Development of an online XRD pharmaceutical process analyzer

描述(由申请人提供)：目前的制药技术和工艺受到严格的监管，并基于数十年的经验。这些技术从实验室开始，在试点活动中继续，最后逐步进入全面生产。为了改善药品质量和生产，2001年，美国食品和药物管理局(FDA)启动了制药业设计质量(QBD)和过程分析技术(PAT)指南。该项目将提供遵守该指导方针的能力，并在生产过程中持续监测药品质量。活性药物成分(API)的结晶包括获得特定的晶相，对于晶相也可以有多种不同的形式，这是药物有效性的关键因素。粉末X射线衍射仪是测定原料药晶相组成和晶型的“金标准”分析工具。遗憾的是，由于传统PXRD的配置要求，目前不能在线实时使用PXRD。它目前在实验室中离线应用，因为受样品演示要求的限制，以及传统PXRD系统的系统规模、复杂性和操作员技能要求。X射线光学系统(XOS)在准直光学和探测器系统方面的最新发展为克服这些问题和实现广泛的在线PXRD应用提供了机会。该项目的目标是开发一种可靠、易用、紧凑和安全的PXRD系统，用于在药物开发和制造过程中连续实时监测原料药的结晶特性。这将通过直接测量药品的关键质量属性，而不是依赖于相对较少的抽样支持的监测工艺条件，来改进过程控制，从而保证产品质量。该项目侧重于原料药结晶阶段的在线测量。这将与百时美施贵宝(BMS)的制药行业合作伙伴一起完成。在第一阶段的研究中，这种测量的可行性已经在台面上得到了证明。它将在第二阶段在BMS的一家制药研究和制造设施进行在线演示。第二阶段将包括设计、组装和测试原型所需的所有必要仪器开发步骤。这包括样品介绍、固定检测器方法，以及将分析仪与BMS的现有反应堆集成。XOS在在线光学X射线衍射仪和X射线荧光(XRF)应用方面拥有丰富的经验。建议的项目与NIH作为系统级技术的医疗、牙科和生物技术制造过程的研究目标主题相匹配。提高药品质量、改善公众健康、降低生产成本和降低医疗成本是最终目标。

DESCRIPTION (provided by applicant): Current pharmaceutical manufacturing technologies and processes are highly regulated and based on decades of experience. The techniques start in a lab, are continued in a pilot campaign, and finally graduate to full-scale manufacturing. To improve drug quality and manufacturing, in 2001, the Food and Drug Administration (FDA) initiated Quality by Design (QbD) and Process Analytical Technology (PAT) Guidance for the pharmaceutical industry. This project will provide the ability to comply with that guidance and continuously monitor pharmaceutical quality during manufacturing. Crystallization of active pharmaceutical ingredients (API) involves achieving a specific crystalline phase, for which there can also be multiple polymorphic forms, a critical factor for drug effectiveness. Powder X-ray diffraction (PXRD) is the 'gold standard' analytical tool to determine API crystalline phase composition and polymorphic form. Unfortunately, PXRD is not currently used online real-time because of the configuration requirements for conventional PXRD. It is currently applied offline in the laboratory because of constraining sample presentation requirements and the system size, complexity, and operator-skill requirements of conventional PXRD systems. Recent developments at X-Ray Optical Systems (XOS) of collimating optics and detector systems provide an opportunity to overcome these problems and enable a wide range of online PXRD applications. The objective of the proposed project is development of a reliable, easy-to-use, compact, and safe PXRD system for continuous monitoring of crystalline characteristics of API real-time during drug development and manufacture. This will improve process control and, therefore, assurance of product quality by directly measuring the pharmaceutical critical quality attributes rather than reliance on monitoring process conditions supported by relatively infrequent sampling. The project focuses on online measurements during the API crystallization phase. This will be done with pharmaceutical industry collaborators at Bristol-Myers Squibb (BMS). Feasibility for such measurements has been demonstrated on the benchtop during Phase I studies. It will be demonstrated online at a BMS pharmaceutical research and manufacturing facility in Phase II. Phase II will include all of the necessary instrument development steps required to design, assemble, and test the prototype. This includes sample presentation, the fixed detector approach, and integrating the analyzer with an existing reactor at BMS. XOS has extensive experience with online optic-enabled XRD and X-ray fluorescence (XRF) applications. The proposed project is a match with the NIH Research Objectives for the Manufacturing Processes of Medical, Dental, and Biological Technologies topic as a systems-level technology. Improved drug quality, improved public health, reduced manufacturing costs, and reduced health-care costs are the ultimate goals.