International – Guideline for Elemental Impurities Q3D(R1)

Elemental impurities in drug products may arise from several sources; they may be
residual catalysts that were added intentionally in synthesis or may be present as
impurities (e.g., through interactions with processing equipment or container/closure
systems or by being present in components of the drug product). Because elemental
impurities do not provide any therapeutic benefit to the patient, their levels in the drug
product should be controlled within acceptable limits. There are three parts of this
guideline: the evaluation of the toxicity data for potential elemental impurities; the
establishment of a Permitted Daily Exposure (PDE) for each element of toxicological
concern; and application of a risk-based approach to control elemental impurities in drug
products. An applicant is not expected to tighten the limits based on process capability,
provided that the elemental impurities in drug products do not exceed the PDEs. The
PDEs established in this guideline are considered to be protective of public health for all
patient populations. In some cases, lower levels of elemental impurities may be warranted
when levels below toxicity thresholds have been shown to have an impact on other quality
attributes of the drug product (e.g., element catalyzed degradation of drug substances). In
addition, for elements with high PDEs, other limits may have to be considered from a
pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH
This guideline presents a process to assess and control elemental impurities in the drug
product using the principles of risk management as described in ICH Q9. This process
provides a platform for developing a risk-based control strategy to limit elemental
impurities in the drug product…