Introduction Elemental impurities in drug substance and 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). Elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. Long term exposure even to low concentrations of impurities can cause many adverse health effects and even toxicity

1. Elemental Impurities in Pharmaceutical Products
Introduction
Elemental impurities in drug substance and 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). Elemental impurities do not provide any
therapeutic benefit to the patient, their levels in the drug product should be controlled within
acceptable limits. Long term exposure even to low concentrations of impurities can cause many
adverse health effects and even toxicity.
The following diagram shows an example of typical materials, equipment and components used
in the production of a drug product.
Classification of Elemental impurities –
Class Included elemental impurity
Class 1 Arsenic, Lead, Cadmium, Mercury

2. Class 2A Cobalt, Vanadium, Nickel
Class 2B Thallium, Gold, Palladium, Iridium, Osmium, Rhodium, Ruthenium, Selenium,
Silver, Platinum
Class 3 Lithium, Antimony, Barium, Molybdenum, Copper, Tin, Chromium
The method used for establishing the PDE for each elemental impurity is discussed in “Q3D
(R1) Guideline for elemental impurities” in detail. 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.
Different Analytical techniques for determination of elemental impurities-
Many instrumental analytical methods may beemployed to measure the concentration level
ofheavymetals in various samples. The mostpredominant techniques are Atomic
AbsorptionSpectrometry (AAS); Atomic Emission/Fluorescence Spectrometry
(AES/AFS);Inductively Coupled Plasma Mass Spectrometry(ICP-MS); Inductively Coupled
Plasma OpticalEmission Spectrometry (ICP-OES); NeutronActivation Analysis (NAA), X-ray
Fluorescence(XRF); and Anodic Striping Voltammetry (AVS).
Most widely used technique is ICP-OES which has high sample throughput enabling the efficient
analysis of large number of batches, simultaneous determination of multiple elements in each
sample, large dynamic linear range and low chemical and matrix interference effect as well.
General comparison of different analytical techniques –
Method validation plan –
General validation plan has been elaborated below and can be used for method validation
approach for elemental testing.

3. Conclusions
The ICH Q3D guideline can be achieved through using an appropriate risk assessment and
analytical testing. A risk assessment should be performed to identify any elemental impurities
that may potentially be present at significant levels in the drug product. Such an assessment is
then used to define an appropriate control strategy. ICH Q3D allows the option that the scope
and extent of quality control testing may be reduced, or even eliminated provided there is
adequate control.
References:
1. ICH harmonized guideline “ Guideline for Elemental impurities: Q3D(R1)
2. https://www.fda.gov/drugs/pharmaceutical-quality-resources/elemental-impurities
3. Elemental Impurities in Drug Products- Guidance for Industry, U.S. Department of
Health, Human Services Food and Drug Administration Center for Drug Evaluation and
Research (CDER)
4. Elemental impurity analysis in regulated pharmaceutical laboratories, Agilent
technologies
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