Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Modifying factor F2 (default = 10) can be subdivided into two subfactors, one for toxicokinetics (TK) and one for toxicodynamics, each with a range from 1 to 3.16. Using the plasma half-life of 5 days, the TK adjustment factor could be decreased to 1.58 for once weekly administration (~1 half-life), and to 1 for administration once a month (~5 half-lives). Using the subfactor approach for F2, the proposed level for element X administered once weekly can be calculated as follows:

Proposed level = 1.1 mg/kg/d x 50 kg / 5 x (1.6 x 3.16) x 5 x 1 x 1 = 440 µg/day

For practical purposes, this value is rounded to 400 µg/day.

Example 2: The TK adjustment factor approach may also be appropriate for elemental impurities that were not developed using the modifying factor approach. For element Z, a Minimal Risk Level (MRL) of 0.02 mg/kg/day was used to derive the oral PDE. From literature sources, the plasma half-life was reported to be 4 days. This element is an impurity in an oral drug product administered once every 3 weeks (~ 5 half-lives). Using first-order kinetics, the established PDE of 1000 µg/day is modified as follows:

Proposed level = 0.02 mg/kg/d x 50 kg / 1/3.16 = 3.16 mg/day

For practical purposes, this value is rounded to 3000 µg/day.

3.4

Parenteral Products

Parenteral drug products with maximum daily volumes up to 2 liters may use the maximum daily volume to calculate permissible concentrations from PDEs. For products whose daily volumes, as specified by labeling and/or established by clinical practice, may exceed 2 liters (e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), a 2-liter volume may be used to calculate permissible concentrations from PDEs. (Ref. 4)

4.

E LEMENT C LASSIFICATION

The elements included in this guideline have been placed into three classes based on their toxicity (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived from several factors including: probability of use in pharmaceutical processes, probability of being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical processes, and the observed natural abundance and environmental distribution of the element. For the purposes of this guideline, an element with low natural abundance refers to an element with a reported natural abundance of < 1 atom/10 6 atoms of silicon (Ref. 5). The classification scheme is intended to focus the risk assessment on those elements that are the most toxic but also have a reasonable probability of inclusion in the drug product (see Table 5.1). The elemental impurity classes are: Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment, across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls which may in some cases include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met. Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided in sub-classes 2A and 2B based on their

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