In order to underpin the competitiveness of the UK pharmaceutical industry, a step change improvement in manufacturing efficiency is needed. This project aims to deliver this for production of the largest proportion of dosage forms (tablets). The efficiency gains are targeted at improved manufacturing precision, improved productivity and improved mass yield, and will be deliverable at approximately 70% of the capital cost of conventional technology. In developing this capability, significant technical knowledge to be delivered which will enhance the offering of the equipment manufacturers who are part of our consortium. The project will use advanced manufacturing equipment, process measurement, control and information management to deliver the claimed benefits. Previous work has been fragmented; this project will deliver an integrated advanced manufacturing / product release data acquisition platform. It is proposed to set up and use test facilities to prove the feasibility of the required manufacturing platform, enabling the optimal design of a commercial plant capable of making saleable product. The key deliverables are (i) an optimised integration strategy, (ii) performance benchmarks, (iii) a de-risked design for a full scale integrated facility, and (iv) data to demonstrate design effectiveness to key stakeholders including regulatory agencies. The process uses continuous twin screw granulation, fluid bed drying, inline blending and tablet compression, whilst PAT instruments along with standard process parameters such as temperature, pressure and work input are used to monitor the stability and control the process Product release is focused around real time continuous process monitoring and control. It is based on an understanding of the process acquired during the experimental trials following DfM/QbD principles. A concept factory of the future will be designed for the layout and operation of continuous OSD pharmaceutical manufacture. Peripheral work to the above this project will also is deliver a POC continuous tablet coater that coats at a rate to compliment the continuous trial equipment and a continuous powder blender.

LyoDEA™ is a technology that allows in-line measurement of the freeze drying process using impedance analysis of a single vial. Put simply it measures electrical capacitance changes over a range of frequencies as the freeze drying process progresses through its’ key stages; freezing, annealing & sublimation (primary drying). The changes in ice structure during the freezing & annealing stages are critical to the final product quality so it is important that these can be monitored and controlled. LyoDEA facilitates the characterization of structural changes in-line as part of product development. As such it has the potential to shorten development time and produce a more efficient production process,thus saving energy. The LyoDEA™system measures a “pseudo-relaxation” process associated with the interfacial polarization of the glass wall of the freeze-drying vial through the resistance of the sample. The model represented by the equivalent circuit (below) describes the behaviour of a sample in a freeze drying vial in a course of freeze drying cycle, Where,C0is the capacitance formed by the electrodes and glass walls of a vial, C1 is the capacitance of the internal volume of a vial and R1 is the electrical resistance of a sample. The measured changes in electrical capacitance are very small. The initial challenge was to produce equipment sensitive enough to detect these changes beyond the normal fluctuations from the instrument, i.e. to increase the signal to noise ratio. The second challenge is to relate the changes in capacitance to the actual physical changes in the process. We are now seeing a correlation between the signal recorded & physical changes • Z-view fitting of the LyoDEA spectra provides valuable information relating to eutectic, glass transition and early primary drying. • Peak data effectively records and phase transition or temperature changes during freezing annealing. • T slice data from lactose and sucrose based formulations taken at specific frequency (1 kHz) satisfactorily described the end of primary drying in agreement with the thermocouple response. The project is now in its’ fourth year. There are three LyoDEA™ systems running so data is being constantly generated & analysed which is leading to a greater understanding of the data, what it is showing us and to improvement’s to the LyoDEA™ system. This project is the result of the collaboration of four partners each with their own specific expertise. Astra Zenecarepresents a technology end user;using LyoDEA™tofocuson the development of the freeze dried products &processes. De Montfort University have developed the initial dielectric theory & continue to produce and analyse data.AmetekAdvanced Measurement Technology is an OEM of signal processing hardware & GEA Pharma Systems are an OEM of freeze dryers and are the project lead partner. The project is still on-going. The output so far has largely been dissemination; presentations of the technology have been given at the AAPS in New Orleans, & the PDA in Vienna. We are in the process of establishing a facility at De Montfort University for demonstrating the technology to potential end users. A patent is pending for the LyoDEA™technology.

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