Elemental impurities in drug substance and drug products may arise from several sources; they may be residual catalysts that were added intentionally in the 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.
|Class||Included elemental impurity|
|Class 1||Arsenic, Lead, Cadmium, Mercury|
|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.
Many instrumental analytical methods may be employed to measure the concentration level of heavy metals in various samples. The most predominant techniques are Atomic Absorption Spectrometry (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 Stripping Voltammetry (AVS).
The most widely used technique is ICP-OES which has high sample throughput enabling the efficient analysis of a 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.
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.