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.

新药产品的开发需要设计一种配方，该配方在大规模制造时以及患者在现实世界中使用药物时提供一致的性能。为了满足医学性能的高监管负担，必须满足许多质量（Q）要求。即，每批产品必须以定义的定量比（Q2）包含正确的定性材料组成（Q1），该定量比（Q2）生成了这些材料的特定三维布置（Q3，微结构）。设计制造运营以满足这些质量要求。在过去的15年中，在质量设计的概念下，对分子/过程建模的大量研发工作和数字孪生已经开始在加速配方设计方面收获奖励。 Q3微观结构已成为产品性能工程的关键知识差距。公式的微观结构决定了制造行为和质量属性，例如粉末流量和片剂压实，悬浮液和局部乳霜的分散状态和粘度，凝胶和药膏，以及吸入药物的液化和雾化。表征微观结构以绘制和量化其对性能的影响的能力是一个未满足的挑战，尤其是对于粉末的产品而言。尽管存在许多技术和计算屏障来释放其潜力。在该项目中，我们旨在开发定量的X射线成像技术来表征干粉吸入（DPI）产品的微观结构。由于高颗粒密度，活性药物成分（API）的小粒径和低浓度的API相对于赋形物质，DPI制剂是X射线成像的具有挑战性的产品。然而，研究DPI是一个值得研究的挑战，因为对评估微观结构的技术的需求已被确定为欧洲（EMA，MHRA）和美利坚合众国（US FDA）的监管机构（EMA，MHRA）之间建立创新者和通用产品之间的生物等效性的主要障碍。这为更便宜的通用产品的市场进入造成了障碍，并且这可能会带来医疗保健系统的经济优势。该项目的结果将是分析工具的可用性，以支持生产创新的治疗剂，并专门针对微观结构指导的产品工程。英国的几个研究中心已经成为转化开发和药品制造业领域的世界领导者。微观结构表征的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大的途径。我们研究的最终目的是从开发开始，从其开发开始，从而将制定微观结构的早期鉴定为早期产品，并加速临床供应的规模。