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Practical Pharmaceutical Engineering

Gary Prager

ISBN: 978-1-119-41871-9 November 2018 576 Pages

Description

A practical guide to all key the elements of pharmaceuticals and biotech manufacturing and design

Engineers working in the pharmaceutical and biotech industries are routinely called upon to handle operational issues outside of their fields of expertise. Traditionally the competencies required to fulfill those tasks were achieved piecemeal, through years of self-teaching and on-the-job experience—until now. Practical Pharmaceutical Engineering provides readers with the technical information and tools needed to deal with most common engineering issues that can arise in the course of day-to-day operations of pharmaceutical/biotech research and manufacturing.

Engineers working in pharma/biotech wear many hats. They are involved in the conception, design, construction, and operation of research facilities and manufacturing plants, as well as the scale-up, manufacturing, packaging, and labeling processes. They have to implement FDA regulations, validation assurance, quality control, and Good Manufacturing Practices (GMP) compliance measures, and to maintain a high level of personal and environmental safety. This book provides readers from a range of engineering specialties with a detailed blueprint and the technical knowledge needed to tackle those critical responsibilities with confidence. At minimum, after reading this book, readers will have the knowledge needed to constructively participate in contractor/user briefings.

  • Provides pharmaceutical industry professionals with an overview of how all the parts fit together and a level of expertise that can take years of on-the-job experience to acquire
  • Addresses topics not covered in university courses but which are crucial to working effectively in the pharma/biotech industry
  • Fills a gap in the literature, providing important information on pharmaceutical operation issues required for meeting regulatory guidelines, plant support design, and project engineering
  • Covers the basics of HVAC systems, water systems, electric systems, reliability, maintainability, and quality assurance, relevant to pharmaceutical engineering

Practical Pharmaceutical Engineering is an indispensable “tool of the trade” for chemical engineers, mechanical engineers, and pharmaceutical engineers employed by pharmaceutical and biotech companies, engineering firms, and consulting firms. It also is a must-read for engineering students, pharmacy students, chemistry students, and others considering a career in pharmaceuticals. 

