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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SMART-GRAN (Development and Commercialisation of a Self-Guided Fluidised Bed Granulation Solution)

Teaser

Summary

Compared to other industries, the production performance of pharmaceutical plants is relatively low according to Duennibier, Riehle and Tups. The introduction of analytical technologies and sensors has been considered over the past fifteen years to bring greater understanding and control to pharmaceutical processes. The introduction of such technologies was termed Process Analytical Technology by the Food and Drug Administration (FDA) in 2004. PAT is a system for designing, analysing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. Central to PAT is improving final product quality through knowledge of the fundamental scientific principles behind it, and continuous online control of a process. The hypothesis behind PAT is that the quality of the products can and should be incorporated by process design and not by postproduction quality testing.
In pharmaceutical processes particles and granules play a key role in process efficacy and final product quality. The pharmaceutical manufacturing platform of fluid bed granulation is widely used, whereby powders are fluidized and a binder solution or suspension is sprayed onto the fluidized particles, creating liquid bridges which form agglomerates from the powder. However, the adoption of PAT to monitor and control this process is difficult, due to its dynamic nature. These physical and chemical variables can have a significant effect on final product behaviour such as blend homogeneity, drug absorption rates, product robustness, etc and thus overall product quality. Addressing these problems delivers a drug product that meets quality, safety and efficacy requirements and therefore improves patient safety. A right first time approach to manufacturing will ensure the production of high quality medications and also reduce the cost of medicines for the worlds seven billion people.

Overall Objectives
The overall objective was to develop and commercialise the worldâ€™s first Self-Guided Fluidised Bed Granulation Solution. The SMART-GRAN solution incorporates a suite of PAT analysers for the in-process monitoring and closed loop control of the Critical Process Parameters coupled with soft-sensoring, for obtaining consistent product quality and safety. The ability of the system to confirm cleaning process success between batches will reduce equipment downtime, increase product throughput and lead to increased productivity. Through a cloud-based data management platform, the SMART-GRAN solution enables historical data to be available for interrogation. This enables intelligence-based manufacturing (IbM) concepts which focus on harnessing the complementary power of data, modelling, engineering and IT infrastructure by transforming data into knowledge and ultimately intelligence, to equip industry to move to proactive manufacturing strategies that deliver predictable manufacturing performance.

Work performed

With respect to the generation of the systems specifications, in order to accurately identify the need and specifications for the SmartGran technology a bottom-up approach was mobilised by consulting with industry stakeholders and carrying out research to obtain a clear understanding of the technological needs of the pharmaceutical manufacturing industry and also the specifications expected for these technologies. These consultations served to understand and detail the current needs and limitations of the process control technologies currently in use with FBG processes.
In conjunction with the industry consultations, IPL personnel participated in a number of presentations and discussions on technological solutions and regulatory expectations for process monitoring/control with industry leaders and FBG equipment manufacturers.

The focus of this collaboration was to ensure that the tasks in WP2, WP3 and WP4 could be executed effectively and also provided guidance for the verification and validation of a fully integrated process monitoring, control and reporting solution for fluid bed granulation as well as understanding the current best practices for the fabrication and control of fluid bed granulation processes. The outcome of WP2 was system hardware that met industry and regulatory requirements and could be readily integrated onto the vision ports of fluid bed granulators.
Through WP 3 We have Smart enabled a fluid bed granulator by developing an informatics structure that allows intercommunication between the granulator, its onboard process sensors, analytical instruments such as Eyecon and Multieye and the Cloud. The informatics infrastructure facilitates the aggregation and processing of the machine derived data for process insights monitoring and autonomous control decisions. The cloud infrastructure developed enables data to be available for monitoring and review/analysis when and where required.
The capability of the SmartGran technology was challenged and confirmed through industrial trials carried out as part of WP 6 on a number different fluid bed granulators.
A review of the regulatory and standard landscape was carried out. Its influence on the proposed system development and its features, such as GAMP requirements for automated process and software structure, labelling, and revision control, the FDA 21 CFR part 11 compliance challenges for electronic data generation and protection and current regulatory guidelines for analytical technology validation, were all evaluated.
The regulatory bodies are very supportive and encouraging of the introduction of in-process monitoring and process control technologies. This support was reinforced when, after a presentation at the IFPAC conference in Washington in Feb 2017 given by Innopharma personnel we were invited to a meeting at the FDA headquarters in Washington to present to the FDA reviewer. This gave Innopharma the opportunity to present to a group of 80 on advanced manufacturing for fluid bed granulation. The FDA are very supportive of any initiative that will improve product quality and ultimately patient safety.

Final results

The SMART-GRAN project realized a new concept on self-guided fluidized bed granulation that will in the medium to long term benefit the pharmaceutical industry. Particle physics governs process variables such as flow, blending, granulation, compression and coating which can have a significant effect on final product behaviour such as blend homogeneity, drug absorption rates, product robustness, etc. Similarly, the chemistry variation (moisture) within the products has a critical effect on product quality. Through the SmartGran project Innopharma have developed a technology capable of monitoring physical and chemical parameters of the fluidized bed granulation process in real time and used this information along with the process parameters of spray rate and inlet air temperature to control the fluid bed granulation process.

As FBG technology is an important manufacturing platform in numerous industries beyond the pharmaceutical sector, such as food and nutritionals, improved monitoring and control of the physical and chemical characteristics of particles during food granulation processing will benefit the competitiveness of the European food industry, which is the cornerstone of the European economy and the lifeblood of our rural regions will also be significant