Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Table A.4.8: Elemental Impurity Assessment – Evaluation of Daily Contribution to the Total Mass of Elemental Impurities in the Drug Product

Daily intake, g

Measured Concentration (µg/g)

Total Daily Mass of Elemental Impurity, µg

Component

Pb

As

Cd

Hg

Pd

V

Ni 50

Pb

As

Cd

Hg

Pd

V

Ni

Drug Substance

0.2 1.1

0

0.1

0

0

4 0 0 0 0 0 0

0 0 0

10

MCC

0.1 0.1 0.1 0.5 0.1 20 10 1

0.1 0.1 0.1 0.5 0.1 1

0.1 0.1 0.1 0.5 0.1 1

0.1 0.1 0.1 0.5 0.1 1

* * * * * * * *

0.11

0.11

0.11

0.11

0 0

Lactose

0.45 0.35

Ca Phosphate Crospovidone Mg stearate

10

5

0.35

0.35

0.35

0.35

3.5

1.75

0.265 0.035

0

0

0 0.0175

HPMC

0.06

0

0 0

Titanium Dioxide 0.025

1

1

1

1

0.5 0.025 0.025 0.025

0 0.025

Iron Oxide

0.015 2.5 g

10

10

10

400

50

0.15

0.15

0.15

0.15

0

6

0.75 12.5 µg

TOTAL

-

-

-

-

-

-

-

1.2 µg 0.8 µg 0.7 µg 0.7 µg 4 µg 9.5 µg

* The risk assessment determined that Pd was not a potential elemental impurity; a quantitative result was not obtained. The next step in the risk assessment is to compare the measured or predicted levels in the drug product to the control threshold, using the information in Table A.4.8, and determine appropriate actions. Table A.4.9: Assessment Example – Data Entry Descriptions Column 1: Review the components of drug product for any elements intentionally added in the production (the primary source is the drug substance). For those used, record the elements for further consideration in the assessment. Column 2: Identify any potential elements or impurities that are associated with excipients used in the preparation of the drug product. Record the source(s) for further consideration in the assessment. Column 3: Identify any elemental impurities known or expected to be leached from the manufacturing equipment. Record the specific elemental impurities for further consideration in the assessment.

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