Module 3 - Strategic case studies in practice
ICH Q3D(R1) Guideline
Column 4: Identify any elemental impurities known or expected to be leached from the container closure system. Record the specific elemental impurities for further consideration in the assessment. Column 5: Calculate the total contribution of the potential elemental impurity by summing the contributions across the components of the drug product. Column 6: Assess the variability of the elemental impurity level(s) in the components Column 7: Enter the control threshold of each potential elemental impurity identified. If the variability is known and it is within acceptable limits, the control threshold (30% of the PDE) for each elemental impurity can be applied. Column 8: Describe action taken – none if the value in column 5 is less than or equal to the control threshold (Column 7). Define control element if material variability is high or control threshold is exceeded. 1 2 3 4 5 6 7 8
Leached from container closure systems
Total elemental impurity contribution µg/
Acceptable variability of elemental impurity contribution
Intentionally added (if used in the process)
Elemental impurities with a relatively high abundance and/or are impurities in excipients Observed impurity in all excipients and drug substance Observed impurity in all excipients Observed impurity in all excipients Observed impurity in all excipients
Manufacturing equipment
Control threshold
Element
Action
As
No
No
No
0.8
yes
4.5
no further controls required no further controls required no further controls required no further controls required no further controls required no further controls required no further controls required
Cd
No
No
No
0.7
yes
1.5
Hg
No
No
No
0.7
yes
9
Pb
No
No
No
1.2
yes
1.5
Pd
API catalyst
No
No
No
4.0
yes
30
Ni
API catalyst
Observed in 3 excipients
No
No
12.5
yes
60
V
No
Observed in 3 excipients
No
No
9.5
yes
30
82
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