Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing -- Contents -- Preface -- Contributors -- About the Authors -- 1 Background and Introduction -- 1.1 RISK MANAGEMENT OF PHARMACEUTICAL AND BIOPHARMACEUTICAL MANUFACTURE -- 1.2 A PRACTICAL GUIDE TO RISK MANAGEMENT -- 1.2.1 Additional Points to Consider -- 1.3 OVERVIEW OF THE BOOK -- 1.4 FINAL THOUGHTS -- REFERENCES -- 2 Risk Management Tools -- 2.1 APPLICABILITY -- 2.2 RISK MANAGEMENT -- 2.3 RISK MANAGEMENT PROCESS -- 2.3.1 Risk Assessment -- 2.3.2 Risk Control -- 2.3.3 Risk Review/Communication -- 2.4 RISK ANALYSIS/ASSESSMENT TOOLS -- 2.4.1 Preliminary Hazard Analysis (PHA) -- 2.4.2 Failure Mode Effects Analysis (FMEA) and Failure Mode Effects and Criticality Analysis (FMECA) -- 2.4.3 Hazard and Operability Analysis (HAZOP) -- 2.4.4 Fault Tree Analysis (FTA) -- 2.4.5 Hazard Analysis and Critical Control Point (HACCP) -- 2.4.6 Risk Ranking and Filtering (RRF) -- 2.4.7 Other Risk Analysis Tools -- 2.5 BASIC FACILITATION TOOLS -- 2.5.1 Flowcharts -- 2.5.2 Process Mapping -- 2.5.3 Check Sheets -- 2.5.4 Cause and Effect Diagrams (Fishbone or Ishikawa Diagram) -- 2.5.5 5 Why Analysis -- 2.5.6 Histograms -- 2.5.7 Pareto Analysis -- 2.5.8 Control Charts -- 2.6 COMPARISON OF RISK ASSESSMENT TOOLS -- 2.7 RESIDUAL RISK EVALUATION -- 2.8 SOURCES OF RISK INFORMATION -- 2.9 CONCLUSION -- DEFINITIONS -- ACKNOWLEDGMENT -- REFERENCES -- FURTHER READING -- 3 Risk Management: Regulatory Expectation, Risk Perception, and Organizational Integration -- 3.1 INTRODUCTION -- 3.2 QRM REGULATORY EXPECTATIONS -- 3.2.1 General System Expectations -- 3.2.2 Establishing Risk Communication and Reporting Mechanisms -- 3.2.3 Risk Registers -- 3.2.4 Audit of the Risk Management Systems -- 3.3 PROBLEMS OF SUBJECTIVITY AND UNCERTAINTY DURING QRM EXERCISES.

3.3.1 Cognitive Operations When Assessing Risk: "This is Your Brain on Risk" -- 3.3.2 Perception and Perspectivism -- 3.3.3 Risk's Precautionary Principle -- 3.3.4 Risk Regulation's Unintended Consequence: Asymmetry of Risk Knowledge -- 3.4 INTEGRATION INTO ORGANIZATIONAL PROCESSES -- 3.4.1 Training -- 3.5 CONCLUSION -- REFERENCES -- 4 Statistical Topics and Analysis in Risk Assessment -- 4.1 INTRODUCTION -- 4.2 UNCERTAINTY -- 4.3 LUCK AND PROBABILITY -- 4.4 DEFINITIONS OF PROBABILITY -- 4.5 RULES OF PROBABILITY -- 4.6 CAUTIONS -- 4.7 RISK -- 4.7.1 Venn Diagram -- 4.7.2 Conditional Probability -- 4.8 STATISTICAL RISK -- 4.9 RARE EVENTS -- 4.9.1 Calculating POISSON -- 4.10 COINCIDENCES -- 4.11 ESTIMATING PROBABILITIES -- 4.12 CONCLUSION -- REFERENCES -- FURTHER READING -- 5 Quality by Design -- 5.1 BACKGROUND -- 5.2 DEVELOPMENT OF PRODUCTS USING A QBD APPROACH -- 5.3 MAIN STEPS FOR A QUALITY BY DESIGN APPROACH FOR A NEW PRODUCT -- 5.4 EXAMPLES OF QBD APPROACHES -- 5.5 CONCLUSION -- GLOSSARY AND DEFINITIONS -- REFERENCES -- 6 Process Development and Clinical Product Manufacturing -- 6.1 QUALITY VISION OF PHARMACEUTICAL DEVELOPMENT -- 6.2 BASIS FOR DESIGN-TARGET PRODUCT PROFILE AND PRELIMINARY HAZARD ANALYSIS -- 6.3 PRODUCT CONTROL STRATEGY -- 6.4 USE OF DESIGN OF EXPERIMENT (DOE) TO ELIMINATE AND STUDY (C)PPS AT LABORATORY SCALE -- 6.5 PRECLINICAL STUDIES AND RISK MANAGEMENT FOR FIRST-IN-HUMAN TRIALS -- 6.6 PHASE 1 THROUGH PHASE 3 CLINICAL TRIALS -- 6.7 PRODUCT SPECIFICATION FILE, DEVELOPMENT HISTORY, AND TECHNOLOGY TRANSFER -- 6.8 SUMMARY -- REFERENCES -- 7 Points to Consider for Commissioning and Qualification of Manufacturing Facilities and Equipment -- 7.1 INTRODUCTION AND BACKGROUND -- 7.1.1 Qualification, Risk, and Regulatory Expectations -- 7.1.2 Risk-Based Qualification and Assurance of Quality.

