Degradation Product
A molecular species resulting from chemical breakdown of the active pharmaceutical ingredient during manufacturing, storage, or use. Common peptide degradation pathways include oxidation, deamidation, hydrolysis, and aggregation. Degradation products must be identified, quantified, and kept below established safety limits.
Technical Context
Common peptide degradation pathways: (1) Oxidation — Met oxidation to Met sulphoxide (most common, catalysed by trace metals and peroxides; reversible with reducing agents), Trp oxidation to N-formylkynurenine (irreversible), His oxidation, Cys oxidation. (2) Deamidation — Asn→Asp/isoAsp (rate depends on n+1 residue; Asn-Gly is fastest, t1/2 days-weeks; follows succinimide intermediate), Gln→Glu (much slower). (3) Hydrolysis — peptide bond cleavage, particularly at Asp-Pro sites (acid-catalysed). (4) Disulphide exchange — scrambling of disulphide bonds, producing misfolded isomers. (5) Aggregation — non-covalent (hydrophobic) and covalent (disulphide-mediated) association forming dimers, oligomers, and higher-order aggregates. Each pathway has characteristic analytical signatures: oxidation products detected by MS (+16 Da), deamidation products by MS (+1 Da) and charge variants by ion-exchange chromatography, and aggregation by size-exclusion chromatography (SEC).