Abstract
RNA interference (RNAi) is an exciting new therapeutic approach, using small interfering RNA (siRNA) to silence specific genes for treating various diseases. Ultrafiltration has been widely used for the concentration and purification of monoclonal antibodies and other biotherapeutics; however, its application in the downstream processing of double-stranded oligonucleotides remains underexplored. This study investigates the use of ultrafiltration in the final formulation for concentrating a siRNA drug substance. Initial experiments were conducted with Ultracel™ composite regenerated cellulose membranes over a range of molecular weight cutoffs (MWCO) at different siRNA feed concentrations. Results demonstrated significant effects of both fouling and concentration polarization, with the maximum achievable concentration falling well below the target required for subcutaneous injection. Novel surface-modified ultrafiltration membranes were made by reaction of the cellulose with bromopropanesulfonic acid. These negatively charged membranes showed improved siRNA retention, reduced fouling, and a large increase in the maximum achievable siRNA concentration (from 52 to >180 mg/mL). These findings offer critical insights into novel approaches for developing high performance ultrafiltration processes for siRNA concentration.
Published Version
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