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

制定微观结构等效性：药物生产持续扩大规模的途径

• 批准号: EP/Z532988/1
• 负责人: Darragh Murnane
• 金额: $ 19.21万
• 依托单位: University of Hertfordshire
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ532988%2F1
• 关键词: Formulating; microstructural; equivalence; route; consistent

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.

新药品的开发需要设计一种配方，该配方在大规模生产时以及患者在现实世界中使用药物时提供一致的性能。为了满足药物性能的高监管负担，必须满足许多质量（Q）要求。也就是说，每批产品必须包含正确的定性材料成分（Q1），以定义的定量比例（Q2），产生这些材料的特定三维排列（Q3，微观结构）。在过去的十五年里，在质量源于设计的理念下，大量的研发工作进入分子/过程建模和数字孪生，已经开始在加速配方设计方面获得回报。Q3微观结构已成为产品性能工程的关键知识缺口。制剂的微观结构决定了其制造行为和质量属性，如粉末流动和片剂压实，悬浮液和局部乳膏、凝胶和软膏的分散状态和粘度，以及吸入药物的流化和雾化。对微观结构进行分析以绘制和量化其对性能的影响的能力是一个尚未满足的挑战，特别是对于粉末基产品。尽管释放其潜力存在许多技术和计算障碍，但X射线成像已成为粉末分析的潜在解决方案。在本项目中，我们的目标是开发定量X射线成像技术来表征干粉吸入剂（DPI）产品的微观结构。DPI制剂对于X射线成像是具有挑战性的产品，这是由于活性药物成分（API）的高颗粒密度、小颗粒尺寸以及相对于赋形剂物质的低浓度的API。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产品和仿制药之间生物等效性的主要障碍。这为廉价仿制药的市场准入创造了障碍，并为医疗系统带来了经济优势。该项目的成果将是提供分析工具，以支持创新疗法的制造，特别关注微结构引导的产品工程。英国的几个研究中心已经成为转化开发和药物制造的世界领导者。微结构表征科学将为利用该研究中出现的数字产品建模工具开辟一条强有力的途径。我们研究的最终目标是利用配方微结构的早期识别，从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。