Drug, Device and Diagnostic Manufacturing

Transcription

1 Drug, Device and Diagnostic Manufacturing The Ultimate Resource Handbook Second Edition by Carol DeSain

2 Table of Contents I. BIOMEDICAL RESEARCH AND DEVELOPMENT 1 A. Biomedical Research/Design 4 1. Identification of Raw Materials 4 a. Chemical Specifications 4 b. Cell Line Specifications 5 c. Device Biomaterial Requirements 5 2. Identifying the Production Processes 6 a. Drug Substance Processing Requirements 7 b. Cell Culture Processing Requirements 7 c. Device Product Requirements 8 3. Final Product Requirements 8 a. Drug Product Requirements 8 b. Biological Product Requirements 9 c. Device Product Requirements Quality Assurance During Research/Design Activities 11 a. Documentation Requirements 11 b. Change Control 12 c. Product Review What Development Needs to Know from Research Recommended Reading 15 B. Biomedical Product Development Characterization of Raw Materials 20 a. Chemical Specifications 20 b. Cell Line Specifications 22 c. Device Biomaterial Specifications Processing Controls and Scale-up 27 a. Drug Product Processing and Scale-up 27 b. Cell Culture Processing and Scale-up 29 c. Device Product Assembly/Sterilization 31

3 vi Drug, Device and Diagnostic Manufacturing 3. Final Product Specifications 31 a. Final Product: Drugs and Biologicals 31 b. Device Software Quality Assurance 34 c. Final Product: Devices 35 d. Variable Product Configurations During Development The Facility Requirements 36 a. Equipment 38 b. Processing 39 i) Establishing the Production Process 39 ii) Scale-up 40 c. Environmental Controls 43 d. Facility Qualification Planning 43 e. Facility Audit The Development of Departmental Responsibilities a. Quality Control 45 i) Quality Control: Microbiology 45 ii) Quality Control: Chemistry 46 iii) Quality Control: Biological Analysis 48 iv) Quality Control: Engineer 49 b. Production 49 c. Material Handling 50 d. Maintenance Quality Assurance During Development 51 a. Vendor Certification Programs 51 b. Method Development and Validation 53 c. Packaging Qualification Programs 54 i) Packaging Material Specifications 55 ii) Packaging Process Validation 56 iii) Package Integrity Testing 57 iv) Packaged Product Quality Testing 58 v) Packaging as Contamination Control 58 d. Documentation Systems 58 e. Product Reveiw What Manufacturing and Regulatory Need to Know from Development 59 Recommended Reading 61 C. Regulatory Requirements Regulatory Application to FDA: Drugs 68 a. Investigational New Drug (IND) Applications 68 b. Clinical Investigations of New Drugs 69

4 Table of Contents vii c. New Drug Applications (NDA) 70 i) Chemistry, Manufacturing and Control 71 ii) Non-Clinical Pharmacology and Toxicology iii) -Human Pharmacokinetics and Bioavailability. 72 iv) Microbiology 72 v) Clinical Study Data 73 vi) Statistical Evaluations 74 vii) Commitment 74 d. Paper NDAs and Abbreviated New Drug Applications (ANDAs) 74 e. Accelerated Review Processes 75 f. Drug Master Files 75 g. Post Marketing Surveillance (PMS)/ Phase IV Trials Regulatory Application to the FDA: Biologicals 78 a. IND Notices to CBER : 79 b. Product License Application (PLA)/ Establishment License Applications (ELA) 81 c. Post Licensure Phase Regulatory Application to the FDA: Devices 81 a. Device Establishment Registration 83 b. Device Classification 84 c. Special Controls/Performance Standard Development 85 d. Premarket Notification (PMN) or 510k 86 e. Investigational Device Exemptions (IDE) 87 f. Premarket Approval (PMA) 88 g. Device Master File (MAF) 89 h. Adverse Device Reporting 90 i) User Reports 90 ii) Distributor Reports 90 iii) Device Tracking and Post Market Surveillance 90 iv) Complaints and Medical Device Reporting Regulatory Application to the FDA: Diagnostics Combination Products 92 Recommended Reading 92 II. GOOD MANUFACTURING PRACTICES 101 A. The Facility Qualification Master Protocol The Company, the 'Business and the Product Departmental Organization/Staffing Facility Layout/Flow of Materials 105

