Intelligent Manufacturing of Pharmaceutical Film Coating Using Terahertz Pulsed Imaging, Optical Coherence Tomography and Numerical Modelling

Functional coatings are highly engineered drug delivery systems whose structure and composition is critical to the controlled release of the active pharmaceutical ingredient in the human body. This increase in manufacturing complexity coincides with a time when companies are looking to reduce costs while regulators exert pressure on the sector to ascertain a greater understanding of the products' critical quality attributes (CQAs) and associated process control. To date the development and manufacture of these high value products is challenging owning to the fact that pharmaceutical processing is complex and dominated by empirical knowledge with large gaps remaining in the full scientific understanding of the underlying processes. It is an essential need, and also a big business opportunity, to develop a step change technology-a "smart factory" capable of manufacturing these high-value products to user-defined specifications. This EPSRC call provides the consortium with the necessary funding to develop the basic components of a "smart factory" by the integration of process modeling and in-process diagnostic capability for real-time in-situ process control of advanced tablet manufacturing. By utilizing the unique diagnostic information obtained by a range of in-line sensors including our THz imaging and optical coherence tomography (OCT) sensors, we will develop theoretical models to identify key process parameters that will ultimately allow the development of an active feedback loop for advanced process control and optimisation. This EPSRC project will allow Cambridge and Liverpool University to use their combined expertise and proven technology, steered by a world leading supplier of manufacture equipment (Bosch, Liverpool, UK) and a global pharmaceutical company (Pfizer, Sandwich, UK) and supported by academia (Professor De Beer, Ghent University, Belgium), a technology SME (TeraView, Cambridge, UK) and with additional insight from the regulators (Dr Wu, FDA), to provide a highly advanced manufacturing capability currently not available to the industry.

We have identified several key industries where we believe this research could lead to considerable impact and partnered with leading companies in this industry: the pharmaceutical industry (Pfizer), and the THz industry (Teraview). The fields are key high value manufacturing industries where UK is a world leader with potential to provide considerable jobs and revenue. The majority of the research active pharmaceutical companies in the UK are already using THz imaging technology in dosage form development and process troubleshooting. The development of an in-house tablet coating drum coupled with a previously demonstrated in-line THz sensor setup will allow us to better understand the tablet coating process. This will significantly enhance the research capabilities in the pharmaceutical industry thereby allowing the UK to maintain its competitive advantage over emerging markets and to further grow these sectors through more innovative products such as advanced drug delivery systems and pharmaceutical dosage forms.
In addition to the academic and industrial beneficiaries this project will also be of great interest to the regulatory authorities such as the FDA and MHRA. The technology we are developing as part of this project is highly innovative and has not been assessed systematically by the regulators. However, regulators have started to show an interest in THz sensors for applications in process analytical technology and quality by design. Our project will provide the regulators with an independent and rigorous assessment of THz sensors for in-process coating measurements and has the potential to offer an industry standard method for this application.

The developments achieved in this project could have wider benefits to other industrial sectors including automotive (e.g., process control of car paints) where non-destructive and non-contact inline monitoring and control techniques are highly desirable. Other high value manufacturing industries include heterogeneous catalysis, where catalyst is sprayed onto ceramic support pellets using exactly the same process (and indeed equipment) as in the pharmaceutical industry to produce eggshell catalysts.

With THz and OCT this project brings together two rapidly rising fields in order to create a set of new process sensors that will have immediate impact in pharmaceutical manufacturing. While there are several process sensors that can measure the tablet coating thickness such as near-infrared frequencies and Raman spectroscopy all these technologies measure chemical constituents within the coating or tablet core and the coating thickness is inferred indirectly from pre-created complex multivariate calibration models. The models, however, are labour intensive in construction and the prediction performance is highly dependent on process conditions. Any slight variation degrades the quantitative prediction power significantly. Other tools such as laser-induced breakdown spectroscopy (LIBS) ablate and atomise the tablet coat for thickness measurement and are thus inherently unsuitable for in-process measurements. Our technique measures the tablet coating thickness directly and has sufficient time resolution to measure the thickness of individual tablets and thus is advantageous over the aforementioned modalities which all yield measurements that are averaged over time (10s of seconds) and are spatially averaged (sampling area in the coating pan of 10s of cm). Our approach is novel and to our knowledge there is no other group in the UK, or indeed internationally, working directly in this field of sensor development and process translation in the pharmaceutical industry. The project is ambitious and there are a number of significant challenges including the amount of data and signal processing required to perform in real time; the complexity of the numerical models as well as the sensor integration and stability.