Model-Based Analysis of Membrane-Enhanced Liquid-Phase Oligonucleotide Synthesis ⁎ ⁎ This work was supported by Innovate UK under grant number 10103756 (Sustainable bioprocess for oligonucleotide manufacture using Nanostar Sieving – BioNanostar)

Oligonucleotides show great promise for therapeutic applications. While traditional solid-phase oligonucleotide synthesis presents manufacturing challenges due to low scalability, lack of real-time monitoring and high process mass-intensity, liquid-phase synthesis (LPOS) combined with soluble anchors and membrane diafiltration has emerged as a viable alternative. Herein, we formulate a multi-stage dynamic model of the LPOS process using a multi-branched homostar support hub. We exploit this model to analyse the interplay between the durations of the reaction and diafiltration steps on the oligonucleotide yield and purity through the solution of an inverse feasibility problem.