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

工程研究中心的规划赠款竞争是作为ERC计划内的试点招标运行。ERC竞赛不需要规划赠款，但旨在培养团队规划集中的中心规模工程研究的能力。连续膜制药的发展将为化学、精细化学品和石化行业的常规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，能源效率高，能够以连续的方式进行非凡的分离。膜反应器可以达到传统管式反应器无法达到的合成水平，并且现在已被公认为过程强化工具。为了克服批量生产的许多不足之处，我们提出了一个ERC的连续膜使能制造的药物（CMMP）使用膜技术。拟议的ERC有三个目标：（1）开发、调整和过渡CMMP团队和其他人开发的新膜、新膜技术和膜反应分离概念，使其成为分子量约为150-1000 Da的活性药物成分（API）连续生产的各个步骤;（2）将各个基于膜的步骤整合到多步API生产工艺中，并证明配备有过程分析技术（PAT）的主要基于膜的连续工艺的可行性，以经济高效地合成API，质量和安全;（3）制定教育计划，并培养一种环境，改变与制药生产相关的教育，并通过计划开发的创新影响精细化学品制造工艺。在这项计划补助金中，来自六所大学的学术利益相关者将与来自主要制药公司，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，以确定具有合成和分离步骤的关键制药系统，为引入新的膜技术做好准备。在此期间，利益相关者将审议潜在的基于膜的示范系统，用于选择API的多步合成。这些系统将构成ERC预提案的基础。将形成一个利益相关者社区，以指导CMMP的进展，并创建一个强大的学术计划，以帮助高中，本科生和研究生学习从批量生产过渡到连续膜基API生产时的范式变化。膜技术在药物制造中具有非常有限的足迹，这是由于对有机溶剂基系统中降低的耐溶剂性和有限的选择性的关注。新的致密膜正在出现，具有非常高的耐溶剂性（HSR）和精确的选择性，其可以通过诸如有机溶剂反渗透、有机溶剂纳滤和膜渗透蒸发的过程分离较小分子和有机溶剂的混合物。他们的进一步发展将迎来一个新时代的膜与非凡的性能和理解如何设计它们。微孔HSR膜可用于非分散溶剂萃取、气液膜接触器和加氢、脱氢、臭氧化、膜混合、结晶和吸附反应器。致密的纳米多孔膜可用于膜反应器中以实现高选择性和产率。将这种连续操作的膜引入API合成系列的每个步骤中将从根本上改变药物生产，从而利用紧凑/可扩展的膜模块引入高效率。这项资助将使利益相关者能够确定用于API生产的膜工艺，这些工艺可以大大提高反应和分离步骤的性能。该基金还将指导ERC预提案选择API合成实例，这些实例具有一系列连续操作的基于膜的反应和分离步骤，从而证明膜装置以高效率和低成本操作的能力。该奖项反映了NSF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.