Impurities and Potential Immunogenicity Associated With Follow-on and Compounded Glucagon-like Peptide-1 Receptor Agonists.

PURPOSE: To assess impurity profiles/potential immunogenicity of multiple samples of follow-on or compounded products for two glucagon-like peptide-1 receptor agonists (GLP-1 RAs): semaglutide and liraglutide. METHODS: Major histocompatibility complex-II-associated peptide proteomics assay (MAPPs), liquid chromatography-mass spectrometry analysis, photostability testing, and fibrillation assay were performed. RESULTS: For semaglutide and liraglutide, various potentially immunogenic peptides (distinct number/distribution vs originators) were presented on impurity-stimulated monocyte-derived dendritic cells from healthy donors. The follow-on drug substance and follow-on or compounded products had distinct impurity profiles (amino acid deletions/additions and unidentified impurities) versus the originators. Significant disparity in strength, impurity sum, and high-molecular-weight protein level were observed between compounded semaglutide and originator products when exposed to light. The liraglutide follow-ons had reduced physical stability versus the originator. CONCLUSIONS: The tested peptide impurities pose increased immunogenicity potential. Follow-on or compounded products also had different impurity profiles, which could be affected by the sourcing of the active pharmaceutical ingredient, manufacturing process, and degradation during storage. The distinct impurity profiles of follow-on and compounded products could lead to an undesirable immune response in patients. These results underscore the importance of in vitro immunogenicity assays/clinical immunogenicity studies for GLP-1 RA follow-on or compounded products.