Formulating microstructural equivalence: A route to consistent scale-up of medicine manufacture
Lead Research Organisation:
University of Hertfordshire
Department Name: School of Life and Medical Sciences
Abstract
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.
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.
