Messerian Kevork Oliver, Zverev Anton, Kramarczyk Jack F, Zydney Andrew L
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.
Moderna, Inc., Cambridge, Massachusetts, USA.
Biotechnol Bioeng. 2022 Nov;119(11):3221-3229. doi: 10.1002/bit.28200. Epub 2022 Aug 8.
The COVID-19 pandemic has generated growing interest in the development of mRNA-based vaccines and therapeutics. However, the size and properties of the lipid nanoparticles (LNPs) used to deliver the nucleic acids can lead to unique phenomena during manufacturing that are not typical of other biologics. The objective of this study was to develop a more fundamental understanding of the factors controlling the performance of sterile filtration of mRNA-LNPs. Experimental filtration studies were performed with a Moderna mRNA-LNP solution using a commercially available dual-layer polyethersulfone sterile filter, the Sartopore 2 XLG. Unexpectedly, increasing the transmembrane pressure (TMP) from 2 to 20 psi provided more than a twofold increase in filter capacity. Also surprisingly, the effective resistance of the fouled filter decreased with increasing TMP, in contrast to the pressure-independent behavior expected for an incompressible media and the increase in resistance typically seen for a compressible fouling deposit. The mRNA-LNPs appear to foul the dual-layer filter by blocking the pores in the downstream sterilizing-grade membrane layer, as demonstrated both by scanning electron microscopy and derivative analysis of filtration data collected for the two layers independently. These results provide important insights into the mechanisms governing the filtration of mRNA-LNP vaccines and therapeutics.
2019年冠状病毒病（COVID-19）大流行引发了人们对基于信使核糖核酸（mRNA）的疫苗和治疗药物研发的日益浓厚兴趣。然而，用于递送核酸的脂质纳米颗粒（LNP）的尺寸和性质在制造过程中可能会导致一些独特现象，这些现象在其他生物制品中并不常见。本研究的目的是更深入地了解控制mRNA-LNP无菌过滤性能的因素。使用市售的双层聚醚砜无菌过滤器Sartopore 2 XLG对莫德纳（Moderna）mRNA-LNP溶液进行了实验性过滤研究。出乎意料的是，将跨膜压力（TMP）从2 psi增加到20 psi，过滤器容量增加了两倍多。同样令人惊讶的是，与不可压缩介质预期的与压力无关的行为以及可压缩污垢沉积物通常出现的阻力增加相反，污染过滤器的有效阻力随着TMP的增加而降低。扫描电子显微镜以及对两层独立收集的过滤数据的导数分析均表明，mRNA-LNP似乎通过堵塞下游除菌级膜层中的孔来污染双层过滤器。这些结果为控制mRNA-LNP疫苗和治疗药物过滤的机制提供了重要见解。
