Continuous synthesis, crystallization, and isolation (CSCI) of an API: process model-controlled enzymatic synthesis of beta-lactam antibiotics

项目摘要 在连续过程中生产药物，而不是传统的批处理，是 设想在出现短缺时，实现更一致的产品质量、更快的生产速度，例如 如在疫情暴发期间，生产工厂对环境的影响较小。 我们建议演示连续合成、结晶和 一例酶催化β-内酰胺类抗生素活性的分离(CSCI) 原料药(原料药)生产。头孢氨苄和阿莫西林的代表 头孢菌素和青霉素将分别成为我们的目标产品。因为FDA已经发布了 关于预防青霉素和青霉素类药物交叉污染的指导意见 头孢菌素类药物，重新设计β-内酰胺类制造厂以建立专用设施 切中要害，发挥优势。我们流程的主要特点包括使用i)和 已建立的生物催化剂，Pen G酰基酶，ii)最近开发的改进的动力学模型，以及iii) 反应结晶，以提高选择性和减少循环时间。我们建议开发 支持PAT的新型集成反应器和分离器以及整体流程模型 并围绕选定的工作点进行过程控制。 我们的设计旨在使β-内酰胺原料药能够在专用的、紧凑的、 资本密集型工厂，这反过来又有助于更好地获得药品 患者，并最终转向更便宜的药物。

Project Summary Manufacturing of drugs in continuous processes, instead of the traditional batch processing, is envisioned to lead to more consistent product quality, faster ramp-up in times of shortages, such as during outbreaks of pandemics, and less environmental impact of the production plants. We propose to demonstrate the concept of continuous synthesis, crystallization, and isolation (CSCI) on the example of enzyme-catalyzed beta-lactam antibiotics active pharmaceutical ingredient (API) production. Cephalexin and amoxicillin, representative for cephalosporins and penicillins, respectively, will be our target products. As the FDA has issued Guidances regarding precautions against cross-contamination for both penicillins and cephalosporins, redesign of beta-lactam manufacturing plants towards dedicated facilities will be pertinent and advantageous. Key features of our process include employment of i) an established biocatalyst, Pen G acylase, ii) a recently developed improved kinetic model, and iii) reactive crystallization to enhance selectivity and reduce cycle time. We propose to develop novel integrated reactors and separators as well as an overall process model, to support PAT and process control around a chosen operating point. Our design is intended to enable beta-lactam API production in dedicated, compact, less capital-intensive plants, which in turn is envisioned to lead to better access to medicines for patients and ultimately to less expensive drugs.