Preface xiii

1 US Regulations for the Pharmaceutical Industries 1

1.1 Introduction 1

1.2 The FDA: Formation of a Regulatory Agency 2

1.3 FDA’s Seven Program Centers and Their Responsibility 6

1.3.1 Center for Biologics Evaluation and Research 6

1.3.2 Center for Drug Evaluation and Research 6

1.3.3 Center for Devices and Radiological Health 6

1.3.4 Center for Food Safety and Applied Nutrition 6

1.3.5 Center for Veterinary Medicine 6

1.3.6 Office of Combinational Products 6

1.3.7 Office of Regulatory Affairs 7

1.4 New Drug Development 7

1.4.1 Discovery 7

1.4.2 Investigational New Drug Application 8

1.4.3 Preclinical Studies (Animal) 9

1.4.4 Clinical Studies 10

1.5 Commercializing the New Drug 16

1.5.1 New Drug Application 17

1.6 Harmonization 23

1.6.1 Common Technical Document 23

1.7 Review Process of US NDA 25

1.8 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs 27

1.8.1 Organization and Personnel 27

1.8.2 Building and Facilities 28

1.8.3 Equipment 28

1.8.4 Control of Components and Drug Product Containers and Closures 29

1.8.5 Production and Process Controls 29

1.8.6 Packaging and Labeling Control 30

1.8.7 Holding and Distribution 31

1.8.8 Laboratory Controls 31

1.8.9 Records and Reports 32

1.8.10 Returned and Salvaged Drug Products 33

1.8.11 Other 33

1.9 Compliance 34

1.9.1 Quality System 35

1.9.2 Facilities and Equipment System 35

1.9.3 Materials System 36

1.9.4 Production System 36

1.9.5 Packaging and Labeling System 36

1.9.6 Laboratory Control System 36

1.10 Electronic Records and Electronic Signatures 37

1.10.1 Electronic Records 37

1.10.2 Electronic Signatures 38

1.11 Employee Safety 38

1.11.1 Process Safety Information 39

1.11.2 Process Hazard Analysis 40

1.11.3 Operating Procedures 41

1.11.4 Training 41

1.11.5 New Facility Startup 41

1.11.6 Mechanical Integrity 42

1.11.7 Hot Work Permit 42

1.11.8 Management of Change 42

1.11.9 Incident Investigation 43

1.11.10 Emergency Planning and Response 43

1.11.11 Compliance Audits 43

1.12 US EPA 43

1.12.1 Clean Air Act 44

1.12.2 Safe Drinking Water Act 45

1.12.3 Resource Conservation and Recovery Act 46

1.12.4 Emergency Planning and Community Right‐to‐Know Act 47

1.12.5 Clean Water Act 48

1.13 Process Analytical Technology 49

1.13.1 Process Understanding 49

1.13.2 Principles and Tools 50

1.13.3 Strategy for Implementation 51

1.14 Conclusion 51

References 51

Further Reading 52

2 Pharmaceutical Water Systems 53

2.1 Pharmaceutical Water Systems Basics 53

2.1.1 Fundamentals of Fluid Mechanics for Pharmaceutical Water Systems 58

2.2 Pharmaceutical Water Equipment 77

2.2.1 Centrifugal Pumps 77

2.2.2 Centrifugal Pump Installation Considerations 81

2.3 Thermodynamics Interlude 82

2.4 Heat Transfer for Pharmaceutical Water Production 90

2.5 Evaporation 109

2.6 Ion Exchange Systems 115

2.7 Reverse Osmosis 116

2.7.1 Principles of Reverse Osmosis 118

2.7.2 Reverse Osmosis Installation and Operational Costs 121

2.7.3 Reverse Osmosis Design Hint 122

2.8 cGMP Design and Facility Maintenance Considerations for Pharmaceutical Water Systems 122

References 128

Further Reading 129

3 Heating, Ventilating, and Air Conditioning 131

3.1 Fundamentals of HVAC Electrical Systems 132

3.1.1 Electric Motors 133

3.1.2 Motor Plate and Associated Data 134

3.2 Design Considerations 140

3.2.1 Weather Data 143

3.2.2 Temperature and Humidity 143

3.2.3 Ventilation 147

3.2.4 Air Filtration 149

3.2.5 Internal Loads 150

3.2.6 Air Distribution 150

3.2.7 Room Pressurization 151

3.2.8 Sound and Acoustic Criteria 152

3.2.9 Building Control Systems 158

3.3 Cleanrooms 158

3.3.1 Cleanroom Design Fundamentals 158

3.3.2 Cleanroom Monitoring, Maintenance, and Design Considerations for USP and USP Facilities 169

References 172

Further Reading 172

4 Pressure Vessels, Reactors, and Fermentors 175

4.1 Introduction 175

4.1.1 Pressure Vessels 175

4.1.2 Basics of Pressure Vessel Design and Specifications 178

4.1.3 Pharmaceutical Reactors 188

4.1.4 Kinetics and Reactor Fundamentals 188

4.1.5 Bioreactor Principles 197

4.1.6 Fermentor Principles 209

4.1.7 Heat Transfer Aspects of Fermentors 211

4.1.8 Bioreactor and Fermentor Design, Maintenance, Operating, and cGMP Considerations 214

4.2 Safety Relief Valves and Rupture Discs 219

4.2.1 Safety Relief Devices, Definition of Terms 219

4.2.2 Relief Valve Design and Specifications 223

4.2.3 Requirements and Capacity 223

References 237

Further Reading 238

5 Reliability, Availability, and Maintainability 239

5.1 Introduction to RAM 239

5.2 The Role of Reliability 240

5.3 The Role of Maintainability 247

5.4 The Preventive Maintenance Program 252

5.4.1 System Replacement Considerations 253

5.5 Human Factors 254

5.6 The Role of Availability 259

5.7 Basic Mathematics for Reliability, Availability, and Maintainability 259

5.8 Series and Parallel Configurations 271

5.9 Spares and Replacement Parts 271

References 276

Further Reading 277

6 Parenteral Operations 279

6.1 Introduction 279

6.2 Parenteral Definitions, Regulations, and Guidelines 280

6.2.1 Nomenclature and Definitions 280

6.3 Lyophilization 282

6.3.1 Background 282

6.3.2 Lyophilization Glossary 283

6.3.3 Lyophilizer Design and Operation 284

6.4 Lyophilizer Maintenance Issues 294

6.4.1 Maintenance Systems Analysis 294

References 296

Further Reading 296

7 Tableting Technology 299

7.1 Introduction 299

7.2 The Role of the FDA in the Manufacturing, Processing, Packing, and Holding of Drugs: The Relationship Between Regulations and Pharmaceutical Engineering 300

