Abstract：
Transferring an existing marketed pharmaceutical product from batch to continuous manufacturing (CM) without changes in regulatory registration is a challenging task in the pharmaceutical industry. Continuous manufacturing can provide an increased production rate and better equipment utilisation while retaining key quality attributes of the final product. Continuous manufacturing necessitates the monitoring of critical quality attributes in real time by appropriate process analytical tools such as near infra-red (NIR) probes. The present work reports a successful transfer of an existing drug product from batch to continuous manufacturing process without changing the formulation. A key step was continuous powder blending, whose design and operating parameters including weir type, agitation rate, dynamic hold-up and residence time were systematically investigated with respect to process repeatability. A NIR-based multivariate data model for in-line composition monitoring has been developed and validated against an existing quality control method for measuring tablet content uniformity. A continuous manufacturing long-run with a throughput of 30 kg/h (approx. 128,000 tablets per hour), uninterrupted for 320 min, has been performed to test and validate the multivariate data model as well as the batch to continuous process transfer. The final disintegration and dissolution properties of tablets manufactured by the continuous process were found to be equivalent to those manufactured by the original batch process.
摘要：
在不改变监管注册的情况下,将现有的市售药物产品从批量制造转移到连续制造(CM)是制药行业中的一项具有挑战性的任务。连续制造可以提供提高的生产率和更好的设备利用率，同时保留最终产品的关键质量属性。连续制造需要通过适当的过程分析工具(例如近红外(NIR)探头)实时监测关键质量属性。本工作报告了在不改变配方的情况下将现有药物产品从分批生产过程成功转移到连续生产过程。一个关键步骤是连续的粉末混合，其设计和运行参数包括堰型,搅动速率,系统研究了动态滞留量和停留时间对工艺重复性的影响。已经开发了用于在线成分监测的基于NIR的多变量数据模型，并针对现有的用于测量片剂含量均匀性的质量控制方法进行了验证。一个连续的生产长期运行与30公斤/小时的吞吐量（约。每小时128,000片），不间断320分钟，已经进行了测试和验证多变量数据模型以及批次到连续过程的转移。发现通过连续方法制造的片剂的最终崩解和溶解性质与通过原始分批方法制造的那些相同。
