x
Table 18-1. Selected FDA Regulations for the Labeling of Prescription Drugs. ..........................................................................248
Table 18-2. Selected FDA Regulations for Device Labeling......................................................................................................... 249
Table 18-3. FDA’s Categorization of Promotional Materials (21 CFR 202.1(l)). .........................................................................250
Table 18-4. Summary of PI Sections Under the PLR, Including Relevant Regulations and Available Guidance. .......................257
Table 18-5. Other Product Claim Types. ......................................................................................................................................266
Table 18-6. Risk-Related Sections of the PI Ranked From Most to Least Important.................................................................. 271
Table 19-1. Regional Regulatory Authorities................................................................................................................................ 302
Table 19-2. Trial Master File Essential Documents. .....................................................................................................................310
Table 20-1. Contents of a CTA Submission Package.................................................................................................................... 317
Table 20-2. Quality Changes-Biologics and Radiopharmaceuticals.............................................................................................. 318
Table 20-3. Quality Changes—Pharmaceuticals........................................................................................................................... 319
Table 20-4. Postapproval Requirements. .......................................................................................................................................322
Table 22-1. Significant Legislation Relevant to Clinical Trials in the US..................................................................................... 335
Table 22-2. Comparison of 21 CFR and ISO-GCP Requirements for Protocol Deviations in Medical Device Clinical Trials.. 341
Table 22-3. Comparison of 21 CFR and ISO GCP Requirements for Investigator Responsibilities in Medical Device Clinical Trials... 367
Table 22-4. Comparison of 21 CFR and ISO-GCP Requirements for Recordkeeping in Medical Device Clinical Trials. .........370
Table 22-5. Comparison of 21 CFR and ISO-GCP Requirements for Device Accountability in Medical Device Clinical Trials. ...370
Table 23-1. Applicability of GxPs to Standardized Market Authorization Application Formats. ................................................388
Table 24-1. FDA Enforcement Actions. .......................................................................................................................................405
Table 26-1. ETASUs Approved Per Year. .....................................................................................................................................414
Table 28-1. Content Deviations Between ISO 14971:2007 and Directive 93/42/EEC on Medical Devices. ..............................424
Figures
Figure 1-1. Basic Process Model. ......................................................................................................................................................3
Figure 1-2. PDCA Cycle in Resource Management......................................................................................................................... 4
Figure 1-3. Mandatory Procedures and Documents for ISO 13485:2003...................................................................................... 11
Figure 1-4. Implementing an ISO 13485:2016 QMS..................................................................................................................... 13
Figure 1-5. Sample Schedule for QMS Implementation. ...............................................................................................................15
Figure 1-6. QMS Documentation Defining Responsibilities.......................................................................................................... 16
Figure 1-7. Typical QMS Document Hierarchy. ............................................................................................................................17
Figure 1-8. Iterative PDCA Cycle. .................................................................................................................................................20
Figure 1-9. ISO 17021 QMS Certification Cycle........................................................................................................................... 21
Figure 1-10. Design Process............................................................................................................................................................ 27
Figure 2-1. Process Flow of Interrelated QMS Processes. ..............................................................................................................36
Figure 2-2. PDCA Methodology.................................................................................................................................................... 37
Figure 2-3. Requirements Clauses in ISO 13485:2016. ..................................................................................................................38
Figure 2-4. Design and Development Control Steps. .....................................................................................................................40
Figure 2-5. Influence of Design Controls on the Design Process.................................................................................................... 40
Figure 2-6. Process Validation Decision Tree. .................................................................................................................................43
Figure 2-7. Key Activities for Supplier Control. .............................................................................................................................45
Figure 3-1. MDSAP Audit Sequence. ............................................................................................................................................55
Figure 3-2. MDSAP Nonconformity Grading Overview............................................................................................................... 57
Figure 3-3. MDSAP Nonconformity Grading Matrix. ..................................................................................................................58
Figure 3-4. MDSAP Post-Audit Activities and Timeline............................................................................................................... 59
Figure 4-1. Drug Lifecycle Regulations. .........................................................................................................................................63
Figure 4-2. Assessors and Inspectors............................................................................................................................................... 64
