Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Mg Stearate

5

10

5 1

125

* * * *

100

HPMC

2.5 50 50

5

5

Titanium Dioxide

40

10 50

35

20

Iron Oxide 1200 * The risk assessment determined that Pd was not a potential elemental impurity; a 100 200 5000

quantitative result was not obtained. Option 3: Finished Product Analysis

For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients) used in Option 1, 2a and 2b. The drug substance synthesis uses Pd and Ni catalysts, and Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The maximum concentration of each elemental impurity in the drug product may be calculated using the daily intake of drug product and the PDE of the elemental impurity using Equation 1. The total mass of each elemental impurity should be not more than the PDE. Table A.4.6: Calculation of Concentrations for the Finished Product Maximum Permitted Concentration (µg/g) Daily Intake (g) Pb As Cd Hg Pd V Ni Drug Product 2.5 2 6 2 12 40 40 80 Maximum Daily Intake (µg) 5 15 5 30 100 100 200 Illustrative Example – Elemental Impurities Assessment The following example is intended as illustration of an elemental impurities risk assessment. This example is intended for illustrative purposes and not as the only way to document the assessment. There are many different ways to approach the risk assessment process and its documentation. This example relies on the oral drug product described in Appendix 4. Consider a solid oral drug product with a maximum daily intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients). The drug substance synthesis uses Pd and Ni catalysts. The applicant conducts the risk assessment starting with the identification of potential elemental impurities following the process described in Section 5. Because the applicant had limited historical data for the excipients used in the drug product, the applicant determined that the Class 1 elements (As, Cd, Hg, Pb) would be taken through the evaluation phase. The table below shows a summary of the findings of the identification stage of the assessment. Table A.4.7: Identification of Potential Elemental Impurities Potential Elemental Impurities Component Intentionally added Potential elemental

Potential elemental impurities from manufacturing equipment

Potential elemental impurities from container closure systems

impurities with a relatively high abundance and/or are impurities in excipients

Drug Substance

Pd, Ni

As

Ni

None

79