Potential Sources of Elemental Impurities

In considering the production of a drug product, there are broad categories of potential sources of elemental impurities.

Residual impurities resulting from elements intentionally added (e.g., catalysts) in the formation of the drug substance, excipients, or other drug product components. The risk assessment of the drug substance should address the potential for inclusion of elemental impurities in the drug product.
Elemental impurities that are not intentionally added and are potentially present in the drug substance, water or excipients used in the preparation of the drug product.
Elemental impurities that are potentially introduced into the drug substance and/or drug product from manufacturing equipment.
Elemental impurities that have the potential to be leached into the drug substance and drug product from container closure systems.

The following diagram shows an example of typical materials, equipment and components used in the production of a drug product. Each of these sources may contribute elemental impurities to the drug product, through any individual or any combination of the potential sources listed above. During the risk assessment, the potential contributions from each of these sources should be considered to determine the overall contribution of elemental impurities to the drug product.

* The risk of inclusion of elemental impurities can be reduced through process understanding, equipment selection, equipment qualification and Good Manufacturing Practice (GMP) processes.

** The risk of inclusion of elemental impurities from water can be reduced by complying with compendial (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality requirements, if purified water or water for injection is used in the manufacturing process(es).

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Reference: ICH Q3D(R2)