Formulating microstructural equivalence: A route to consistent scale-up of medicine manufacture

开发一种新的医药产品需要设计一种配方，这种配方在规模化生产和患者在现实世界中使用时提供一致的性能。为了满足药品性能的高监管负担，必须满足一些质量(Q)要求。也就是说，每一批产品必须包含正确的定性材料成分(Q1)，在定义的定量比率(Q2)中，产生这些材料的特定三维排列(Q3，微观结构)。制造操作的设计使产品满足这些质量要求。在过去的15年里，在按设计质量的理念下，在分子/过程建模和数字孪生方面的大量研发工作已经开始在加速配方设计方面获得回报。第三季度的微观结构已经成为产品性能工程的关键知识缺口。配方微结构决定了生产行为和质量属性，如粉末流动和片剂压实、混悬剂和外用乳膏、凝胶和软膏的分散状态和粘度，以及吸入性药物的流态化和雾化。表征微观结构以映射和量化其对性能的影响的能力是一项尚未满足的挑战，特别是对于粉末产品。X射线成像已经成为粉末分析的一种潜在解决方案，尽管存在许多技术和计算障碍来释放其潜力。在这个项目中，我们的目标是开发定量的X射线成像技术来表征干粉吸入(DPI)产品的微观结构。由于DPI配方的高颗粒密度、活性药物成分(API)的小颗粒尺寸以及相对于辅料的低浓度，DPI配方对X射线成像是具有挑战性的产品。然而，研究DPI是一项值得研究的挑战，因为欧洲(EMA，MHRA)和美国(US FDA)的监管机构已将评估微观结构的技术需求确定为建立创新者和仿制药之间生物等效性的主要障碍。这为更便宜的仿制药进入市场创造了障碍，并可能为医疗保健系统带来经济优势。该项目的结果将是提供分析工具来支持创新疗法的制造，特别是以微结构引导的产品工程为重点。英国的几个研究中心已经成为翻译开发和药品制造领域的世界领先者。微结构表征的科学将开辟一条强有力的途径，利用这项研究中出现的数字产品建模工具。我们研究的最终目标是利用配方微结构的早期识别，从产品开发开始就将可制造性设计到早期产品中，并加速扩大到临床供应。

The development of a new medicinal product requires a formulation to be designed that provides consistent performance when manufactured at scale, and when the medicine is used by patients in real-world scenarios. To meet the high regulatory burden for medicine performance a number of quality (Q) requirements must be met. Namely that each batch of the product must contain the correct qualitative material composition (Q1), in a defined quantitative ratio (Q2), that generates a specific three-dimensional arrangement of those materials (Q3, the microstructure). Manufacturing operations are designed so that products meet these quality requirements.Over the last fifteen years under the quality-by-design concept, substantial R&D effort into molecular/process modelling and digital twinning has begun to reap rewards in terms of accelerated formulation design. The Q3 microstructure has emerged as key knowledge gap to the engineering of product performance. A formulation microstructure dictates the manufacturing behaviour and quality attributes as diverse as powder flow and tablet compaction, the dispersion state and viscosity of suspensions and topical creams, gels and ointments, and the fluidization and aerosolization of inhalation medicines. The ability to characterise microstructure to map and quantify its impact on performance is an unmet challenge, particularly for powder-based products. X-ray imaging has emerged as a potential solution to powder analysis, although many technical and computational barriers exist to unlocking its potential.In this project, we aim to develop quantitative x-ray imaging techniques to characterize the microstructure of dry powder inhalation (DPI) products. DPI formulations are challenging products for x-ray imaging, due to high particle density, small particle size of the active pharmaceutical ingredient (API) and the low concentrations of API relative to excipient substances. Nevertheless, studying DPIs is a challenge worth investigating, since the need for techniques to assess microstructure has been identified as a major barrier to establishing bioequivalence between innovator and generic products by regulatory agencies in Europe (EMA, MHRA) and the United States of America (US FDA). This creates a barrier for market entry of cheaper generic products, and the economic advantages that this could bring for healthcare systems.The outcome of this project will be the availability of analytical tools to support the manufacture of innovative therapeutics with a specific focus on microstructure-guided product engineering. Several research centres in the UK have emerged as world-leaders in translational development and medicines manufacturing. The science of microstructural characterization would open up a powerful route to exploiting the digital product modelling tools that are emerging from that research. The ultimate goal of our research is to exploit early identification of a formulation microstructure to engineer manufacturability into early-stage products right from the start of their development, and accelerate the scale-up to clinical supply.