Liquid Distribution and Mixing in Continuous Granulation

全球制药行业正准备通过实施过程分析技术（PAT）来摆脱狭窄的验证过程的限制：过程理解和过程仪表的结合，使制造商能够控制过程，以在定义的操作空间内保持质量。与传统的窄操作窗口相比，预计这将提供更大的灵活性和更少的浪费，而传统的窄操作窗口是从实验台到批次的经验性放大产生的。连续加工，在本项目中，连续造粒，被广泛认为是实施PAT的途径。稳态操作和直接实施反馈和前馈控制（采用适当的测量技术和过程模型）的优点，已经看到连续处理在除制药外的大多数化学制造中占主导地位。该项目的具体挑战是进一步发展我们对制粒机制的理解，从而了解连续制粒中的混合工艺;这一点至关重要，因为制粒是工艺中决定药物是否均匀准确分布在最终剂型中的阶段。我们为此使用的技术包括：粒度分布;使用示踪剂来量化颗粒中液体粘合剂的分布;使用正电子发射粒子跟踪技术，在真实的中测量颗粒内的流动、混合、填充水平和RTD;扭矩和功率测量; X射线显微断层扫描技术，将颗粒结构的分辨率提高到优于5微米;颗粒的机械性能。该项目旨在探索造粒机制及其结果，以建立对关键产品质量和关键工艺参数的全面理解，并以制度图的形式呈现。其关键是开发用于测量颗粒产品中液体粘合剂和固体药物和辅料分布的方法。这方面的知识，预计将有助于基本了解制粒机制，以及如何影响颗粒和片剂的性质。

The global pharmaceutical industry is gearing up to escape the constraints of narrow validated processes through implementation of Process Analytical Technology (PAT): a combination of process understanding and process instrumentation that will allow manufacturers to control processes to maintain quality within a defined operating space. This is expected to give more flexibility and less waste than the traditional narrow operating windows that result from empirical scale up from the bench to batch. Continuous processing and, in the case of this project, continuous granulation, is widely seen as route to implementation of PAT. The advantages of steady state operation and straightforward implementation of feedback and feedforward control (with appropriate measurement technology and process models), has seen continuous processing dominate most of chemical manufacture apart from pharma. The specific challenge for this project is to further develop our understanding of granulation mechanisms and hence mixing processes in continuous granulation; this is fundamentally important since granulation is the stage in the process that determines whether the drug is uniformly and accurately distributed among the final dose forms (e.g. tablets).The techniques we have used for this include: Particle Size Distribution; use of tracers to quantify distribution of liquid binder among particles; use of Positron Emission Particle Tracking to characterise flow, mixing, fill level and RTD within the granulator in real; torque and power measurement; x-ray micro-tomography to characterise particle structure to a resolution of better than 5 micron; mechanical properties of granules. This project aims to explore granulation mechanisms and their outcome in order build a full understanding of Critical Product Qualities and Critical Process Parameters and to present this in the form of a regime map. Key to this is will be development of methodologies for measurement of the distribution of liquid binders and solid drugs and excipients within the granulated product. This knowledge is expected to contribute fundamental understanding of granulation mechanisms and how these impact granule and tablet properties.