Final Report Summary - PARTICLE-PRO (Development of a hybrid process analytical technology to characterise the physical and chemical properties of particles)
Executive Summary:
The ParticlePro project was devised and coordinated to develop a hybrid technology for the analysis in-line of both the physical and chemical properties of granulate in typical pharmaceutical applications and process platforms. The structure and size distribution of granulate and indeed spheres or beads is critical to the functionality of the finished solid dose product. Particle structure, API distribution, moisture content and particle or sphere size can all influence the therapeutic effect of pharmaceutical products. No single physical or chemical property will be wholly responsible for the lack of efficacy of a solid dosage form. It will be a combination of factors influenced by both the physical and chemical makeup of the formulation. To this end securing the knowledge to understand the process and the formulation is key to ensuring consistency and reproducibility in manufacture and continuity of supply. To address this much required need the ParticlePro consortium have strived to develop a hybrid device constructed through the integration of two background IP systems, the Eyecon particle characteriser and the MultiEye NIR spectrometer. the combination of these two systems provides the opportunity to secure both physical and chemical attributes from the same in-line sample in real time so that informed decisions can be made as to the actions to be taken during the processing steps.
the research and development activity was carried out be a combination of 3 RTDs, VTT in Oulu, Finland providing the background IP knowledge for both the physical and chemical characterise design and construction. DIT in Dublin Ireland, providing the resources to complete proof of concept studies in both a laboratory and an industrial capacity and IRIS in Barcelona, Spain to complete the final pre-competitive prototype design, build and integration.
The consortium consulted with both project and industry end users to ensure appropriate system specification and application identification. The consortium successfully designed built and tested the application of the technology in both laboratory and industrial applications and on a range of platforms including, spheronisation, fluid bed coating and granulation, continuous roller compaction and twin screw wet granulation platforms. The system proved technically capable of monitoring and tracking process changes in real-time on both the industrial and laboratory scale processes.
The Consortium cooperation was excellent through out the course of the project and the level of communication and interaction was significant in the final successful outcome of the project.
Exploitation and dissemination activities have been clearly defined and even at this early stage in the process of moving to a commercially viable system by mid 2015 there is already a significant level of interest from both pharmaceutical and non pharmaceutical entities in the results and the technical solution. These range from food and fertiliser applications within Europe, a major fine chemical application in the USA, to pharmaceutical applications within the European and Indian markets.
Project objectives were achieved on schedule and within the budget allocations of the project.
Project Context and Objectives:
The technological problem or need
In the face of the gravest economic times in living memory, Europe needs to position itself as an attractive manufacturing location; this is fundamental for job creation and growth. However, in order to help our SME sector to survive and grow, and indeed to anchor down multinationals and prevent them from migrating to cheaper manufacturing bases, Europe needs to brand itself as a region of innovation and outstanding product quality. The category of cheap manufacturing location belongs firmly to other regions in the world. Europe must stake a claim as the “region of innovation”. Undoubtedly, innovation could play a major role in retaining and strengthening Europe’s pharmaceutical industry.
70% of pharmaceutical drugs are consumed as powders in the form of tablets or capsules. 50 billion aspirin tablets alone are consumed worldwide each year. As tablets are the most common drug dosage form today, granulation, which allows primary powder particles to adhere and form granules, is one of the most important unit operations in drug manufacturing . Batch rejects that result from process problems can be higher than 20%, the root cause being a lack of process understanding and control. Batch rejects can be a major issue as some APIs can be worth as much as €1million / kg.
As products become increasingly complex, understanding pharmaceutical processing is growing more difficult. Regulatory bodies are encouraging the drug lifecycle concept which links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. The FDA guidance document, Process Validation: General Principles and Practices , promotes modern manufacturing principles, process improvement, innovation, and sound science.
Key to better understanding is knowledge, and access to real-time on-line measurements is fundamental. Indeed, the concept of “Process Analytical Technology” (PAT) is the new framework for better understanding in pharmaceutical processes of which granulation is a very big part. Central to PAT is improving final product quality by process design through knowledge of the fundamental scientific principles behind it, and continuous online control of a process.
