Elemental impurities in drug products may arise from several sources; they may be added intentionally in synthesis, or may be present as contaminants (e.g., through interactions with processing equipment or by being present in components of the drug product) and are consequently detectable in the drug product. Since elemental impurities do not provide any therapeutic benefit to the patient, element impurity levels should be controlled within acceptable limits in the drug product.
The elemental impurities have been placed into categories that are intended to facilitate decisions during the risk assessment.
- Class 1 elemental impurities, As, Cd, Hg, and Pb, are significantly toxic across all routes of administration. Typically they have limited or no use in the manufacture of pharmaceuticals but can be present as impurities in commonly used materials (e.g., mined excipients) and can not be readily removed from the material. Because of their unique nature, these four elemental impurities require consideration during the risk assessment across all potential sources of elemental impurities.
- Class 2 elemental impurities are toxic to a greater or lesser extent based on route of administration. In addition, some of the elements present in this category are infrequently observed as impurities in materials used to produce drug products and as such, unless intentionally added have a low probability of inclusion in the drug product and do not present a significant risk. Class 2 elemental impurities are further categorized to establish when they should be considered in the risk assessment and when their contribution can be judged to be negligible.
- Class 2A: The following elemental impurities require assessment across all potential sources and routes of administration: V, Mo, Se, and Co due to their higher relative natural abundance.
- Class 2B: The following elemental impurities require assessment across potential elemental impurity sources only if they are intentionally added to the processes used to generate the material under evaluation: Au, Tl, Pd, Pt, Ir, Os, Rh, Ag and Ru.
- Class 3 elemental impurities are impurities with relatively low toxicity (high PDEs) by the oral route administration but require consideration in the risk assessment for other routes of administration (e.g., inhalation and parenteral routes). For oral routes of administration, unless these elements are intentionally added as part of the process generating the material, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment. The elemental impurities in this class include: Sb, Ba, Li, Cr, Cu, Sn, and Ni.
- Class 4 elemental impurities are elemental impurities that have been evaluated but for which a PDE has not been established due to their low inherent toxicity and/or regional regulations. If these elemental impurities are present or included in the drug product they are addressed following the practices defined by other guidelines and regional regulation. The elements in this class include: Al, B, Fe, Zn, K, Ca, Na, Mn, Mg, and W. The classification system is summarized in Table.
Table:- Elemental Impurity Classification
|Included Elemental Impurities||Include in Risk Assessment?|
|Class 1||As, Pb, Cd, Hg||Yes|
|Class 2A||V, Mo, Se, and Co||Yes|
|Class 2B||Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, and Ru||Yes only if intentionally added|
|Class 3||Sb, Ba, Li, Cr, Cu, Sn, Ni||Dependent upon route of administration – see Class 3 description|
|Class 4||B, Fe, Zn, K, Ca, Na, Mn, Mg, W, Al||No|
FIND MORE AT…
ICH Guideline Q3D for elemental impurities.