A Very Large-Scale Microfluidic Integration (VLSMI) chip for producing lipid nanoparticles (LNPs) for RNA vaccines and therapeutics

摘要 Infini Fluidics正在开发用于生产脂质的超大规模微流控集成（VLSMI）芯片 用于RNA治疗的纳米颗粒（LNP），其可以通过1000倍的动态范围缩放-从100 mL/hr到100 mL/hr， 100 L/hr-从而能够在药物开发的所有阶段有效且经济地使用。LNP很有前途 在RNA治疗和疫苗的临床转化中至关重要的药物递送载体， 特别是辉瑞和Moderna生产的COVID-19 mRNA疫苗。2019冠状病毒病大流行造成了 在全球范围内对LNP的快速生产的前所未有的需求，这突出了一些 目前生产方法的主要局限性。事实上，对广泛的临床翻译的一个关键挑战是， 基于LNP的RNA治疗剂和疫苗是可以稳健地 生产精确定义的配方，同时适应可扩展的吞吐量， 发展到临床翻译。 为了解决这个问题，Infini Fluidics正在开发VLSMI芯片，使生产规模扩大1000倍 同时保持使用微流体产生的LNP的典型效力，从而使得能够有效和 在药物开发的各个阶段，以负担得起的价格生产高质量的LNP。Infini的VLSMI 这种架构将数十到数百个微流体混合单元集成到一个4英寸的硅芯片上，就像 计算机芯片中的晶体管。单独的混合装置可对LNP的理化性质进行前所未有的控制 和功能特性，而数百个这样的单元允许灵活制造用于临床阶段的LNP 试验或工业规模生产。 本项目的具体目标是：1.评价交错人字形搅拌的搅拌效率 (SHM)设计单位在不同的长度和流速使用荧光图像，英菲尼将评估四个不同的 器件设计，在硅和玻璃中实现，更符合 制药业。将对混合动力学进行评估，以确定性能最佳的SHM设计 2：评价LNP性质以通过包封LNP来确定LNP的均匀性 poly（C）作为模型核酸;在这里，Infini将评估LNP特性，以证明LNP生产是 可预测和准确的商业规模。 Infini Fluidics的VLSMI芯片解决方案将实现对LNP理化和功能特性的精细控制 这是高LNP质量和效力所必需的，并且迄今为止还没有大规模LNP生产 方法.这项技术可以广泛应用于加速开发，评估和分发 基于RNA的疗法和疫苗，有助于发展这一新兴和有前途的领域。这将使 在新的治疗领域取得成功，并允许对新出现的病原体作出更及时的反应。

Abstract Infini Fluidics is developing a Very Large-Scale Microfluidic Integration (VLSMI) chip for producing lipid nanoparticles (LNPs) for RNA therapeutics that can be scaled by a dynamic range of 1000x—from 100 mL/hr to 100 L/hr—thus enabling efficient and affordable use across all phases of drug development. LNPs are promising drug delivery vehicles that have been critical in the clinical translation of RNA therapeutics and vaccines, most notably the COVID-19 mRNA vaccines produced by Pfizer and Moderna. The COVID-19 pandemic has created unprecedented demand for rapid production of LNPs on a global scale, and this has highlighted some of the major limitations of current production methods. Indeed, a key challenge toward the broad clinical translation of LNP-based RNA therapeutics and vaccines is the development of formulation strategies that can robustly produce precisely defined formulations while accommodating scalable throughputs ranging from early development to clinical translation. To solve this problem, Infini Fluidics is developing the VLSMI chip, enabling scaling of production by 1000-fold while maintaining the potency typical of LNPs generated using microfluidics, thus enabling efficient and affordable production of high-quality LNPs across the phases of drug development. Infini’s proposed VLSMI architecture integrates tens to hundreds of microfluidic mixing units onto a single, 4-inch silicon chip, just like transistors in a computer chip. The individual mixing units allow unprecedented control of LNP physiochemical and functional properties, while hundreds of these units allow flexible manufacturing of LNPs for clinical-phase trials or industrial-scale manufacturing. The specific aims of this Phase I project are 1: To evaluate the mixing efficiency of staggered herringbone mixing (SHM) design units at various lengths and flow rates using fluorescent images, Infini will evaluate four different device designs, implemented in silicon and glass, which is more compatible with the stringent requirements of pharmaceutical manufacturing. Mixing dynamics will be evaluated to identify the best performing SHM designs to synthesize LNPs, and 2: To evaluate LNP properties to determine the uniformity of the LNPs by encapsulating poly(C) as a model nucleic acid; here, Infini will evaluate LNP properties to demonstrate LNP production is predictable and accurate for commercial scale. Infini Fluidics’ VLSMI chip solution will enable the fine control over LNP physiochemical and functional properties that is necessary for high LNP quality and potency and that has so far eluded macroscale LNP production methods. This technology can be widely applied to accelerate the development, evaluation, and distribution of RNA-based therapeutics and vaccines, helping to grow this burgeoning and promising field. This will enable success in new therapeutic areas and allow a timelier response to emerging pathogens.