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

摘要 英飞尼流体公司正在开发一种用于生产油脂的超大规模微流控集成(VLSMI)芯片 用于RNA疗法的纳米颗粒(LNP)，可以动态范围扩展到1000倍-从100毫升/小时到 100 L/小时--从而在药物开发的所有阶段实现高效和负担得起的使用。LNPs前景看好 在RNA疗法和疫苗的临床翻译中起到关键作用的药物输送载体，大多数 特别是辉瑞公司和莫德纳公司生产的新冠肺炎基因疫苗。新冠肺炎大流行创造了 在全球范围内对快速生产LNPs的需求前所未有，这突显了一些 当前生产方法的主要局限性。事实上，广泛的临床翻译面临的一个关键挑战是 基于LNP的RNA疗法和疫苗是配方策略的发展，可以强有力地 生产精确定义的配方，同时适应可扩展的生产能力，从早期到 向临床翻译发展。 为了解决这个问题，英飞尼流体公司正在开发VLSMI芯片，使生产规模扩大1000倍 同时保持使用微流体产生的LNPs的典型效力，从而能够高效和 在药物开发的各个阶段以负担得起的价格生产高质量的LNPs。英飞尼提出的VLSMI 架构将数十到数百个微流控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。单独的混合单元允许对LNP物理化学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地制造用于临床阶段的LNPs 试验或工业规模生产。 本项目一期工程的具体目标是：1.评价人字形交错搅拌的混合效率 (SHM)不同长度和流速的设计单元使用荧光图像，Infini将评估四种不同的 器件设计，在硅和玻璃中实现，更符合 医药制造业。将对混合动力学进行评估，以确定性能最佳的SHM设计 合成LNPs，2：评价LNPs的性质，通过包埋来确定LNPs的均匀性 Poly(C)作为模型核酸；在这里，Infini将评估LNP的属性，以证明LNP的生产 对于商业规模而言，可预测且准确。 英飞尼流体公司的VLSMI芯片解决方案将实现对LNP物理化学和功能特性的精细控制 这对于高质量和高效力的LNP是必要的，但到目前为止还没有大规模生产LNP 方法：研究方法。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，帮助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，并使对新出现的病原体做出更及时的反应。

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.