7.1.3 Role of Quality and the Quality Unit in Risk-Based Qualification -- 7.1.4 Role of Commissioning in Risk-Based Qualification -- 7.1.5 Qualification and Risk Management -- 7.2 RISK-BASED QUALIFICATION PLANNING -- 7.2.1 Project Description -- 7.2.2 Project Controls -- 7.2.3 Project Performance Metrics -- 7.2.4 Schedules -- 7.2.5 Program-Level Alignment -- 7.2.6 System Boundaries -- 7.2.7 Leveraging Risk-Based Qualification Information -- 7.2.8 Other Types of Information Leveraging -- 7.2.9 Information Management as a Tool for Risk Management -- 7.3 IMPLEMENTATION -- 7.3.1 Risk-Based Qualification Plan -- 7.3.2 Define which Items to Qualify -- 7.3.3 Linking Product Quality Risk to Qualification Testing -- 7.3.4 Impact Assessment: Deciding What to Qualify -- 7.3.5 System- and Component-Level Impact Assessments -- 7.3.6 System Impact Assessments -- 7.3.7 Component Impact Assessments -- 7.3.8 To What Extent Would it be Qualified? -- 7.3.9 Criticality Analysis -- 7.3.10 Risk Ranking Level of Detail -- 7.3.11 Test Function and Acceptance Criteria -- 7.3.12 Qualification Plan Implementation Notes -- 7.3.13 Risk-Based Design Review -- 7.3.14 Risk of Using Information before Identification of Critical Process Parameters -- 7.3.15 Installation Qualification -- 7.3.16 Operational Qualification -- 7.3.17 Computer System Validation -- 7.3.18 Requalification -- 7.3.19 Performance Qualification: Contamination Control -- 7.3.20 Change Control -- 7.3.21 Failure Investigation -- 7.3.22 Project Close Out -- 7.4 CONCLUSION -- REFERENCES -- 8 Process Lifecycle Validation -- 8.1 INTRODUCTION -- 8.2 REGULATORY GUIDANCE FOR QRM IN PROCESS VALIDATION -- 8.3 TYPICAL QRM TOOLS USED -- 8.4 GENERAL CONSIDERATIONS OF QRM IN PROCESS VALIDATION -- 8.4.1 Process Steps -- 8.4.2 Closeness to Patient -- 8.4.3 Level of Testing and Number of Studies -- 8.4.4 Validation Approach.

