Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Titanium Dioxide Iron Oxide Maximum Daily

3

10

20

0.5 0.5

1.5 1.5

0.5 0.5

10 10

3

10

20

intake

1.25 3.75

1.25

7.5

25

25

50

(µg)

PDE (µg)

5

15

5

30

100

100

200

Option 2a: Permitted common concentration limits across drug product component materials for a product with a specified daily intake: 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, see Table A.4.1) used in Option 1. As Option 2a 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, Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The maximum concentration of each elemental impurity identified in the risk assessment can be calculated using the PDEs in Table A.2.1 and Equation 1. 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.4.3 (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.4.3. This calculation also 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. The factor of 4 increase in Option 2a for permitted concentration seen when comparing Option 1 and Option 2a concentration limits is due to the use of 10 grams and 2.5 grams, respectively, as daily intake of the drug product. Table A.4.3: Calculation of Maximum Permitted Concentrations Assuming Uniform Concentrations in a Product with a Specified Daily Intake:

Maximum Permitted Concentration (µg/g)

Component

Pb

As

Cd

Hg

Pd 40

V

Ni 80

Drug Substance

2

6

2

12

40

MCC

2 2 2 2 2 2 2

6 6 6 6 6 6 6

2 2 2 2 2 2 2

12 12 12 12 12 12 12

40 40 40 40 40 40 40

40 40 40 40 40 40 40

80 80 80 80 80 80 80

Lactose

Ca Phosphate Crospovidone Mg Stearate

HPMC

Titanium Dioxide Iron Oxide Maximum Daily

2

6

2

12

40

40

80

intake

5

15

5

30

100

100

200

(µg)

PDE (µg)

5

15

5

30

100

100

200

77