7.3 Tablet Blending Operations 304

7.3.1 Dry Granulation 305

7.3.2 Wet Granulation 320

7.4 Tableting Operations 322

7.4.1 Tablet Manufacturing 324

7.4.2 Tablet Press Maintenance 329

7.5 Coating 330

7.5.1 Tablet Coating 330

7.5.2 Tablet Coater Maintenance 331

7.6 Capsules 333

7.6.1 Capsule Fundamentals 334

7.6.2 Capsule Materials and Manufacturing 334

References 337

Further Reading 338

8 Corrosion and Passivation in Pharmaceutical Operations 339

8.1 Corrosion 339

8.2 Corrosion and Corrosion Protection in Pharmaceutical Operations 339

8.2.1 Definition of Corrosion 343

8.2.2 Corrosion Fundamentals 343

8.3 General Corrosion Protection in Pharmaceutical Operations 344

8.3.1 Electrochemical Action 344

8.3.2 Environmental Characteristics and Corrosion 349

8.3.3 Properties of Metals that Influence Corrosion 350

8.3.4 Effects of Fabrication and Assembly on Corrosion 350

8.3.5 Protective Films and Corrosion 352

8.3.6 Corrosion Activity in Solutions 352

8.3.7 Types of Corrosion 354

8.4 Corrosion‐ Resistant Metals and Alloys 365

8.4.1 Iron Alloys 366

8.4.2 Aluminum and Aluminum Alloys 367

8.5 Passivation and Rouging 368

8.5.1 Passivation 368

8.5.2 Rouging 369

8.6 General Corrosion Protective Measures 370

8.6.1 General Design Considerations for Corrosion Prevention 370

8.7 Pourbaix Diagrams 374

References 377

Further Reading 378

9 Pharmaceutical Materials of Construction 379

9.1 Introduction 379

9.2 Materials Selection and Performance Requirements 379

9.2.1 Introduction of Polymeric Materials for Single Use Systems 380

9.3 Advantages and Disadvantages of Stainless Steels and Polymers for cGMP and Non‐cGMP Pharmaceutical Applications 381

9.4 Disposal of Single Use Components 382

9.5 Performance Considerations for Pharmaceutical Materials of Construction 392

9.5.1 Stainless Steels 392

9.5.2 Copper and Copper Alloys 394

9.5.3 Carbon Steels and Alloy Steels 396

9.5.4 Polymeric Materials: Overview 399

9.5.5 Preventing Pharmaceutical Materials Component Materials Failures 402

9.6 Practical Piping Calculations 403

References 408

Further Reading 409

10 Commissioning and Validation 411

10.1 Introduction to Commissioning and Validation 411

10.1.1 Introduction to Construction Specifications 411

10.2 Commissioning 416

10.2.1 Description of Tasks 419

10.2.2 Commissioning Costs 425

10.3 Validation 425

10.4 Process Validation 459

10.5 Electronic Records and Electronic Signatures 484

10.5.1 Application of Risk Assessment Methods to Outsourcing 491

10.5.2 Validation Costs 492

10.6 Comparison Between Commissioning and Validation 493

References 493

Further Reading 493

11 Topics and Concepts Relating to Pharmaceutical Engineering 495

11.1 Preliminary Concepts 495

11.1.1 Basic Statistical Concepts and Computational Techniques 495

11.2 Introduction to Six Sigma 508

11.2.1 Six Sigma Organization and Background 508

11.2.2 DMAIC: The Basic Six Sigma Acronym 514

11.2.3 Define 514

11.2.4 Measure 516

11.2.5 Analyze 519

11.2.6 Improve 520

11.2.7 Control 523

11.2.8 Lean Six Sigma 524

11.3 Process Analytical Technology 530

11.4 Quality by Design 537

References 540

Further Reading 540

Index 543