Sterile processing of pharmaceutical products: Engineering practice, validation, and compliance in regulated environments / Sam Hout.

Table of contents

Preface xiii

Acknowledgments xvii

1 Introduction 1

2 Sterilization 4

Steam Sterilization 5

Flash Sterilization 5

Low-Temperature Sterilization Technologies 6

Ethylene Oxide Gas Sterilization 6

Hydrogen Peroxide Gas Plasma 7

Disinfection and Surface Sterilization Using Peracetic Acid 7

Ionizing Radiation 8

Dry-Heat Sterilizers 8

Filtration 9

Microwave 9

Vaporized Hydrogen Peroxide (VHP®) 9

Ozone 9

Formaldehyde Steam 10

Gaseous Chlorine Dioxide 10

Vaporized Peracetic Acid 10

Infrared Radiation 10

Sterilization Cycle Verification 11

Monitoring 11

3 Sterile Manufacturing Facilities 15

4 Sanitary Process Piping and Equipment 17

QA Procedures 18

Standard Operating Procedures – cGMP Installations 19

Heat Exchangers 19

Sanitary Pumps 20

Sanitary Tanks 20

Instruments 21

Pressure Transmitter (Various Sources) 21

Temperature Transmitter (Various Sources) 21

Standard Operating Procedures – cGMP Installations 25

Surface Finish 30

Welding 32

Applicability 33

Process/Procedure 39

Records (General) 41

Records 44

Automatic Orbital Welding 47

Weld Acceptance Criteria for Automatic Orbital Weld Qualifications 47

5 Passivation 49

In-house Passivation Using Vats 51

Spot Passivation 53

Astro Pak UltraPass Gel Passivation 53

Alternative Process 54

Control of Passivated Items 57

Preparing, Testing, and Adjusting Cleaning and Passivation Chemicals (Passivation in Vats) 58

