Advanced continuous upstream manufacturing of biotherapeutics

项目摘要/摘要。 该提案的总体目标是开发和实现一个基于平台技术的完全 自动化、集成化的连续上游生物工艺。试验台将整合集成的 过程模型、传感器(物理和虚拟)、控制软件和硬件以及数据的组件 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，建议工作的这一输出可用作完全集成的连续 商业生物制造，由学者、工业从业者和监管机构共同完成 合作将这些部件安装到位，用于先进制造基于生物的产品，该产品由 连续生物制造。为此，将重点抓好以下几个方面的工作，实现总体目标 具体目标： 具体目标1：通过过程中纠正反馈实现哺乳动物细胞生物合成行为操纵 关键工艺和细胞培养参数的快速检测。 具体目标2：为故障模式识别、风险评估、 工艺备选方案的比较和基于硅胶模型的分析。 具体目标3：综合(软)计量、控制、数据管理和持续执行 上游生物工艺，以展示更高的实时产品质量保证。 拟议的工作涉及一种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捉到预测模型来采用它的关键障碍 这可用于开发后续的过程控制和自动化。在食品和药物管理局的指导下进行这项工作 赞助与行业互动相结合，为商业采用提供了一条途径 随之而来的监管框架。此外，人们越来越感兴趣地认识到 连续的生物处理，最初的工作已经指出了这项技术的好处。与 美国食品和药物管理局关于大分子和小分子连续(生物)加工的最新指导意见(S) 空间，以及最近工业公司转向更多以生物药物为基础的组合的趋势，在那里 迫切需要推动这项技术的状态，以便更快地采用和监管。 拟议的工作符合罗格斯大学的战略方向和该大学对 在机构一级支持这一领域的工作。最后，调查团队的一部分也是关键 C-SOPS团队成员，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，以开发和实施概念验证连续 在罗格斯大学测试的制造(CM)药物产品，最终形成了Janssen的基础 通过CM批准PharmPharmticals Prezista药物。

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.