Planning Grant: Engineering Research Center for Continuous Membrane-enabled Manufacturing of Pharmaceutical (CMMP)

工程研究中心规划拨款竞赛是ERC项目的试点征集。规划补助金不需要作为ERC竞赛的一部分，但它旨在在团队之间建立能力，以规划聚合的、中心规模的工程研究。连续膜制药业的发展将为化学、精细化工和石化工业的常规分离和反应分离提供迄今为止不存在的机会。膜技术结构紧凑，模块化，易于扩展，高能效，并且能够连续进行非凡的分离。膜反应器可以达到传统管式反应器无法达到的合成水平，现在已经被公认为是一种过程强化工具。为了克服批量生产的许多缺陷，我们提出了一个使用膜技术的连续膜制造药物（CMMP）的ERC。拟议的ERC有三个目标：(1)开发、适应和过渡由CMMP团队和其他人开发的新膜、新膜技术和膜反应分离概念，用于连续生产分子量约为150-1000 Da的活性药物成分（api）的单个步骤；(2)将单个膜基步骤整合到一个多步骤原料药生产过程中，并论证了配备过程分析技术（PAT）的主要膜基连续工艺在经济、高效、高质量、安全的情况下合成原料药的可行性；(3)制定一项教育计划，并营造一种环境，使教育与制药生产相关，并通过计划开发的创新影响精细化学品制造过程。在这项计划资助中，来自六所大学的学术利益相关者将与主要制药公司、合同制造组织、膜制造商和工艺系统开发商的利益相关者合作，确定具有合成和分离步骤的关键制药系统，为引入新膜技术做好准备。在此资助期间，利益相关者将审议潜在的基于膜的演示系统，用于选择原料药的多步骤合成。这些系统将构成ERC预提案的基础。将成立一个利益相关者社区来指导CMMP的进展，并创建一个强大的学术项目，以帮助高中、本科生和研究生学习从批量生产过渡到连续的基于膜的原料药生产的范式变化。膜技术在制药制造中的应用非常有限，因为人们对有机溶剂型系统中耐溶剂性降低和选择性有限的担忧。新型致密膜具有非常高的耐溶剂性（HSR）和精细的选择性，可以通过有机溶剂反渗透、有机溶剂纳滤和膜渗透蒸发等过程分离小分子和有机溶剂的混合物。它们的进一步发展将迎来一个具有非凡性能和对如何设计它们的理解的膜的新时代。微孔HSR膜可用于非分散溶剂萃取、气液膜接触器和反应器进行加氢、脱氢、臭氧氧化、膜混合、结晶和吸附。致密的纳米多孔膜可用于膜反应器，以获得高选择性和产率。在原料药合成流程的每个步骤中连续使用这种膜，将从根本上改变制药生产，通过紧凑/可扩展的膜模块引入高效率。这笔拨款将允许利益相关者确定原料药生产的膜工艺，大大提高反应和分离步骤的性能。这笔拨款还将指导ERC的预提案，以选择具有一系列连续操作的基于膜的反应和分离步骤的原料药合成示例，从而展示膜装置高效运行和降低成本的能力。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The Planning Grants for Engineering Research Centers competition was run as a pilot solicitation within the ERC program. Planning grants are not required as part of the full ERC competition, but intended to build capacity among teams to plan for convergent, center-scale engineering research.Development of continuous membrane-enabled manufacturing of pharmaceuticals will open hitherto nonexistent opportunities for both conventional and reactive separations in the chemical, fine chemicals and petrochemical industries. Membrane technologies are compact, modular, easily scalable, highly energy efficient and are capable of extraordinary separations in a continuous fashion. Membrane reactors can achieve a synthesis level not achievable by conventional tubular reactors and are now well-established as a process intensification tool. To overcome many deficiencies of batch manufacturing, we propose an ERC for Continuous Membrane-Enabled Manufacturing of Pharmaceuticals (CMMP) using membrane technologies. The proposed ERC has three goals: (1) Develop, adapt and transition new membranes, novel membrane technologies and membrane reaction-separation concepts developed by the CMMP team and others into individual steps of continuous manufacturing of active pharmaceutical ingredients (APIs) in the molecular weight range of about 150-1000 Da; (2)Integrate the individual membrane-based steps into a multistep API production process and demonstrate the feasibility of a primarily membrane-based continuous process equipped with process analytical technology (PAT) to synthesize APIs economically with high efficiency, quality, and safety;(3) Develop an educational program and foster an environment that transforms education relevant to pharmaceutical production as well as influences fine chemicals manufacturing processes with the program-developed innovations. In this Planning Grant, academic stakeholders from six universities will work with stakeholders from major pharmaceutical companies, contract manufacturing organizations, membrane manufacturers, and process system developers to identify key pharmaceutical systems with synthesis-cum-separation steps ready for introduction of new membrane technologies. During this grant, stakeholders will deliberate on potential membrane-based demonstration systems for multistep synthesis of select APIs. These systems will form the basis of the ERC pre-proposal. A stakeholder community will be formed to guide progress of CMMP and creation of a strong academic program to assist high school, undergraduate and graduate students learn the paradigm change when transitioning from batch production into continuous membrane-based API manufacturing. Membrane technologies have very limited footprint in pharmaceutical manufacturing due to perceived concerns regarding reduced solvent resistance and limited selectivities in organic solvent-based systems. New dense membranes are emerging with very high solvent resistance (HSR) and exquisite selectivities that can separate mixtures of smaller molecules and organic solvents via processes such as, organic solvent reverse osmosis, organic solvent nanofiltration and membrane pervaporation. Their further development will usher in a new era of membranes with extraordinary performance and understanding of how to design them. Microporous HSR membranes can be used for nondispersive solvent extraction, gas-liquid membrane contactors and reactors for hydrogenation, dehydrogenation, ozonation, membrane mixing, crystallization and adsorption. Dense, nanoporous membranes may be used in membrane reactors to achieve high selectivity and yield. Introduction of such membranes operating continuously into each step of the API synthesis train will radically transform pharmaceutical production introducing high efficiencies with compact/scalable membrane modules. This grant will allow stakeholders to identify membrane processes for API production that substantially enhance performances of reaction and separation steps. This grant will also guide an ERC pre-proposal in selecting API synthesis examples having a train of continuously operated membrane-based reaction and separation steps thereby demonstrating the capability of membrane devices to operate with high efficiency and reduced cost.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.