Fundamentals of Pharmaceutical and Biologic Regulations: A Global Perspective
xii Regulatory Affairs Professionals Society
Table 4-2. CV Study Designs and End Points............................................................................................................................................... 39
Table 4-3. Stand-Alone CV or Combined Cardio-Respiratory Telemetry Studies – Latin Square (4x4) Study Design ..............................40
Table 4-4. Integrated CV or Cardio-Respiratory Telemetry End Points in a Nonrodent, Repeat-Dose, Toxicology Study Design ............41
Table 4-5. Stand-Alone Rodent Respiratory or CNS (FOB or modified Irwin) Parallel Study Design .......................................................42
Table 4-6. Combined Respiratory and CNS (FOB or modified Irwin) Study in Rodent Repeat Dose Toxicology Study Design ...............42
Table 4-7. Safety Pharmacology Strategies for Pharmaceuticals and Biopharmaceuticals .............................................................................44
Table 5-1. Parameters for Comparing Drug Exposure Across Studies ..........................................................................................................55
Table 5-2. Global Implementation of Major ICH Guidance Relevant to Pharmacokinetic and Toxicokinetic Studies ...............................56
Table 5-3. Preclinical Case Study: ZILRETTA ............................................................................................................................................61
Table 6-1. International Regulatory and Guidance Documents ....................................................................................................................66
Table 6-2. Standard List of Clinical Chemistry Parameters Evaluated in GLP Toxicology Studies .............................................................69
Table 6-3. Standard List of Clinical Chemistry Parameters Evaluated in GLP Toxicology Studies .............................................................70
Table 6-4. Common Species Used in General Toxicology Studies ................................................................................................................73
Table 7-1. Maximum Applicable Volume (mL) for Local Tolerance Testing of Parenteral Drugs in Two Commonly Used Animal
Models ....................................................................................................................................................................................................79
Table 7-2. Study Design for Single Dose Subcutaneous Local Tolerance Study in Male New Zealand White Rabbits ...............................80
Table 7-3. Testing Procedures for Local Tolerance Testing ..........................................................................................................................81
Table 8-1a. ICH S2(R1) Recommendations for In Vitro Genotoxicity Testing ...........................................................................................85
Table 8-1b. ICH S2(R1) Recommendations for In Vitro Genotoxicity Testing ...........................................................................................86
Table 8-2a. ICH S2(R1) Recommendations for In Vivo Genotoxicity Testing ............................................................................................87
Table 8-2b. ICH S2(R1) Recommendations for In Vivo Genotoxicity Testing ............................................................................................87
Table 8-3. Overview of Common In Vitro and In Vivo Genotoxicity Testing Assays ..................................................................................89
Table 9-1. Global Implementation of Major ICH Guidance on Carcinogenicity .........................................................................................97
Table 9-2. Key Weight of Evidence Factors for Integrated Assessments of Carcinogenic Potential ...........................................................104
Table 10-1. DART Strategy for Pharmaceuticals and Biologics Depending on Relevant Species ..............................................................111
Table 10-2. Embryofetal Development Study Design Parameters for Rodent, Rabbit and Nonhuman Primate Species ...........................111
Table 10-3. Considerations for the Design of an Enhanced Pre- and Postnatal Development Toxicity Study in Nonhuman
Primates ................................................................................................................................................................................................113
Table 10-4. Considerations for Design of a Pre- and Postnatal Development Toxicity Study in Rats ........................................................114
Table 10-5. Potential Species for DART Studies ........................................................................................................................................115
Table 11-1. Studies Required During the EU Environmental Risk Assessment Process ............................................................................126
Table 12-1. Global Regulatory Active Substances Filing Requirements ......................................................................................................139
Table 12-2. Master File Classifications ........................................................................................................................................................142
Table 12-3. Type of Fee (Active Substance Manufacturers) ........................................................................................................................144
Table 12-4. Type of Fee (Active Substance Importers and Distributors) ....................................................................................................144
Table 13-1. Differences and Similarities in Manufacturing Information Provided in Commercial Product Applications ..........................156
Table 13-2. Elucidation of Structure Requirements Based on ICH Guidelines: Q6A and Q6B ................................................................157
Table 13-3. Impurities Requirements Based on ICH Q3A, Q3C, Q5C, Q6A, and Q6B and Applicable National Health Authority
Guidance............................................................................................................................................................................................... 157
Table 13-4. Representative Analytical Methods and Rationale Recommended by ICH Q6A and Q6B and ATMP Guidance ................158
Table 14-1. Components of Clinical Supply Chain Strategy .......................................................................................................................164
Table 14-2. Clinical Development Stages ....................................................................................................................................................164
Table 14-3. Comparing Clinical and Commercial Supply ...........................................................................................................................166
Table 15-1. Comparison of Regulatory Guidance Based on Quality by Design Principles in Major Markets ............................................176
Table 15-2. Summary and Comparison of Artificial Intelligence Guidance in Global Markets Related to Pharmaceutical
Development ........................................................................................................................................................................................180
Table 15-3. Container Content/Volume Label Claim/Extractable Volume Test Regional Comparison ....................................................181
Table 15-4. Dosage Form Compatibility Cases ...........................................................................................................................................184
Table 15-5. Typical Packaging Suitability Considerations for Common Classes of Drug Products ............................................................184
Table 15-6. Extent and Design of Interaction Studies .................................................................................................................................185
Table 15-7. Dissolution Test Methods Most Commonly Used ...................................................................................................................186
Table 15-8. Biopharmaceutics Classification System ...................................................................................................................................187
Table 15-9. Considerations for Specific Dosage Forms ...............................................................................................................................187
Table 15-10. Most Common Routes of Administration: Advantages and Disadvantages........................................................................... 188