5 viii Drug, Device and Diagnostic Manufacturing 4. Major Utility and Processing Equipment Documentation System Design Master Plan Validation Master Plan Monitoring and Control System Master Plan 107 B. Documentation and Document Control General Guidelines 109 a. Language 109 b. Change Control 110 c. Format, Approval and Control Ill d. Investigations and Deviations Ill 2. Numbering Systems 113 a. Production Batch Numbers 113 b. Part Numbers 114 c. Change Control Numbers 115 d. Standard Operating Procedure Numbers e. Master Batch Record Numbers 115 f. Receiving Code Numbers 116 g. Form Numbers 116 h. Equipment Numbers 116 i. Edition Numbers Raw Material, Subassembly and Final Product Specifications Standard Operating Procedures Master Batch Records 123 C. Departmental Organization/Responsibilities Production 127 a. The Production Environment 127 b. The Production Process 129 i) Production Process Control: Accountability ii) Production Process Control: Traceability iii) Production Process Control: Documentation c. Controlling Production Activities Material Handling 136 a. Receiving, b. Control and Movement of Materials 139 c. Inventory Control and Storage 140 d. Shipment 140 e. Hazardous Materials Maintenance/Engineering 141 a. Departmental'Management and Organization b. Maintenance/Engineering Programs 142 i) Facility Upkeep 142

6 Table of Contents ix ii) Routine Use of Equipment and Utilities 143 iii) Preventive Maintenance Programs 144 iv) Unscheduled and Emergency Maintenance Quality Control/Quality Assurance 146 a. Departmental Organization and Management i) Quality Department Sections 147 ii) Laboratory Design Requirements 149 b. Systems Quality Control 150 c. Process Quality Assurance 151 d. Quality Control of Quality Control 152 e. Qualification and Validation Activities 153 f. Biological Hazard Control 154 g. Employee Training Programs 154 i) Training: Who, What, When and Why 154 ii) Training in Biotechnology Industries 156 iii) Training Program Topics 156 h. Product Review 160 D. Master Validation Protocol Equipment Validation Protocols 163 a. Installation Qualification 163 b. Operational Qualification 166 c. Performance Qualification Method Validation Protocols Process Validation Protocols 174 E. Quality Assurance Monitoring and Control Programs 176 Recommended Reading 180 III. SPECIAL TOPICS 189 A. Clean Rooms for Aseptic Processing Clean Room Design Considerations 189 a. Room Size and Layout 189 b. Airflow Characteristics in Clean Rooms 190 c. Critical vs. Controlled Areas 191 d. Construction Materials. 192 e. Air Velocity and Volume 193 f. Environmental Considerations/Classifications i) Temperature and Humidity Control 194 ii) Particulate Classifications 194 iii) Viable Particulates 195 g. Special Considerations 195

7 Drug, Device and Diagnostic Manufacturing 2. Clean Room Validation 196 a. Installation Qualification 196 b. Operational Qualification 196 c. Performance Qualification: Sampling and Interpretation of Data 198 d. Validation of Aseptic Processing in Clean Rooms Routine Documentation and Control Compliance 202 Recommended Reading 202 B. Endotoxin Testing and Depyrogenation Techniques History of LAL Endotoxin Testing LAL Testing Methods and Validation 207 a. LAL Testing Methods 207 b. Validation of LAL Procedures 207 i) Endotoxin Standardization 208 ii) Lysate Sensitivity 208 iii) Technician Proficiency 208 iv) LAL Endotoxin Test or Rabbit Pyrogen Test. 208 v) Product Inhibition and Enhancement Testing 209 c. Routine Testing Controls Sample Preparation Depyrogenation Methods 210 a. Endotoxin Deactivation Techniques 211 i) Acid or Base Hydrolysis 211 ii) Oxidation 211 iii) Alkylation 212 iv) Dry Heat 212 v) Moist Heat ' b. Endotoxin Removal Techniques 212 i) Rinsing or Dilution 213 ii) Distillation or Reverse Osmosis 213 iii) Ultrafiltration 213 iv) Cationic Adsorbents 214 v) Hydrophobic Attraction 214 vi) Activated Carbon.' 214 vii) Affinity Chromatography 214 c. Endotoxin Challenge Preparation LAL Reactive Material 215 Recommended Reading 216

8 Table of Contents xi C. Lyophilization The Drying Process 220 a. Freezing 220 b. Primary Drying 221 c. Secondary Drying Product Cycle Design 223 a. Freezing Characteristics 224 b. Drying Equipment Design Considerations Validation 226 a. Installation Qualification 226 b. Operational Qualification 226 i) Temperature Distribution 227 ii) Leak Testing 227 iii) Disinfection/Sterilization 228 c. Media Fills 228 d. Performance Qualification Cycles Cleaning and Sterilization 229 a. Sources of Chemical Contamination 229 b. Cleaning/Disinfecting Agents and Techniques Special Considerations 231 a. Stoppers 231 i) Composition 231 ii) Moisture Content 231 iii) Siliconization/Sealing Capability 231 b. Head-space Conditions of Final Product 232 c. High Moisture Content of Final Product 232 d. Transfer of Cycles from Unit to Unit; Product to Product 232 Recommended Reading 232 D. Particulate Monitoring and Control for Parenteral and Implantable Product Manufacturing Particulate Contamination: Sources and Control a. Personnel 235 b. Components 236 c. Clean Rooms Particulate Sampling Plans Particulate Sampling Techniques 237 a. Air or Gas Sampling 237 b. Surface Sampling 238 c. Solid or Powder Sampling 238 d. Liquid Sampling 238

