ICH Q3D(R2) - Elemental Impurities

What it says

A risk assessment must be conducted to identify potential sources of elemental impurities in a drug product, including raw materials, manufacturing equipment and container-closure systems, with permitted daily exposure limits established for each element based on its toxicity and route of administration.

Paraphrased for plain-language clarity. Always verify against the current published regulation text.

What it means in practice

• This guideline requires a documented, product-specific risk assessment identifying every plausible source of elemental impurities, rather than only testing the finished product against a generic limit without understanding where elements could actually originate.
• Manufacturing equipment itself, particularly metal components in prolonged product contact, is an explicit potential source this risk assessment must consider, not just raw material composition.
• Permitted daily exposure limits vary by route of administration, meaning the same elemental impurity level can be acceptable for an oral product and unacceptable for a parenteral one.

What inspectors look for

• Whether a documented elemental impurity risk assessment exists covering raw materials, equipment and container-closure systems specific to the product.
• Whether the control strategy resulting from the risk assessment is proportionate to identified risk, with testing focused on genuinely plausible sources rather than a token generic panel.
• Whether a change to equipment, raw material source or container-closure system triggers reassessment of the elemental impurity risk profile.

Related regulations