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

Lead Research Organisation: University of Cambridge
Department Name: Chemical Engineering and Biotechnology

Abstract

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.

Planned Impact

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.

Publications

10 25 50

 
Description We have developed a lab scale film coating unit that mimics pharmaceutical coating operations as performed in industrial processing but coupled to a set of novel sensing technologies, namely terahertz pulsed imaging (TPI) and optical coherence tomography (OCT). These sensing techniques allow for the first time to measure the thickness, quality and distribution of the film coating while the coating process takes place. In parallel we have developed a numerical model of the same process using discrete element modelling (DEM) which provides us with a mechanical model of the same process at the same scale based on computational analysis. Using this setup we are now able to systematically investigate the impact of modifying the film coating process parameters on the achieved coating quality.
Exploitation Route We have been contacted by a number of pharmaceutical companies who are interested in our technology and our new process understanding. This is an ongoing process and we are still in active dialogue with potential end users as well as equipment manufacturers who are interested in adapting our approach.
Sectors Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description We have had a industry engagement forum in Cambridge where we met with representatives of Pfizer, GSK, Bosch and Colorcon Update 03/2017: We have had a further one of these engagement activities with Pfizer, GSK, Bosch and Colorcon in the summer of 2016. We have received a small amount of funding by the Research Centre for Pharmaceutical Engineering (Graz, Austria) to develop a related application for the pharmaceutical industry based on some of the technology developed in this project. Update 03/2018: We have used the fast measurement technology developed in this grant to measure porosity in pharmaceutical tablets. On the back of this development we have secured Innovate UK funding to develop a fast porosity measurement sensor for the pharmaceutical industry to help with real time release testing and continuous manufacturing.
First Year Of Impact 2016
Sector Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Economic

 
Description Medicines manufacturing round 1: challenge fund
Amount £733,744 (GBP)
Funding ID 5804 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 02/2018 
End 02/2020
 
Description Project funding by industrial partner
Amount £0 (GBP)
Organisation Research Center Pharmaceutical Engineering (RCPE) GmbH 
Sector Private
Country Austria
Start 03/2017 
End 06/2017
 
Title Research data supporting "Analysis of 3D Prints by X-Ray Computed Microtomography and Terahertz Pulsed Imaging" 
Description - X-ray computed microtomography data of 12 different 3D printed samples consisting of two different geometries (one and two compartments) - The geometries used for the 3D printing. - Terahertz pulsed imaging data of two different samples. - Dissolution d 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
 
Title Research data supporting "Asymptotic limits on tablet coating variability based on cap-to-band thickness distributions: a discrete element model (DEM) study" 
Description In this compressed .zip file, the open data is provide to reproduce the data on the paper: Asymptotic limits on tablet coating variability based on cap-to-band thickness distributions: a discrete element model (DEM) study. The data can be divided into 3 categories: DEM input files are used to generate the dynamics of tablets in drum mixing; Ray-tracing and image analysis codes and input files use the position and orientation of tablets to model the spray coating process; .m files are Matlab scripts for data analysis. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Research data supporting "Mathematical modelling of liquid transport in swelling pharmaceutical immediate release tablets" 
Description The dataset includes data from terahertz reflection measurements. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Research data supporting "Measurement of the Inter-Tablet Coating Uniformity of a Pharmaceutical Pan Coating Process With Combined Terahertz and Optical Coherence Tomography In-Line Sensing" 
Description The data was used to produce the figures in the linked publication and it consists of the data for the individual figures as well as the raw data of the terahertz (in-line and off-line data), optical coherence tomography (in-line and off-line) and X-ray computed microtomography data. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Research data supporting "Pharmaceutical film coating catalogue for spectral-domain optical coherence tomography" 
Description The data set contains the optical coherence tomography images presented in the publication. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Description Academic conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The research talk initiated discussion on the technique presented from the industry and general academic audience.

Nil
Year(s) Of Engagement Activity 2015
URL http://www.irmmw-thz2015.org/
 
Description Academic conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The research talk initiated discussion on the technique presented from the industry and general academic audience.
Year(s) Of Engagement Activity 2016
URL http://www.irmmw-thz2016.org/
 
Description Industry talk at Bosch 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The talk underpins collaborative opportunities with Bosch Packaging Technology and the possibility of equipment loan, use of in-house facilities etc. The talk also facilitated research collaborations with BASF.

Immediately after the talk, there were dialogues exchanged in regarding to the technicalities of the coating unit. This was further strengthened by a visit to our lab. Furthermore, Bosch also attended an industrial meeting that we hosted several months after.
Example coating specimens were provided to us by BASF.
Year(s) Of Engagement Activity 2014
 
Description Industry talk at Bosch 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The talk initiated discussion about the technology and the possibility of applications in other areas of research.

A confidentiality agreement between the institutions were formed and agreed upon. A telephone conference was subsequently held to discuss immediate steps forward and project direction.
Year(s) Of Engagement Activity 2015
 
Description Industry talk at Bosch 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The talk initiated discussion about the technology and the possibility of applications in other areas of research.
Year(s) Of Engagement Activity 2016