<p>There is limited regulatory guidance that outlines the globally acceptable level of individual and total impurities present in peptide and oligonucleotide drug substances that can be supported and accepted during clinical testing. In early clinical development, there is uncertainty regarding the potential toxicological and immunogenicity risk of these impurities relative to the active pharmaceutical ingredient; however, as pharmaceutical development companies move closer to marketing applications, this uncertainty lessens through knowledge gained by clinical and toxicology studies. While these peptide and oligonucleotide related impurities are predicted to be under process control and to have the same safety profile as the parent drug substance, they do not offer any inherent advantages to the patient. Thus, the safety and specification control of these impurities is frequently challenged by regulatory agencies. In support of phase-appropriate control strategies, this manuscript presents a risk-based approach to evaluate the safety of peptide and oligonucleotide impurities from a toxicology and immunogenicity perspective. In many cases, the proposed safety threshold is higher than what&#xa0;is accepted by regulatory bodies, but still is expected to be safe based upon sound toxicological principles which should be the focus for clinical studies. The risk assessment strategies presented here consider the stage of development, indication, potential impact of unintended cross reactivity with endogenous proteins, dose, and frequency of dosing throughout development to inform chemistry manufacturing and control of inherent safety risks associated with API-related impurities. Importantly, for the first time, this manuscript establishes a threshold of immunogenicity concern along with an experimental mitigation plan specifically for peptide impurities as a function of the development phase.</p> Graphical Abstract <p></p>