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Establishing specifications for impurities in linker-payloads during the early stages of development presents significant challenges, particularly considering impurities’ conjugatable nature and feedback from regulatory agencies. The presence of multiple chiral centers, various homologues of polymeric spacers, and the propensity for epimerization, along with other reaction-related impurities in linkers and payloads, complicates the formulation of impurity specifications in the initial phases of an antibody-drug conjugate (ADC) project. Adopting a fit-for-purpose development strategy allows preliminary identification of impurity structures using liquid chromatography-mass spectrometry (LCMS) for reaction impurities. However, accurately assigning structures to polymeric homologues and chiral diastereomers and enantiomers remains difficult, creating further obstacles in impurity resolution and identification. The impurities in question might be conjugatable or non-conjugatable, both of which can be present in the final ADC drug substance (DS) and drug product (DP). To address these challenges, WuXi XDC has developed specialized analytical methods to assess the content and conjugatable characteristics of these impurities. WuXi XDC verifies the conjugatable nature of impurities through mock-conjugation experiments and, through analytical techniques, controls homologue impurities in starting materials to reduce their presence in the final linker-payload.