The Medical Device Validation Handbook
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Figure 4-8. Precision and “Accuracy”................................................................................................. 47
Figure 4-9. Bias and “Accuracy”–Focus on “Bias”.............................................................................. 48
Figure 4-10. Precision and Bias........................................................................................................... 49
Figure 4-11. GRR Tree Diagram, Multi-Vari Chart plus Minitab Statistical Output. .......................50
Figure 4-12. GRR Standard Deviations Explained as Trigonometric Function................................. 52
Figure 5-1. DOE in Process Validation Flow. ..................................................................................57
Figure 5-2. Progression of DOE Activities....................................................................................... 58
Figure 5-3. Relation of Process Inputs and Outputs......................................................................... 59
Figure 5-4. Minitab ANOVA Analysis Output................................................................................ 61
Figure 5-5. Minitab Example of Design Options. ............................................................................62
Figure 5-6. Minitab Plackett-Burman Design Analysis.................................................................... 63
Figure 5-7. Two-Level Factorial Design Diagram. ...........................................................................67
Figure 5-8. Three-Level Factorial Design Diagram. .........................................................................67
Figure 5-9. Minitab Regression Analysis Output ............................................................................68
Figure 5-10. EVOP Diagram.............................................................................................................. 68
Figure 5-11. Method of Steepest Ascent/Descent. .............................................................................68
Figure 5-12. Central Composite Design Diagram.............................................................................. 69
Figure 5-13. Minitab CCD Analysis Output. ....................................................................................69
Figure 5-14. Three-Factor Box-Behnken Design Diagram................................................................. 70
Figure 5-15. Minitab Box-Behnken Analysis Output. .......................................................................71
Figure 5-16. Main Effects Plot. ..........................................................................................................71
Figure 5-17. Interaction Effects Plot.................................................................................................. 71
Figure 5-18. Screening Minitab Output. ............................................................................................72
Figure 5-19. Screening Response Optimizer...................................................................................... 72
Figure 5-20. Optimization #1 Main and Interaction Plots. ................................................................72
Figure 5-21. Optimization #1 Minitab Output. .................................................................................73
Figure 5-22. Optimization #1 Response Optimizer............................................................................ 73
Figure 5-23. Optimization #2 Main and Interaction Plots ................................................................73
Figure 5-24. Optimization #2 Contour Plot....................................................................................... 74
Figure 5-25. Optimization #2 Response Optimizer............................................................................ 74
Figure 5-26. Capability Analysis Results. ...........................................................................................75
Figure 6-1. Sterilization Validation. ..................................................................................................78
Figure 7-1. Six Sigma Process........................................................................................................... 97
Figure 7-2. GRR Study Structure. ..................................................................................................101
Figure 7-3. GRR Study Showing Poor Repeatability and Reproducibility. ....................................102
Figure 7-4. GRR Study Showing Excellent Repeatability and Reproducibility.............................. 103
Figure 7-5. Baseline Process............................................................................................................ 104
Figure 7-6. Cause-and-Effect Diagram Showing the “6Ms” of Quality: Man, Machine,
Measurement, Method, Material, and “Mother Nature”............................................... 104
Figure 7-7. Detailed Process Map Example: Sealing Portion of Process......................................... 105
Figure 7-8. Three Types of Cause-and-Effect Relationships........................................................... 106
Figure 7-9. A Process Operating at Full Potential. .........................................................................106
Figure 7-10. Multi-Vari Chart Showing Three Families of Variation: Machine, Cycle, and Tool
Cavity. ..........................................................................................................................108
Figure 7-11. Main Effects Plots Showing the Effects of Temperature, Time, and Pressure on the
Response of Seal Strength (LBF/in)............................................................................. 109
Figure 7-12. DOE Interaction Plot Showing the Effects of Pressure on the Response, Seal
Strength, at Two Temperature Settings (220°F and 260°F). .........................................109
Figure 7-13. Stable Process—Not Capable and Capable. .................................................................110
