Impurity testing

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Since December 2014 ICH guideline Q3D (Guideline for elemental impurities) has reached step 4, meaning that the guideline is recommended for adoption to the regulatory bodies of the European Union, Switzerland, Japan, USA and Canada.  The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. Wihtin the scope of this guidleine are the drug products containing purified proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates), synthetically produced polypeptides, polynucleotides, and oligosaccharides.

Drug products that are used during clinical research stages of development are not wihtin the scope of this guidleine. However, as the commercial process develops, this guideline will become important.
Application of ICH Q3D to existing products is not expected prior to 36 months after publication (December 2017) of the guideline by ICH.

The elemental impurities are categorized in classes, based on their toxicity.
Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment, across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls which may in some cases include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met.
Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product.

  • Class 2A elements have relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated). The class 2A elements are: Co, Ni and V.
  • Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product. The elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl.

Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 µg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, 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, unless the route specific PDE is above 500 µg/day. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.

Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline. If these elemental impurities are present or included in the drug product they are addressed by other guidelines and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn.

During the development of specifications for elements, the principles of risk management as stated in ICH Q9 should be applied. The risk assessment should be linked to patient safety, but also on knowledge of the production process. So which elements are likely to be introduced during the manufacturing process?

In table 5.1 of the guideline, the elemental impurities are mentioned and whether they are necessary to be included in the risk assessment.