Particles and granules play a key role in process efficacy and final product quality of pharmaceuticals. Particle physics governs process variables such as powder flow, blending, granulation, compression and coating. The identified key physical parameters include granule size/shape and the key chemical parameters include moisture content and ingredient identity (active versus excipient concentration). The size/shape and moisture variables can have a significant effect on final product behaviour including content uniformity, drug absorption rates and product robustness. Similarly, the ingredient distribution within granules and between granules has a critical effect on product acceptance and patience safety.
In the pharmaceutical industry, while granulation is frequently employed to obtain a particular blend quality as well as improving the flow and compression properties of the powder mixture, a more recent field of application is the use of such dry granules as independent forms of a drug, which release the active substances as uniformly as possible throughout a prolonged period (8-12 hours). These so-called retardant drug forms benefit the patient by having longer administration intervals and accordingly a reduced administration frequency when compared with conventional drug forms. As there is a mathematical relationship between the rate of active substance release and the surface/volume ratio of the granules, reliable data about the granulation process is of paramount importance.
A significant portion of pipeline products are intended for manufacture using granulation, roller compaction and milling manufacturing platforms. There is also a trend towards continuous manufacture of pharmaceutical products. In short, the development of a technology capable of monitoring physical and chemical parameters of a process in-line would significantly increase process understanding and control thereby assuring product quality, patient safety, and lean operational costs.
The current method of determining the end-point of pharmaceutical processes such as granulation is typically a combination of (1) off-line analysis of size and shape characteristics, (2) off-line analysis of moisture content and (3) end product analysis of active content uniformity. The size and shape characteristics are important as they can significantly impact on the compression process. The moisture content is important as it can impact on compression and product stability (negatively leading to hydration of the active ingredient). The active content uniformity is important to ensure that each patient receives the correct active dosage.
The development of one hybrid technology that is capable of assessing these four characteristics (granule size, shape, moisture content and ingredient distribution) in real time would significantly advance pharmaceutical manufacturing control leading to greater product quality and patient safety. In fact this would represent a global breakthrough with a technology, which could provide the physical and chemical nature of granules as they form within the process environment. The ability to identify the chemical signature of particles spatially will allow profiling of ingredient distribution and ultimately content uniformity. The output of this project will be an advance control strategy for end point determination of the highly variable process of pharmaceutical granulation. Such innovative technologies are in line with the recently published FDA guideline on process validation where the use of process controlling technologies to support the continued verification of manufacturing process is recommended. Miniaturization of novel spectrograph approaches, new calibration strategies and the rapid development of computational processing speeds have facilitated the feasibility of such advanced technologies.
One important reason why many companies shy away from developing NIR-based sensors is the need for multivariate calibration. The absorbance bands of NIR spectra are small and typically heavily overlapped. Quantitative analysis therefore requires multivariate data analysis, i.e. involves absorbance values at multiple wavelengths. The so-called science-based method (SBC) has recently provided a solution to the calibration problem. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. In SBC, with response defined a-priori by spectroscopic expertise and application knowledge, spectroscopy is no longer a “secondary” method that needs calibration against a “primary” reference method. Instead, it becomes a “primary” method, firmly rooted in physics and chemistry. Significant practical benefits become available from this change whenever a responsible application scientist is able to define the shape of the response spectrum “manually”. One great advantage is that specificity of response can be proven to regulatory agencies and concerned end-users, which in today’s increasingly regulated and controlled environment this is a major competitive benefit for reassuring consumers and the market and heightening confidence. The calibration process itself becomes fully transparent and “communicate-able,” or in the words of the pharmaceutical industry, science-based. This fact in itself creates a multitude of opportunities for adapting calibrations to given measurement situations, always keeping the result under user control.
