Large and medium size synthetic tides molecules, such as peptide/protein derived incretins and oligonucleotides have become an important new modality therapeutic area in recent years. Those tides molecules contain complex non-natural coded monomers that need to utilize solid phase and/or liquid phase synthesis approaches. Many impurities can arise from the synthesis process. For synthetic peptides/proteins, it includes amino acid addition and/or deletion impurities, backbone degradation and isomeric impurities etc. For synthetic oligonucleotides, undesired capping impurities, phosphate diester impurities and others may arise too. For this reason, subsequent purification unit operations, such as reverse phase and/or anion exchange chromatograph, are applied to purge those impurities. This presentation discusses global control strategy development for the entire tides drug substance synthesis process using automated workflow containing data rich experimentation and mechanistic modelling. This workflow targets medium and high-risk impurities control, i.e. impurities that show partial or no rejection from purification unit operation. The tides synthesis is carried out in a development scale automated synthesizer with options of pulling real time samples for mass spectrometry characterization. The generated data is utilized by fitting mechanistic kinetics model that allow predicting and minimizing impurities formation to arrive at optimal synthesis conditions. Then a research scale chromatography process is applied measuring adsorption isotherm of individual impurities that allow developing mechanistic chromatograph model and optimizing column operating conditions to further purge those impurities. This work will present practical case studies demonstrating effectiveness of this workflow in designing synthesis through purification global control strategies requiring minimal number of experiments.
