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高度监管，并基于数十年的经验。这些技术从实验室开始，在试点活动中继续进行，最后毕业于全面生产。为了提高药品质量和生产，2001年，美国食品药品监督管理局（FDA）为制药行业启动了质量设计（QbD）和过程分析技术（PAT）指南。该项目将提供遵守该指南的能力，并在生产过程中持续监测药品质量。 活性药物成分（API）的结晶涉及获得特定的结晶相，对于该结晶相，也可以存在多种多晶型形式，这是药物有效性的关键因素。粉末X射线衍射（PXRD）是测定API晶相组成和多晶型的“黄金标准”分析工具。不幸的是，由于传统PXRD的配置要求，PXRD目前没有在线实时使用。由于传统PXRD系统的样品呈现要求和系统尺寸、复杂性以及操作员技能要求的限制，目前在实验室中离线应用。最近X射线光学系统（XOS）的准直光学和检测器系统的发展提供了一个机会，以克服这些问题，并使广泛的在线PXRD应用。 该项目的目标是开发一种可靠、易用、紧凑和安全的PXRD系统，用于在药物开发和生产过程中实时连续监测API的结晶特性。这将改善工艺控制，从而通过直接测量药物关键质量属性而不是依赖于由相对不频繁的采样支持的监测工艺条件来保证产品质量。该项目侧重于API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I期研究期间，已在实验台上证明了此类测量的可行性。它将在第二阶段的BMS药物研究和制造设施中在线展示。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。这包括样品展示、固定检测器方法以及将分析仪与BMS现有反应堆集成。 XOS在在线光学XRD和X射线荧光（XRF）应用方面拥有丰富的经验。拟议的项目是一个匹配的NIH研究目标的医疗，牙科和生物技术主题的制造过程作为一个系统级的技术。提高药品质量、改善公共卫生、降低制造成本和降低医疗保健成本是最终目标。 公共卫生相关性：与目前仅监测生产参数的做法相比，拟议的分析仪将通过首次提供在工艺过程中测量实际药物结晶/分子形式的能力来增加对药物质量的控制。该分析仪将是紧凑的，廉价的，并能够设置和操作的操作员和技术人员。在开发、中试放大和全面生产期间直接在线测量药物结晶度的能力将通过提高药物质量的一致性、通过更快的生产加速缩短上市时间、通过增加过程控制降低生产成本以及通过应用FDA的过程分析技术（PAT）药物认证指南提高生产合规性来影响公共健康。

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. PUBLIC HEALTH RELEVANCE: The proposed analyzer will increase control over the quality of pharmaceuticals by providing the ability to measure the actual drug crystalline/molecular form during the process for the first time, compared to current practice of just monitoring the manufacturing parameters. The analyzer will be compact, inexpensive, and able to be set up and operated by operators and technicians. The ability to measure crystallinity in the drug directly online during development, pilot scale up, and full-scale manufacturing will impact public health by improving the consistency of pharmaceutical quality, reducing time to market by faster manufacturing ramp up, reducing manufacturing costs by increased process control, and improving manufacturing compliance through application of the FDA's Process Analytical Technology (PAT) drug certification guidelines.