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Figure 4-8. Precision and “Accuracy”................................................................................................. 47
Figure 4-9. Bias and “Accuracy”–Focus on “Bias”.............................................................................. 48
Figure 4-10. Precision and Bias........................................................................................................... 49
Figure 4-11. GRR Tree Diagram, Multi-Vari Chart plus Minitab Statistical Output. .......................50
Figure 4-12. GRR Standard Deviations Explained as Trigonometric Function................................. 52
Figure 5-1. DOE in Process Validation Flow. ..................................................................................57
Figure 5-2. Progression of DOE Activities....................................................................................... 58
Figure 5-3. Relation of Process Inputs and Outputs......................................................................... 59
Figure 5-4. Minitab ANOVA Analysis Output................................................................................ 61
Figure 5-5. Minitab Example of Design Options. ............................................................................62
Figure 5-6. Minitab Plackett-Burman Design Analysis.................................................................... 63
Figure 5-7. Two-Level Factorial Design Diagram. ...........................................................................67
Figure 5-8. Three-Level Factorial Design Diagram. .........................................................................67
Figure 5-9. Minitab Regression Analysis Output ............................................................................68
Figure 5-10. EVOP Diagram.............................................................................................................. 68
Figure 5-11. Method of Steepest Ascent/Descent. .............................................................................68
Figure 5-12. Central Composite Design Diagram.............................................................................. 69
Figure 5-13. Minitab CCD Analysis Output. ....................................................................................69
Figure 5-14. Three-Factor Box-Behnken Design Diagram................................................................. 70
Figure 5-15. Minitab Box-Behnken Analysis Output. .......................................................................71
Figure 5-16. Main Effects Plot. ..........................................................................................................71
Figure 5-17. Interaction Effects Plot.................................................................................................. 71
Figure 5-18. Screening Minitab Output. ............................................................................................72
Figure 5-19. Screening Response Optimizer...................................................................................... 72
Figure 5-20. Optimization #1 Main and Interaction Plots. ................................................................72
Figure 5-21. Optimization #1 Minitab Output. .................................................................................73
Figure 5-22. Optimization #1 Response Optimizer............................................................................ 73
Figure 5-23. Optimization #2 Main and Interaction Plots ................................................................73
Figure 5-24. Optimization #2 Contour Plot....................................................................................... 74
Figure 5-25. Optimization #2 Response Optimizer............................................................................ 74
Figure 5-26. Capability Analysis Results. ...........................................................................................75
Figure 6-1. Sterilization Validation. ..................................................................................................78
Figure 7-1. Six Sigma Process........................................................................................................... 97
Figure 7-2. GRR Study Structure. ..................................................................................................101
Figure 7-3. GRR Study Showing Poor Repeatability and Reproducibility. ....................................102
Figure 7-4. GRR Study Showing Excellent Repeatability and Reproducibility.............................. 103
Figure 7-5. Baseline Process............................................................................................................ 104
Figure 7-6. Cause-and-Effect Diagram Showing the “6Ms” of Quality: Man, Machine,
Measurement, Method, Material, and “Mother Nature”............................................... 104
Figure 7-7. Detailed Process Map Example: Sealing Portion of Process......................................... 105
Figure 7-8. Three Types of Cause-and-Effect Relationships........................................................... 106
Figure 7-9. A Process Operating at Full Potential. .........................................................................106
Figure 7-10. Multi-Vari Chart Showing Three Families of Variation: Machine, Cycle, and Tool
Cavity. ..........................................................................................................................108
Figure 7-11. Main Effects Plots Showing the Effects of Temperature, Time, and Pressure on the
Response of Seal Strength (LBF/in)............................................................................. 109
Figure 7-12. DOE Interaction Plot Showing the Effects of Pressure on the Response, Seal
Strength, at Two Temperature Settings (220°F and 260°F). .........................................109
Figure 7-13. Stable Process—Not Capable and Capable. .................................................................110