ) .............................

59

4.10 Process Validation (PV) .........................................

60

4.11 Cleaning Validation ................................................

61

4.12 Computer System Validation .................................

68

4.13 Analytical Methods Validation ................................

71

4.14 Change Control and Revalidation ..........................

71

5. Primary Production .............................................

75

5.1

Reaction .................................................................

75

5.2

Key Unit Operations ...............................................

85

5.3

Production Methods and Considerations ..............

96

5.4

Principles for Layout of Bulk Production

Facilities .................................................................. 100

5.5

Good Manufacturing Practice for BPC .................. 109

6. Secondary Pharmaceutical Production ............ 111

6.1

Products and Processes ........................................ 111

6.2

Principles of Layout and Building Design .............. 154

6.3

The Operating Environment ................................... 159

6.4

Containment Issues ............................................... 176

6.5

Packaging Operations ............................................ 177

6.6

Warehousing and Materials Handling .................... 188

6.7

Automated Production Systems ............................ 190

6.8

Advanced Packaging Technologies ...................... 192

7. Safety, Health and Environment (SHE) ............. 202

7.1

Introduction ............................................................. 202

7.2

SHE Management .................................................. 202

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xxv

7.3

Systems Approach to SHE .................................... 207

7.4

Inherent SHE .......................................................... 209

7.5

Risk Assessment .................................................... 211

7.6

Pharmaceutical Industry SHE Hazards ................. 236

7.7

Safety, Health and Environment Legislation ......... 257

8. Design of Utilities and Services ......................... 260

8.1

Introduction ............................................................. 260

8.2

Objectives ............................................................... 261

8.3

Current Good Manufacturing Practice ................... 262

8.4

Design .................................................................... 263

8.5

Utility and Service System Design ......................... 270

8.6

Sizing of Systems for Batch Production ................ 287

8.7

Solids Transfer ....................................................... 289

8.8

Cleaning Systems .................................................. 289

8.9

Effluent Treatment and Waste Minimization .......... 291

8.10 General Engineering Practice Requirements ......... 297

8.11 Installation .............................................................. 299
8.12 In-House Versus Contractors ................................ 300
8.13 Planned and Preventive Maintenance ................... 301
8.14 The Future? ............................................................ 302

9. Laboratory Design .............................................. 304

9.1

Introduction ............................................................. 304

9.2

Planning a Laboratory ............................................ 307

9.3

Furniture Design ..................................................... 321

9.4

Fume Cupboards ................................................... 329

9.5

Extraction Hoods .................................................... 336

9.6

Utility Services ........................................................ 337

9.7

Fume Extraction ..................................................... 337

9.8

Air Flow Systems ................................................... 340

9.9

Safety and Containment ........................................ 344

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Contents

10. Process Development Facilities and Pilot

Plants ................................................................... 346
10.1 Introduction ............................................................. 346
10.2 Primary and Secondary Processing ...................... 347
10.3 Process Development ............................................ 347
10.4 Small-Scale Pilot Facilities ..................................... 352
10.5 Chemical Synthesis Pilot Plants ............................ 361
10.6 Physical Manipulation Pilot Plants ......................... 368
10.7 Final Formulation, Filling and Packing Pilot
Plants ...................................................................... 369
10.8 Safety, Health and Environmental Reviews .......... 371
10.9 Dispensaries ........................................................... 371
10.10 Optimization ........................................................... 371
10.11 Commissioning and Validation
Management .......................................................... 371

11. Pilot Manufacturing Facilities for the

Development and Manufacture of BioPharmaceutical Products ................................... 372
11.1 Introduction ............................................................. 372
11.2 Regulatory, Design and Operating
Considerations ....................................................... 373
11.3 Primary Production ................................................. 388
11.4 Secondary Production ............................................ 402
11.5 Design of Facilities and Equipment ....................... 417
11.6 Process Utilities and Services ................................ 442

Index ........................................................................... 447

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