6 Chilled Water System 63

Process Description 65

Commissioning of HVAC 75

Installation Verification – X Ton Chiller System 78

SystemStartup – X Ton Chiller 81

Functional Testing – X Ton Chiller 82

7 Clean-In-Place (CIP) Systems 84

Life Cycle Requirements 86

Product and Process User Requirements 86

Process Quality Requirements 86

Process Parameter Requirements 87

Installation User Requirements 87

Operational Requirements 91

8 Computerized Automated Systems 95

Functional Requirement Specification 95

Process Automation System 95

EMS User Requirement Specification 96

Automation Overview 96

Software 97

Hardware 97

SCADA 97

Control Panels 97

Main Control Panel 97

Remote I/O Panels 98

Power Distribution Panels 98

Instrumentation Panels 98

System Functions 98

System Overview 98

Control Modules 99

Interfaces 99

User Interface (SCADA) 99

PAS System Overview 99

Graphical Screen Navigation 99

Client EMS Area Graphical Screens 99

Graphical Control Screens 99

Interfaces to Equipment 101

Interfaces to Other Systems 101

Ethernet Network 101

Nonfunctional Attributes 101

Power Failure Recovery 101

PLC Only Failure 101

HMI Only Failure 101

Network Only Failure 101

Maintainability 102

Backup and Recovery 102

Functional Requirement Specification 102

GLC Environmental Monitoring System 102

Automation Overview 103

System Components 104

Software 104

Hardware 104

Control Panels 104

Gateways 105

System Functions 105

System Overview 105

Control Modules 105

Interfaces 105

User Interface (SCADA) 105

GLC EMS Area Graphical Screen 105

Global Logistics Center (GLC) Environmental Monitoring System 105

Interfaces to Equipment 105

Interfaces to Other Systems 106

Ethernet Network 106

Wireless Connections 106

Nonfunctional Attributes 106

Power Failure Recovery 106

PLC Only Failure 106

HMI Only Failure 106

Network Only Failure 106

Maintainability 107

Backup and Recovery 107

Software Module Design Specification 107

Functional Requirement Specification 108

Process Automation System 108

Automation Overview 109

System Components 109

Software 109

Hardware 110

Control Panels 110

System Functions 111

System Overview 111

Control Modules 111

Interfaces 111

User Interface (SCADA) 111

PAS System Overview Screen 112

Graphical Screen Navigation 112

Graphical Control Screens 112

Interfaces to Equipment 113

Interfaces to Other Systems 113

Ethernet Network 113

Nonfunctional Attributes 114

Power Failure Recovery 114

PLC Only Failure 114

HMI Only Failure 114

Network Only Failure 114

Maintainability 114

Backup and Recovery 114

Software Design Specification 115

Prosoft Configuration 115

Enabling and Disabling of the Gateway Default Server Interface 115

Temperature Sensor Settings 116

Humidity Sensor Settings 116

Software Design Specification 116

Continuous Logic 116

Module Classes and Control Modules 116

Virtual Differential Pressure Alarm Disable 116

Room Condition Indication 117

Navigation Links 117

Alarm Daily Report 118

WFI Still Equipment Module Class 118

WFI Silo Equipment Module Class 126

EM_SILO 126

WFI Primary Loop Equipment Module Class 143

EM_PRIM_LOOP 143

WFI Supply Header Equipment Module Class 155

EM_HEADER 155

Electrical – Controls Equipment Specifications 162

Documentation 165

Drives/Motors 165

9 Personal Protective Equipment (PPE) and Process Flow 170

10 Sterile Aseptic Processing 172

11 Integrated Facility Design 174

Case Study 178

Issue 178

Root Cause 178

Corrective Action 179

Preventive Actions 179

12 Barriers and Isolators 180

Isolator Design Considerations 181

13 Guidelines for Statistical Procedure 183

Process Capability Analysis 184

Long-term Studies 186

Acceptance Sampling 187

Attribute and Variable Sampling Plans 187

Variable Sampling Plans – ANSI Z1.9 188

Normality 188

Transformation of Non-normal Data (Normalization) 190

Protocol Sampling 190

Failure Mode and Effect Analysis (FMEA) 191

Calculating or Recalculating Control Limits 193

14 Calibration 194

Contingency Plan/Disaster Recovery 204

15 Cleaning Validation 205

New Products and Product Changes 208

Cleaning Processes and Changes 208

Risk Assessment/Matrix Approach 209

Matrix Development 209

Cleaning Processes (Manual and Automated) 210

CPP/CQA 210

Cleaning Validation Life Cycle – Cleaning Method Development 211

Strategy for Process Controls 211

Worst-Case Identification – Product/Component 211

Equipment 212

Validation Tests/Inspections – Visual Inspection 212

Chemical Testing 212

Microbiological Testing 213

Endotoxin Testing 213

Sampling Methods 213

Direct Swab Sampling 214

Rinse Sampling 214

Coupon Testing 214

Sampling Sites 214

Acceptance Criteria 214

Residual Levels 214

Endotoxin Levels 215

Microbiological Levels 215

Cleaning Agents/Sanitizer Validation Studies 215

Hold Time Development 216

Dirty Hold Time 216

Clean Hold Time 217

Additional Hold Times/Cleaning Frequencies 217

Continuous Process Verification 217

Failure Investigations 217

16 Validation of Filling Equipment 218

Technical References 223

17 Manufacturing Process Validation 224

Stage 2 – Process Qualification 229

Appendix A Installation Test Plans 232

Appendix B Operational Tests Plans 235

Appendix C WFI Turbulence Flow Requirements 238

Appendix D Water For Injection (WFI) – Design Requirements 239

Process Description 240

Specifications 241

Life Cycle Requirements 241

Product and Process User Requirements 241

Product Description 241

Operating Ranges 243

Material of Construction 244

Metallics 244

Plastics 244

Elastomers 244

Glass 244

Welding Requirements 245

Construction Requirements 246

Lubrication Requirements 247

Electrical Requirements 247

Safety Requirements 247

Operational Requirements 248

Process Constraints and Limitations 248

Process Control System 248

Operator Interface 249

Power Loss and Recovery 250

Cleaning and Sanitizing 250

Maintenance Requirements 250

Training and Documentation Requirements 250

Appendix E Solution Transfer System (STS) – Design Requirements 252

System Description 253

Bulk Powder Handling System 255

Glossary 259

Nomenclature 261

References 263

Further Reading 267

Index 335

Describes the methodologies and best practices of the sterile manufacture of drug products

Thoroughly trained personnel and carefully designed, operated, and maintained facilities and equipment are vital for the sterile manufacture of medicinal products using aseptic processing. Professionals in pharmaceutical and biopharmaceutical manufacturing facilities must have a clear understanding of current good manufacturing practice (cGMP) and preapproval inspection (PAI) requirements.

Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments provides up-to-date coverage of aseptic processing techniques and sterilization methods. Written by a recognized expert with more than 20 years of industry experience in aseptic manufacturing, this practical resource illustrates a comprehensive approach to sterile manufacturing engineering that can achieve drug manufacturing objectives and goals. Topics include sanitary piping and equipment, cleaning and manufacturing process validation, computerized automated systems, personal protective equipment (PPE), clean-in-place (CIP) systems, barriers and isolators, and guidelines for statistical procedure. Offering authoritative guidance on the key aspects of sterile manufacturing engineering, this volume:

Covers fundamentals of aseptic techniques, quality by design, risk assessment and management, and operational requirements
Addresses various regulations and guidelines instituted by the FDA, ISPE, EMA, MHRA, and ICH
Provides techniques for systematic process optimization and good manufacturing practice
Emphasizes the importance of attention to detail in process development and validation
Features real-world examples highlighting different aspects of drug manufacturing

Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments is an indispensable reference and guide for all chemists, chemical engineers, pharmaceutical professionals and engineers, and other professionals working in pharmaceutical sciences and manufacturing.