Classification of Pharmaceutical Impurities

Organic, Inorganic and Residual Solvent Impurities Organic impurities may arise at any stage of drug substance manufacture or storage and include starting...

Organic, Inorganic and Residual Solvent Impurities

Organic impurities may arise at any stage of drug substance manufacture or storage and include starting materials, synthetic by-products, intermediates, and degradation products formed during storage. Inorganic impurities encompass reagents, ligands, catalysts, heavy metals, and other elemental impurities that may be introduced during synthesis, and are governed by International Council for Harmonisation guideline Q3D, which establishes permitted daily exposure limits according to the toxicity and route of administration associated with each element. Residual solvents, addressed by International Council for Harmonisation Q3C, are volatile organic compounds employed during synthesis or purification and are classified into three classes according to their toxicological risk, ranging from Class One solvents that should be avoided owing to unacceptable toxicity, through Class Two solvents that should be limited, to Class Three solvents regarded as posing lower toxicological risk.

Degradation Products and Genotoxic Impurities

Degradation products form through chemical instability of the drug substance during manufacture, formulation, or storage and are addressed through stability-indicating analytical methods and forced degradation studies as described in the preceding chapter. Genotoxic impurities represent a special category of concern because they possess the potential to interact directly with deoxyribonucleic acid and induce mutation at exposure levels far below those associated with conventional systemic toxicity, and consequently they are controlled to markedly lower thresholds than typical organic impurities, guided by the threshold of toxicological concern concept and International Council for Harmonisation guideline M7.