Immunogenicity risk assessment of synthetic peptide drugs and their impurities

[Display omitted] •Many peptide drugs have recently become eligible for approval as off-patent generics.•The synthetic production of generic drugs can introduce peptide impurities that have immunogenic potential.•The FDA guidance for generics recommends the use of orthogonal methods to evaluate immunogenicity.•Existing in silico and in vitro immunogenicity risk assessment methods can be adapted to peptide impurities.•Here a stepwise approach to immunogenicity risk assessment of synthetic peptides and their impurities is described. Peptide drugs play an important part in medicine owing to their many therapeutic applications. Of the 80 peptide drugs approved for use in humans, at least five are now off-patent and are consequently being developed as generic alternatives to the originator products. To accelerate access to generic products, the FDA has proposed new regulatory pathways that do not require direct comparisons of generics to originators in clinical trials. The ‘Abbreviated New Drug Application’ (ANDA) pathway recommends that sponsors provide information on any new impurities in the generic drug, compared with the originator product, because the impurities can have potential to elicit unwanted immune responses owing to the introduction of T-cell epitopes. This review describes how peptide drug impurities can elicit unexpected immunogenicity and describes a framework for performing immunogenicity risk assessment of all types of bioactive peptide products. Although this report primarily focuses on generic peptides and their impurities, the approach might also be of interest for developers of novel peptide drugs who are preparing their products for an initial regulatory review.