Table 18-1. Selected FDA Regulations for the Labeling of Prescription Drugs. ..........................................................................248
Table 18-2. Selected FDA Regulations for Device Labeling......................................................................................................... 249
Table 18-3. FDA’s Categorization of Promotional Materials (21 CFR 202.1(l)). .........................................................................250
Table 18-4. Summary of PI Sections Under the PLR, Including Relevant Regulations and Available Guidance. .......................257
Table 18-5. Other Product Claim Types. ......................................................................................................................................266
Table 18-6. Risk-Related Sections of the PI Ranked From Most to Least Important.................................................................. 271
Table 19-1. Regional Regulatory Authorities................................................................................................................................ 302
Table 19-2. Trial Master File Essential Documents. .....................................................................................................................310
Table 20-1. Contents of a CTA Submission Package.................................................................................................................... 317
Table 20-2. Quality Changes-Biologics and Radiopharmaceuticals.............................................................................................. 318
Table 20-3. Quality Changes—Pharmaceuticals........................................................................................................................... 319
Table 20-4. Postapproval Requirements. .......................................................................................................................................322
Table 22-1. Significant Legislation Relevant to Clinical Trials in the US..................................................................................... 335
Table 22-2. Comparison of 21 CFR and ISO-GCP Requirements for Protocol Deviations in Medical Device Clinical Trials.. 341
Table 22-3. Comparison of 21 CFR and ISO GCP Requirements for Investigator Responsibilities in Medical Device Clinical Trials... 367
Table 22-4. Comparison of 21 CFR and ISO-GCP Requirements for Recordkeeping in Medical Device Clinical Trials. .........370
Table 22-5. Comparison of 21 CFR and ISO-GCP Requirements for Device Accountability in Medical Device Clinical Trials. ...370
Table 23-1. Applicability of GxPs to Standardized Market Authorization Application Formats. ................................................388
Table 24-1. FDA Enforcement Actions. .......................................................................................................................................405
Table 26-1. ETASUs Approved Per Year. .....................................................................................................................................414
Table 28-1. Content Deviations Between ISO 14971:2007 and Directive 93/42/EEC on Medical Devices. ..............................424
Figures
Figure 1-1. Basic Process Model. ......................................................................................................................................................3
Figure 1-2. PDCA Cycle in Resource Management......................................................................................................................... 4
Figure 1-3. Mandatory Procedures and Documents for ISO 13485:2003...................................................................................... 11
Figure 1-4. Implementing an ISO 13485:2016 QMS..................................................................................................................... 13
Figure 1-5. Sample Schedule for QMS Implementation. ...............................................................................................................15
Figure 1-6. QMS Documentation Defining Responsibilities.......................................................................................................... 16
Figure 1-7. Typical QMS Document Hierarchy. ............................................................................................................................17
Figure 1-8. Iterative PDCA Cycle. .................................................................................................................................................20
Figure 1-9. ISO 17021 QMS Certification Cycle........................................................................................................................... 21
Figure 1-10. Design Process............................................................................................................................................................ 27
Figure 2-1. Process Flow of Interrelated QMS Processes. ..............................................................................................................36
Figure 2-2. PDCA Methodology.................................................................................................................................................... 37
Figure 2-3. Requirements Clauses in ISO 13485:2016. ..................................................................................................................38
Figure 2-4. Design and Development Control Steps. .....................................................................................................................40
Figure 2-5. Influence of Design Controls on the Design Process.................................................................................................... 40
Figure 2-6. Process Validation Decision Tree. .................................................................................................................................43
Figure 2-7. Key Activities for Supplier Control. .............................................................................................................................45
Figure 3-1. MDSAP Audit Sequence. ............................................................................................................................................55
Figure 3-2. MDSAP Nonconformity Grading Overview............................................................................................................... 57
Figure 3-3. MDSAP Nonconformity Grading Matrix. ..................................................................................................................58
Figure 3-4. MDSAP Post-Audit Activities and Timeline............................................................................................................... 59
Figure 4-1. Drug Lifecycle Regulations. .........................................................................................................................................63
Figure 4-2. Assessors and Inspectors............................................................................................................................................... 64