Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Technical Services/Manufacturing Science, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Science. 2017 Jun 16;356(6343):1144-1150. doi: 10.1126/science.aan0745.
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
药物效力的提高和针对性治疗的发展推动了制药行业从传统的批处理模式向更灵活的连续处理模式转变。在这里，我们报告了一种多步连续流 CGMP（现行良好生产规范）工艺的开发，该工艺生产了 24 公斤适用于人体临床试验的普雷沙替布单乳酸单水合物。使用小型连续式反应器、萃取器、蒸发器、结晶器和过滤器在实验室通风橱中进行了 8 个连续单元操作，每天大约生产 3 公斤目标产物。这得益于化学、工程、分析科学、过程建模和设备设计方面的进展。确定了大量的技术和商业驱动因素，这些因素证明了连续工艺的合理性。与批处理工艺相比，连续工艺具有更好的性能和安全性，并且还能更好地控制高活性化合物。
