Quality and Safety Challenges in Peptide and Oligonucleotide Therapeutics: From Molecular Instability and Drug Delivery to Reactive Impurities and Nitrosamine Risk †

Peptide and oligonucleotide therapeutics are dependent on sequence-defining chemical synthesis, but product complexity additionally arises from structural modifications, formulation and delivery. In this context, their quality cannot be assessed only by determining the identity and content of the respective amino acid or nucleotide sequences. This review examines the links between molecular instability, process- and product-related impurities, formulation and delivery-system chemistry, route-specific administration conditions, and analytical control. A separate focus is placed on nitrosamines and N-nitrosamine drug substance-related impurities (NDSRIs), for which evidence in peptide and oligonucleotide products remains scarce. Directly published data are combined with mechanistic evidence transferred from other pharmaceutical products. Nitrosation susceptibility is considered in relation to molecular structure, availability of nitrite and/or other nitrosating sources during synthesis and formulation, pH and local microenvironments, processing conditions and storage. Analytical strategies and risk-based controls are evaluated according to the likely origin and fate of the impurities. The review identifies where experimental evidence is sufficient for product-specific control and where conservative assumptions remain necessary because direct data are lacking.