xii Regulatory Affairs Professionals Society
Table 4-2. CV Study Designs and End Points............................................................................................................................................... 39
Table 4-3. Stand-Alone CV or Combined Cardio-Respiratory Telemetry Studies – Latin Square (4x4) Study Design ..............................40
Table 4-4. Integrated CV or Cardio-Respiratory Telemetry End Points in a Nonrodent, Repeat-Dose, Toxicology Study Design ............41
Table 4-5. Stand-Alone Rodent Respiratory or CNS (FOB or modified Irwin) Parallel Study Design .......................................................42
Table 4-6. Combined Respiratory and CNS (FOB or modified Irwin) Study in Rodent Repeat Dose Toxicology Study Design ...............42
Table 4-7. Safety Pharmacology Strategies for Pharmaceuticals and Biopharmaceuticals .............................................................................44
Table 5-1. Parameters for Comparing Drug Exposure Across Studies ..........................................................................................................55
Table 5-2. Global Implementation of Major ICH Guidance Relevant to Pharmacokinetic and Toxicokinetic Studies ...............................56
Table 5-3. Preclinical Case Study: ZILRETTA ............................................................................................................................................61
Table 6-1. International Regulatory and Guidance Documents ....................................................................................................................66
Table 6-2. Standard List of Clinical Chemistry Parameters Evaluated in GLP Toxicology Studies .............................................................69
Table 6-3. Standard List of Clinical Chemistry Parameters Evaluated in GLP Toxicology Studies .............................................................70
Table 6-4. Common Species Used in General Toxicology Studies ................................................................................................................73
Table 7-1. Maximum Applicable Volume (mL) for Local Tolerance Testing of Parenteral Drugs in Two Commonly Used Animal
Models ....................................................................................................................................................................................................79
Table 7-2. Study Design for Single Dose Subcutaneous Local Tolerance Study in Male New Zealand White Rabbits ...............................80
Table 7-3. Testing Procedures for Local Tolerance Testing ..........................................................................................................................81
Table 8-1a. ICH S2(R1) Recommendations for In Vitro Genotoxicity Testing ...........................................................................................85
Table 8-1b. ICH S2(R1) Recommendations for In Vitro Genotoxicity Testing ...........................................................................................86
Table 8-2a. ICH S2(R1) Recommendations for In Vivo Genotoxicity Testing ............................................................................................87
Table 8-2b. ICH S2(R1) Recommendations for In Vivo Genotoxicity Testing ............................................................................................87
Table 8-3. Overview of Common In Vitro and In Vivo Genotoxicity Testing Assays ..................................................................................89
Table 9-1. Global Implementation of Major ICH Guidance on Carcinogenicity .........................................................................................97
Table 9-2. Key Weight of Evidence Factors for Integrated Assessments of Carcinogenic Potential ...........................................................104
Table 10-1. DART Strategy for Pharmaceuticals and Biologics Depending on Relevant Species ..............................................................111
Table 10-2. Embryofetal Development Study Design Parameters for Rodent, Rabbit and Nonhuman Primate Species ...........................111
Table 10-3. Considerations for the Design of an Enhanced Pre- and Postnatal Development Toxicity Study in Nonhuman
Primates ................................................................................................................................................................................................113
Table 10-4. Considerations for Design of a Pre- and Postnatal Development Toxicity Study in Rats ........................................................114
Table 10-5. Potential Species for DART Studies ........................................................................................................................................115
Table 11-1. Studies Required During the EU Environmental Risk Assessment Process ............................................................................126
Table 12-1. Global Regulatory Active Substances Filing Requirements ......................................................................................................139
Table 12-2. Master File Classifications ........................................................................................................................................................142
Table 12-3. Type of Fee (Active Substance Manufacturers) ........................................................................................................................144
Table 12-4. Type of Fee (Active Substance Importers and Distributors) ....................................................................................................144
Table 13-1. Differences and Similarities in Manufacturing Information Provided in Commercial Product Applications ..........................156
Table 13-2. Elucidation of Structure Requirements Based on ICH Guidelines: Q6A and Q6B ................................................................157
Table 13-3. Impurities Requirements Based on ICH Q3A, Q3C, Q5C, Q6A, and Q6B and Applicable National Health Authority
Guidance............................................................................................................................................................................................... 157
Table 13-4. Representative Analytical Methods and Rationale Recommended by ICH Q6A and Q6B and ATMP Guidance ................158
Table 14-1. Components of Clinical Supply Chain Strategy .......................................................................................................................164
Table 14-2. Clinical Development Stages ....................................................................................................................................................164
Table 14-3. Comparing Clinical and Commercial Supply ...........................................................................................................................166
Table 15-1. Comparison of Regulatory Guidance Based on Quality by Design Principles in Major Markets ............................................176
Table 15-2. Summary and Comparison of Artificial Intelligence Guidance in Global Markets Related to Pharmaceutical
Development ........................................................................................................................................................................................180
Table 15-3. Container Content/Volume Label Claim/Extractable Volume Test Regional Comparison ....................................................181
Table 15-4. Dosage Form Compatibility Cases ...........................................................................................................................................184
Table 15-5. Typical Packaging Suitability Considerations for Common Classes of Drug Products ............................................................184
Table 15-6. Extent and Design of Interaction Studies .................................................................................................................................185
Table 15-7. Dissolution Test Methods Most Commonly Used ...................................................................................................................186
Table 15-8. Biopharmaceutics Classification System ...................................................................................................................................187
Table 15-9. Considerations for Specific Dosage Forms ...............................................................................................................................187
Table 15-10. Most Common Routes of Administration: Advantages and Disadvantages........................................................................... 188