9 xii Drug, Device and Diagnostic Manufacturing 4. Particulate Evaluation Methods 239 a. Visual Inspection 239 b. Microscopic Analysis of Particulates 239 c. Particulate Analysis by Light Obscuration 239 i) The Light Obscuration Method 239 ii) The Sampling and Measuring Equipment iii) Sampling Variables Particulate Matter in Injections, USP 241 a. Sampling 241 b. Methods of Analysis 242 c. USP Specifications 242 Recommended Reading 243 E. Physical Sterilization Techniques and Validation Dry Heat Sterilization 245 a. Equipment, 245 b. Cycle Considerations 245 c. Validation 246 d. Routine Documentation and Control Steam Sterilization 247 a. Steam: The Pressure/Temperature Relationship b. Equipment 248 c. Cycle Design Considerations 248 d. Validation 249 e. Routine Documentation and Control 250 f. Steam-in-Place Technology Filter Sterilization 251 a. Sterilizing Filters 252 b. The Filtration Process 252 c. Non-Destructive Integrity Testing 252 d. Validation : 253 e. Routine Filter Sterilization Radiation Sterilization 254 a. Validation 255 b. Cycle Design Considerations 255 c. Routine Documentation and Control 255 Recommended Reading 256 F. Stability Testing Programs Stability Studies Throughout Development 260 a. Stability Testing to Eliminate Alternatives 260 i) Raw Material/Drug Substance Stability Testing 261 ii) Processing Intermediates 262

10 Table of Contents xiii iii) Final Product Testing 263 iv) Container-Closure Testing 263 b. Regulatory Milepost Stability Testing 264 c. Final Product Storage Conditions and Expiration Dating The Protocol 265 a. Storage Conditions 266 b. Sampling Plans 266 c. Testing Parameters 266 d. Sampling Schedule/Technique : 267 e. Observations/Interpretation/Documentation 267 f. Commitment to Report Routine Stability Testing for Established Product Lines Process Change or Component Change Evaluation Recommended Reading 268 G. Disinfection Programs Disinfection Program Planning Disinfectants 272 a. Aldehydes 273 b. Phenolics 274 c. Chlorines 274 d. Alcohols 274 e. Oxidizing Agents 275 f. Iodophors 275 g. Surface Active Agents Scheduling and Use of Disinfectants 275 a. Formulation and Application of Disinfectants b. Scheduling of Disinfection Activities In-house Qualification and Monitoring of Disinfectant Effectiveness Disinfectant Residues Control of Retroviruses 278 Recommended Reading 279 H. Water Purification and Water Quality Testing Potable Water Purified Water 283 a. Particulate Removal 283 b. Carbon Filters 283 c. Water Softening 284 d. Deionization 284 i) Reverse Osmosis 284

11 xiv Drug, Device and Diagnostic Manufacturing ii) Ion Exchange 285 iii) Continuous Deionization/Electrodeionization e. Microbial Control Systems 287 i) Ultraviolet (UV Disinfection Systems 287 ii) Filtration Water for Injection 288 a. System Design Considerations 289 i) General Considerations 289 ii) Stainless Steel Construction Materials 289 iii) The Still 290 iv) The Distribution System 290 v) Storage 291 vi) A Cold Water System 291 b. System Integrity Testing 292 c. Cleaning of Water Distribution Systems 292 d. Passivation of Water Distribution Systems e. Sanitization/Sterilization of Distribution Systems Water System Validation 293 Recommended Reading 295 I. Computer Controlled Process Validation Installation Qualification 300 a. Hardware 300 b. Software 300 c. Computerized Interaction with Process Operational Qualification Process Validation Product Validation Routine Documentation and Control 305 Recommended Reading 305 J. Safety Programs Administration Safety Assessments 310 a. Physical Safety 310 b. Chemical Safety 311 c. Biological Safety 311 d. Radiation Safety Safety Plans/Protocols Accidents/Injury Response Plans Safety Information and Training Programs Safety Audits 313 Recommended Reading 313

12 Table of Contents xv IV. APPENDIX A. Information Sources Agencies Associations, Institutes and Laboratories Journals, Newsletters, Periodic Reports Publishers References Seminars, Symposia, Workshops, Training Programs 350 B. Standard Operating Procedures: List of Titles 1. Administrative/Quality Assurance Maintenance 3. Material Handling Production Quality Control 356 C. Glossary of Abbreviations 358 D. Agency Organization Charts 362 E. International Regulatory Agencies 412 INDEX 417