Advanced continuous upstream manufacturing of biotherapeutics

项目概要/摘要。 本提案的总体目标是开发和实施一个基于平台技术的试验床， 自动化和集成的连续上游生物工艺。该试验台将整合 过程模型组件、传感器（物理和虚拟）、控制软件和硬件以及数据 管理，并将作为一个平台，发展必要的科学，技术和监管 框架.然后，可以将拟议工作的这一产出用作充分集成的连续 商业生物制造，由学者，工业从业者和监管机构一样，因为我们共同 合作，将生物基产品的先进制造的零件到位， 持续的生物制造为此，将通过以下重点实现总体目标 具体目标： 具体目标1：通过过程中校正反馈操纵哺乳动物细胞生物合成行为， 关键工艺和细胞培养参数的快速检测。 具体目标2：故障模式识别、风险评估、 工艺替代品和基于计算机模型的分析的比较。 具体目标3：集成（软）-连续的传感、控制、数据管理和实施 上游生物工艺，以证明增加的实时产品质量保证。 拟议的工作解决了新兴的先进制造方法（即，连续生物处理） 以及通过提供进一步的科学知识捕获到预测模型中来实现其采用的关键障碍 可用于开发后续的过程控制和自动化。根据FDA开展此类工作 赞助与行业互动结合提供了一条商业采用的途径， 配套的监管框架。此外，人们越来越关注实现 连续生物处理，其中初步工作已经指出了该技术的益处。连同 FDA关于大分子和小分子中连续（生物）处理的最新指南 空间，以及最近工业公司转向更多生物药物组合的趋势， 迫切需要提高技术水平，以便更快地采用和监管。 拟议的工作与罗格斯大学的战略方向和大学的承诺， 在机构一级支持这一领域的工作。最后，调查小组的一部分也是关键 C-SOPS团队成员，他们成功地与制药公司、供应商和 FDA作为NSF-ERC基础设施的一部分，开发和实施概念验证持续 在Rutgers进行的生产（CM）制剂测试最终形成了Janssen的基础 Prezista药物通过CM批准。

Project Summary/Abstract. The overall goal of this proposal is to develop and implement a platform technology-based testbed of a fully automated and integrated continuous upstream bioprocess. The testbed will incorporate integrated components of process models, sensors (physical and virtual), control software and hardware, and data management and will serve as a platform to develop the necessary scientific, technological and regulatory framework. This output of the proposed effort can then be used as a pre-cursor to fully integrated continuous commercial biomanufacturing, by academics, industrial practitioners and regulators alike, as we collectively collaborate to put the pieces into place for advanced manufacturing of biological based products made by continuous biomanufacturing. To this effect, the overall goal will be realized by focusing on the following specific aims: Specific Aim 1: Mammalian cell biosynthetic behavior manipulation via in-process corrective feedback through the rapid detection of key process and cell-culture parameters. Specific Aim 2: Process model development and validation for failure mode identification, risk assessment, comparison of process alternatives and in-silico model-based analyses. Specific Aim 3: Integrated (soft)-sensing, control, data management and implementation in a continuous upstream bioprocess to demonstrate increased real-time product quality assurance. The proposed work addresses an emerging advanced manufacturing approach (i.e., continuous bioprocessing) and the critical barriers to its adoption by providing further scientific knowledge captured into predictive models that can be used to develop subsequent process control and automation. Performing such work under FDA sponsorship in conjunction with industry interactions provides a pathway to commercial adoption with an accompanying regulatory framework. Furthermore, there is a growing interest in realizing the benefits of continuous bioprocessing where initial work has pointed to the benefits of this technology. Together with the recent guidance(s) expressed by the FDA on continuous (bio)-processing in both the large and small-molecule space, and the recent trend of industrial companies moving toward a more biologic drug based portfolio, there is an immediate need to advance the state of the technology for more expeditious adoption and regulation. The proposed work is aligned with Rutgers University's strategic direction and the University's commitment to supporting work in this field at the institutional level. Finally, part of the investigative team are also key members of the C-SOPS team that have successfully worked with a pharmaceutical companies, vendors and the FDA as part of the NSF-ERC infrastructure to develop and implement a proof-of-concept continuous manufacturing (CM) drug product tested at Rutgers that eventually formed the basis for Janssen Pharmaceuticals Prezista drug approval via CM.