Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

available, a calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1).

3.2

Other Routes of Administration

PDEs were established for oral, parenteral and inhalation routes of administration. When PDEs are necessary for other routes of administration, the concepts described in this guideline may be used to derive PDEs. An assessment may either increase or decrease an established PDE. The process of derivation of the PDE for another route of administration may include the following:  Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE. Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more appropriate starting point.  Assess if the elemental impurity is expected to have local effects when administered by the intended route of administration: o If local effects are expected, assess whether a modification to an established PDE is necessary. o Consider the doses/exposures at which these effects can be expected relative to the adverse effect that was used to set an established PDE. o If local effects are not expected, no adjustment to an established PDE is necessary.  If available, evaluate the bioavailability of the element via the intended route of administration and compare this to the bioavailability of the element by the route with an established PDE: o When a difference is observed, a correction factor may be applied to an established PDE. For example, when no local effects are expected, if the oral bioavailability of an element is 50% and the bioavailability of an element by the intended route is 10%, a correction factor of 5 may be applied.  If a PDE proposed for the new route is increased relative to an established PDE, quality attributes may need to be considered.

3.3 Justification for Elemental Impurity Levels Higher than an Established PDE

Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be acceptable in certain cases. These cases could include, but are not limited to, the following situations:

Intermittent dosing;



 Short term dosing (i.e., 30 days or less);

 Specific indications (e.g., life-threatening, unmet medical needs, rare diseases).

Examples of justifying an increased level of an elemental impurity using a subfactor approach of a modifying factor (Ref. 2,3) are provided below. Other approaches may also be used to justify an increased level. Any proposed level higher than an established PDE should be justified on a case-by-case basis. Example 1: element X is present in an oral drug product. From the element X monograph in Appendix 3, a No-Observed-Adverse-Effect Level (NOAEL) of 1.1 mg/kg/day was identified. Modifying factors F1-F5 have been established as 5, 10, 5, 1 and 1, respectively. Using the standard approach for modifying factors as described in Appendix 1, the PDE is calculated as follows:

PDE = 1.1 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 220 µg/day

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