Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production.
Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production.
复制标题
使用逐滴增材制造和三相沉降进行小规模连续药品制造，以与上游原料药生产相结合。
DOI：
10.1016/j.xphs.2022.03.009
复制
发表时间：
2022
影响因子：
3.8
通讯作者：
Reklaitis,GintarasV
中科院分区：
文献类型：
--
作者：
Sundarkumar,Varun;Nagy,ZoltanK;Reklaitis,GintarasV
传统上，制药行业依靠大规模生产来生产产品。这在药品供应网络中造成了多重问题，包括生产时间长、生产不灵活和缓慢以及缺乏个性化剂量。油气行业正在逐渐适应这些挑战，并开发新技术来解决这些问题。连续制造和3D打印是两种有前途的技术，可以彻底改变制药制造。然而，大多数对这些方法的研究都倾向于将它们分开对待。本研究旨在开发一种新的加工路线，将3D打印平台（按需滴注、DoD、打印）与结晶（通常是活性成分制造的最后一步）持续集成。完成这一整合将能够利用每种方法的优势——3D打印的个性化剂量以及连续制造的灵活性和速度。开发了一种新的单元操作，三相沉淀（TPS），将DoD与上游结晶器集成在一起。为了确保每个打印剂量的生产符合规格，打印机中包含两个过程分析技术工具，以实时监测制造的药品中的药物装载。该系统通过两个案例进行了实验论证：第一个研究使用活性成分塞来昔布测试TPS的独立运行；第二项研究演示了结晶器- TPS - DoD集成系统对活性成分洛莫司汀的连续生产。还对生产的和商业的洛莫司汀药品进行溶出试验，以比较它们的溶出行为。
The pharmaceutical industry has traditionally relied on mass manufacturing to make its products. This has created multiple problems in the drug supply network, including long production times, inflexible and sluggish manufacturing and lack of personalized dosing. The industry is gradually adapting to these challenges and is developing novel technologies to address them. Continuous manufacturing and 3D printing are two promising techniques that can revolutionize pharmaceutical manufacturing. However, most research studies into these methods tend to treat them separately. This study seeks to develop a new processing route to continuously integrate a 3D printing platform (Drop-on-Demand, DoD, printing) with crystallization that is generally the final step of the active ingredient manufacturing. Accomplishing this integration would enable harnessing the benefits of each method- personalized dosing of 3D printing and flexibility and speed of continuous manufacturing.A novel unit operation, three-phase settling (TPS), is developed to integrate DoD with the upstream crystallizer. To ensure on-spec production of each printed dosage, two process analytical technology tools are incorporated in the printer to monitor drug loading in manufactured drug products in real time. Experimental demonstration of this system is carried out via two case studies: the first study uses an active ingredient celecoxib to test the standalone operation of TPS; the second study demonstrates the operation of the integrated system (crystallizer – TPS – DoD) to continuously make drug products for the active ingredient- lomustine. A dissolution test is also performed on the manufactured and commercial lomustine drug products to compare their dissolution behavior.