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

新药品的开发需要设计一种配方，在大规模生产和患者在实际情况下使用该药物时提供一致的性能。为了满足药品性能的高监管负担，必须满足许多质量(Q)要求。即每批产品必须包含正确的定性材料成分（Q1），在定义的定量比例（Q2）中，产生这些材料的特定三维排列（Q3，微观结构）。生产操作的设计是为了使产品满足这些质量要求。在过去的15年里，在设计质量的理念下，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。Q3微结构已成为产品性能工程的关键知识缺口。配方微观结构决定了生产行为和质量属性的多样性，如粉末流动和片剂压实，悬浮液和局部乳霜，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。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尚未遇到的挑战，特别是对于粉末基产品。x射线成像已经成为粉末分析的潜在解决方案，尽管在释放其潜力方面存在许多技术和计算障碍。在这个项目中，我们的目标是开发定量x射线成像技术来表征干粉吸入（DPI）产品的微观结构。DPI制剂是具有挑战性的x射线成像产品，由于高颗粒密度，活性药物成分（API）的小颗粒尺寸和相对于赋形物质的低浓度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（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产品之间生物等效性的主要障碍。这为更便宜的非专利产品进入市场制造了障碍，并为卫生保健系统带来了经济优势。该项目的结果将是分析工具的可用性，以支持创新治疗药物的制造，特别关注微结构引导的产品工程。英国的几家研究中心已成为转化开发和药品制造领域的世界领先者。微观结构表征科学将开辟一条强有力的途径，利用从该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观结构的早期识别，从开发开始就设计早期产品的可制造性，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.