Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Appendix 4: Illustrative Examples

Examples for Converting PDEs into Permitted Elemental Impurity Concentrations

Option 1: Permitted common concentration limits of elemental impurities across drug product component materials for products with daily intakes of not more than 10 grams. For this example, consider a solid oral drug product with a maximum daily intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients, see Table A.4.1). Because this drug product does not exceed a maximum daily intake of 10 grams, the concentrations in Table A.2.2 may be used. As Option 1 has a common permitted concentration, the 9 components can be used in any proportion in the formulation. 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 daily intake of each elemental impurity in the drug product is given in Table A.4.2 assuming that each elemental impurity is present at the concentration given in Table A.2.2. The maximum potential daily intake of an elemental impurity is determined using the actual drug product daily intake and the concentration limit for the elemental impurity in Table A.2.2 (concentration multiplied by the actual daily intake of the drug product of 2.5 grams). The maximum daily intake given for each elemental impurity is not a summation of values found in the individual columns of Table A.4.2. This calculation demonstrates that no elemental impurities exceed their PDEs. Thus if these concentrations in each component are not exceeded, the drug product is assured to not exceed the PDEs for each identified elemental impurity.

Table A.4.1: Maximum Daily Intake of Components of the Drug Product Component Daily Intake, g Drug Substance 0.200 Microcrystalline Cellulose (MCC) 1.100 Lactose 0.450 Ca Phosphate 0.350 Crospovidone 0.265 Mg Stearate 0.035 Hydroxypropylmethyl Cellulose (HPMC) 0.060 Titanium Dioxide 0.025 Iron Oxide 0.015 Drug Product 2.500

Table A.4.2: Permitted Concentrations from Table A.2.2 (assuming uniform concentrations and 10 grams daily intake) Maximum Permitted Concentration (µg/g) Component Pb As Cd Hg Pd V Ni Drug Substance 0.5 1.5 0.5 3 10 10 20 MCC 0.5 1.5 0.5 3 10 10 20 Lactose 0.5 1.5 0.5 3 10 10 20 Ca Phosphate 0.5 1.5 0.5 3 10 10 20 Crospovidone 0.5 1.5 0.5 3 10 10 20 Mg Stearate 0.5 1.5 0.5 3 10 10 20 HPMC 0.5 1.5 0.5 3 10 10 20

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