8.5 CHALLENGES IN USING RISK-BASED VALIDATION -- 8.6 LIFECYCLE APPROACH -- 8.7 PROCESS DESIGN -- 8.7.1 Risk-Based Study Design -- 8.7.2 Critical Process Parameters -- 8.7.3 Example 1: Defining Controls for Tablet Compression/Coating Process -- 8.7.4 Example 2: Mixing Study for Solutions and Product Pool -- 8.7.5 Example 3: Hold Times Study for Solutions and Product Pool -- 8.7.6 Risk Prioritization in Large-Scale Experiments -- 8.8 PROCESS PERFORMANCE QUALIFICATION -- 8.8.1 Technology Transfer -- 8.8.2 Example 4: QRM Application for Multiproduct Operations -- 8.9 CONTINUED PROCESS VERIFICATION -- 8.9.1 Determining the Significance of a Process Change -- 8.9.2 Defining a Periodic Review Schedule of Validated Process/Systems -- 8.10 CLEANING VALIDATION AND CROSS CONTAMINATION RISKS -- 8.10.1 Equipment Dirty Hold Time in Cleaning Validation -- 8.11 SUMMARY -- DISCLAIMER -- REFERENCES -- 9 Aseptic Processing: One -- 9.1 INTRODUCTION -- 9.2 ASEPTIC PROCESS DESIGN RESPONSE -- 9.3 RISK ASSESSMENT -- 9.4 RISK MITIGATION -- 9.4.1 Facilities -- 9.4.2 Environment -- 9.4.3 Equipment/Utensils -- 9.4.4 Containers/Closures -- 9.4.5 Product -- 9.4.6 Procedures -- 9.4.7 Personnel -- 9.5 STERILITY (SAFETY) BY DESIGN -- 9.6 CONCLUSION -- REFERENCES -- 10 Aseptic Processing: Two -- 10.1 INTRODUCTION -- 10.2 PATIENT RISK -- 10.3 RISK ASSESSMENT AND RISK MANAGEMENT -- 10.4 MEASURING AND CONTROLLING RISK -- 10.5 ASEPTIC PROCESSING HAZARDS -- 10.5.1 Intrinsic Hazards -- 10.5.2 Extrinsic Hazards -- 10.5.3 Risk of Endotoxin -- 10.6 MODEL FOR MICROBIAL INGRESS -- 10.7 RISK HIERARCHY -- 10.8 QUALITY BY DESIGN, QUANTITATIVE RISK ASSESSMENT, AND PRODUCT DISPOSITION -- 10.8.1 Improving Assessments of Microbial Risks -- 10.8.2 Culture-Based Microbial Test Methods are Inadequate Measurements of Product Quality.

10.8.3 Superior Assurance of Product Quality is Achieved by Quantitative Risk Assessment -- 10.9 FUTURE TRENDS AND THEMES -- REFERENCES -- 11 Pharmaceutical Product Manufacturing -- 11.1 ROLE OF QUALITY RISK MANAGEMENT -- 11.2 RISK ASSESSMENT IN PHARMACEUTICAL MANUFACTURING -- 11.2.1 Raw Materials -- 11.2.2 Formulation -- 11.2.3 Finish Processing -- 11.2.4 Facility -- 11.2.5 Equipment and Instruments -- 11.2.6 People -- 11.3 CASE STUDY: MICROBIOLOGICAL CONTROL IN NONSTERILE MANUFACTURING -- 11.3.1 Risk-Based Approach Management Tool: What is HACCP? -- 11.3.2 History of HACCP -- 11.3.3 Benefits of HACCP for Microbiological Control -- 11.3.4 HACCP Process -- 11.4 CONCLUSION -- Appendix I: List of Potential Risks Associated with Drug Product Manufacture -- GLOSSARY -- REFERENCES -- 12 Biopharmaceutical Manufacturing -- 12.1 A GENERAL APPROACH TO IMPLEMENTING QRM IN BIOPHARMACEUTICAL MANUFACTURING -- 12.2 UNDERSTANDING CRITICAL QUALITY ATTRIBUTES AND CRITICAL PROCESS PARAMETERS -- 12.2.1 Quality Risk Management in the Identification of CQAS and CPPS -- 12.3 INDIVIDUAL PROCESS STAGES AND ASSOCIATED RISKS -- 12.3.1 Raw Materials -- 12.3.2 Cell Banking -- 12.3.3 Fermentation/Cell Culture -- 12.3.4 Downstream Processing -- 12.3.5 Scale-Up of Production Process -- 12.3.6 Excipients -- 12.3.7 Primary Packaging -- 12.3.8 Extractable/Leachables -- 12.3.9 Distribution and Cold Chain Supply -- 12.4 SUMMARY AND CONCLUSIONS -- APPENDIX A: APPLICATION OF RISK MANAGEMENT TOOLS TO BIOPHARMACEUTICAL MANUFACTURING -- A.1 Case Study: Raw Material Hazard Analysis -- A.2 Prerequisites -- A.3 Risk Assessment -- A.4 Risk Control -- REFERENCES -- 13 Risk-Based Change Control -- 13.1 INTRODUCTION AND KEY POINTS -- 13.1.1 Key Points -- 13.2 CHANGE CONTROL PROCESS -- 13.3 BENEFITS OF USING QRM FOR CHANGE CONTROL -- 13.4 ONE QRM TOOL: FMEA -- 13.5 KEYS TO SUCCESSFUL IMPLEMENTATION.

13.6 USE OF A RISK ASSESSMENT TOOL IN CHANGE CONTROL.