Control of Genotoxic & Elemental Impurities

Industry & Regulatory Perspectives


Based on the presentation by Dr. Atul Awasthi, Director – GTS MSAT AS, Pfizer, at the 8th Annual Global Pharma Regulatory Summit by CPhI Conferences, a division of UBM India.

What are impurities?

  • Impurities are unwanted chemicals present in the drug substance (DS) or drug product (DP) arising from normal manufacture.
  • Examples: Starting materials and by-products from DS synthesis; components resulting from the DS and excipient interaction.
  • Organic impurities (process and drug related): Starting materials; by-products; intermediates; degradation products; reagents, ligands, catalysts; and geometric and structural isomers.
  • Inorganic impurities: Reagents, ligands, catalysts filter aids, charcoal etc.;  heavy metals and other residual metals.
  • Residual solvents: Vehicles used in synthesis and purification / formulation process.

Genotoxic Impurities – ICH M7

ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.

This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.

ICH M7 guideline is intended for new DS and DP for clinical development and marketing applications; current marketed products; and impurities in excipients that are used for the first time in a drug product and are chemically synthesized.

Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities.

Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products.

Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

Threshold of Toxicological Concern

Threshold of Toxicological Concern (TTC) is a key concept in ICH M7. TTC is developed to define an acceptable intake for DNA reactive substances that

have the potential to cause cancer. High potency mutagenic carcinogens are controlled at/below compound specific acceptable limit.

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