Genentech, Inc., Genentech Research and Early Development, Synthetic Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, California 94060, United States.
DIANT Pharma, Inc., 130 Utopia Road, Manchester, Connecticut 06042, United States.
Mol Pharm. 2023 Aug 7;20(8):4285-4296. doi: 10.1021/acs.molpharmaceut.3c00390. Epub 2023 Jul 18.
The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development of new technologies to manufacture LNPs. As new technologies emerge, researchers must determine which technologies to assess and how to perform comparative evaluations. In this article, we use a quality-by-design approach to systematically investigate how the mixer technology used to form LNPs influences LNPstructure. Specifically, a coaxial turbulent jet mixer and a staggered herringbone microfluidic mixer were systematically compared via matched formulation and process conditions. A full-factorial design-of-experiments study with three factors and three levels was executed for each mixer to compare process robustness in the production of antisense oligonucleotide (ASO) LNPs. ASO-LNPs generated with the coaxial turbulent jet mixer were consistently smaller, had a narrower particle size distribution, and had a higher ASO encapsulation as compared to the microfluidic mixer, but had a greater variation in internal structure with less ordered cores. A subset of the study was replicated for mRNA-LNPs with comparable trends in particle size and encapsulation, but more frequent bleb features for LNPs produced by the coaxial turbulent jet mixer. The study design used here provides a road map for how researchers may compare different mixer technologies (or process changes more broadly) and how such studies can inform process robustness and manufacturing control strategies.
最近，脂质纳米粒（LNPs）在核酸递送上的临床和商业成功激励了新技术的发展，以制造 LNPs。随着新技术的出现，研究人员必须确定要评估哪些技术以及如何进行比较评估。在本文中，我们使用质量源于设计的方法系统地研究了用于形成 LNPs 的混合器技术如何影响 LNP 的结构。具体来说，通过匹配的配方和工艺条件，对同轴射流湍流混合器和交错人字形微流控混合器进行了系统比较。对于每个混合器，都执行了三因子三水平的全因子实验设计研究，以比较生产反义寡核苷酸（ASO）LNPs 的工艺稳健性。与微流控混合器相比，同轴射流湍流混合器生成的 ASO-LNP 更小，粒径分布更窄，ASO 包封率更高，但内部结构的变化更大，核心更无序。对该研究的一部分进行了 mRNA-LNP 的复制，其粒径和包封率具有类似的趋势，但同轴射流湍流混合器产生的 LNP 中出现更多的泡囊特征。这里使用的研究设计为研究人员如何比较不同的混合器技术（或更广泛的工艺变化）提供了路线图，以及此类研究如何为工艺稳健性和制造控制策略提供信息。
