CRED Getting the CMC Dossier Right 2024

29/08/2024

Common deficiencies: Impurities

⚫ The issue:

● The key issues:

– genotoxic impurities – organic solvents; Class I solvents etc ● Impurities related to drug substances can be classified into three main categories: – organic impurities, – inorganic (elemental) impurities, – residual solvents

● Within these categories, genotoxic impurities form a special case because they pose a significant safety risk, even at low concentrations, because they may be mutagenic and are therefore potentially damaging to DNA. As a result they can lead to mutations or cause cancer

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Common deficiencies: Impurities

⚫ Exemplary MOs

● The two potentially genotoxic impurities generated in the manufacture of the drug substance should be suitably controlled within the manufacturing process. – The limits applied should be in line with the CHMP guideline on the limits of genotoxic impurities . – In addition, validation data for the HPLC method for the two potential genotoxic impurities should be provided. It should be demonstrated that the analytical method is sufficiently sensitive (i.e. the LOD should be below the concentration limit calculated based on the maximum daily dose and TTC of 1.5 mcg/ml). ● Since this drug substance has not previously been approved for parenteral use , further evidence for qualification of impurity limits should be provided, especially since the proposed IV dosage is greater than that used orally. Evidence of qualification of xxxx at the proposed shelf-life acceptance limit should be provided. ● X, used in the synthesis, has a structural alert to be potentially genotoxic. This compound should be controlled in the final drug substance specification below its TTC level limit. This impurity has not been included in the proposed drug substance specification.

The Organisation for Professionals in Regulatory Affairs

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