Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Application of Q3D to existing products is not expected prior to 36 months after publication of the guideline by ICH.

3. S AFETY A SSESSMENT OF P OTENTIAL E LEMENTAL I MPURITIES

3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration The method used for establishing the PDE for each elemental impurity is discussed in detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing the publicly available data contained in scientific journals, government research reports and studies, international regulatory standards (applicable to drug products) and guidance, and regulatory authority research and assessment reports. This process follows the principles described in ICH Q3C: Residual Solvents. The available information was reviewed to establish the oral, parenteral and inhalation PDEs. For practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 Table A.2.1 have been rounded to 1 or 2 significant figures. A summary safety assessment identifying the critical study for setting a PDE for each element is included in Appendix 3. There are insufficient data to set PDEs by any route of administration for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on the basis of their similarity to palladium. The factors considered in the safety assessment for establishing the PDE are listed below in approximate order of relevance:  The likely oxidation state of the element in the drug product;  Human exposure and safety data when it provided applicable information;  The most relevant animal study; Standards for daily intake for some of the elemental impurities discussed in this guideline exist for food, water, air, and occupational exposure. Where appropriate, these standards were considered in the safety assessment and establishment of the PDEs. The longest duration animal study was generally used to establish the PDE. When a shorter duration animal study was considered the most relevant, the rationale was provided in the individual safety assessment. Inhalation studies using soluble salts (when available) were preferred over studies using particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on available data, inhalation PDEs were based on either local (respiratory system) or systemic toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses were normalized to a 24-hour, 7-day exposure. In the absence of data and/or where data are available but not considered sufficient for a safety assessment for the parenteral and or inhalation route of administration, modifying factors based on oral bioavailability were used to derive the PDE from the oral PDE:  Oral bioavailability <1%: divide by a modifying factor of 100;  Oral bioavailability ≥ 1% and <50%: divide by a modifying factor of 10;  Oral bioavailability ≥50% and <90%: divide by a modifying factor of 2; and  Oral bioavailability ≥ 90%: divide by a modifying factor of 1.  Route of administration;  The relevant endpoint(s).

Where oral bioavailability data or occupational inhalation exposure limits were not

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