To this end, the proposed PARTICLE-PRO project aims to develop a technology that is a hybrid of established imaging platforms. Physical characterization of size and shape will be determined with the EYECON technology (that provides 3D images of particles) owned by INNOPHARMA. To this technology, NIR chemical measurement technologies, based upon novel miniaturized spectrograph advances, will be integrated, to provide chemical and moisture information of the sample. This combined approach will be carried out in real-time to provide on-line granule characterization.
The overall objective of this project will centre on the development of a hybrid device based on collimated 3D imaging of particles’ physical parameters (EYECON technology) and novel miniaturized NIR multipoint or quasi chemical imaging technologies that provide spatial measurements of moisture and ingredient identity from the forming granule. The R&D effort will centre on engineering design, software/algorithm design, user interface design; and integration and validation within pharmaceutical manufacturing equipment.
In this project a device, which can measure physical and chemical properties of pharmaceutical granules, will be designed, realized and tested. Technology challenges relate to building a cost efficient, robust, user friendly device which produces multi point or quasi imaging of chemical information (such as moisture distribution, or ingredient concentration) coupled with 3D physical information (particle size and shape) by one single instrument. Spectral information will be generated with a multichannel detector using Fibre-optic coupled multi-point Fabry-Perot technology. With this technology quasi-images or measure in several spatial points by fibre-optics can be obtained. This technology is available to the consortium and has successfully been developed into other devices such as unmanned remote sensing aircraft. Patented calibration methods specially designed for in-line analysers will also be employed. Physical information will be produced with camera and LED illumination based device (EYECON). Novel 3D algorithms are utilized in calculation of physical information. The technology platform will be selected in tune with industry requirements, as this is a marker-driven approach.
In order to realise this, the scientific and technological objectives, and corresponding Performance Indicators, that will be fulfilled during the PARTICLE-PRO project are provided below. Every effort has been made to ensure that these objectives are S.M.A.R.T. (Specific, Measurable, Achievable, Realistic and Timely) and clearly linked to the WPs and linked to deliverables and milestones in Part A:
1. To implement a ‘bottom-up’ approach whereby the needs and specifications of companies from the pharmaceutical industry will be consulted, as will regulatory aspects, the findings from which will be used to guide the definition of the specifications for the PARTICLE-PRO system. (WP1). Performance Indicator: By M3 a public report on the findings of the bottom-up research will be delivered (Deliverable 1.1) and by M4 a confidential report outlining the industrial specifications for the PARTICLE-PRO system (Deliverable 1.2) will be available for project use in order to guide the evolution of the R&D work to ensure that the PARTICLE-PRO system meets with market needs. At this stage Milestone 1 will have been achieved.
2. To build a laboratory scale test rig to integrating physical imaging and multipoint NIR chemical measurement technology for the physical and chemical characterization of particles (WP2). Performance Indicator: By M6, a PARTICLE-PRO test rig will be designed, built and integrated. The device enables to gather physical and chemical information to be obtained with one single setup. Based on the user requirements and performance criteria a number of approaches to wavelength selection will be evaluated for the multipoint quasi-imaging technology (Fig. 1). Finally, by M11, the scale-up parameters for developing a precompetitive PARTICLE-PRO prototype for industrial-scale granulation monitoring purposes will have been defined (Deliverable 2.4). Milestones 2 and 4 will have been achieved.
- Setting up of phys/NIR chemical imaging test rig: VTT will design and build the laboratory test rig. This test rig will be used for laboratory trials in which the physical and chemical information will be measured with a single unit. The rig will allow the best parameters for the combination of the technologies into the PARTICLE-PRO system to be defined and will therefore contain some of the main parts as the final system. Also the design phase will involve a series of subtasks: software design, design of light sources, control electronics, optics and mechanics and selection of camera. To maximise the usability of the system in the trials, the wavelength scale and spatial resolution will be made as flexible as possible.
- Innovative patented science based calibration methods (SBC) will be used in development and testing of NIR chemical test rig and prototype. These calibration methods have specially been developed for in-line instruments, where large sets of calibration samples needed for PLS or other calibration methods are required are hard to get. In SBC the need for lab-reference values is virtually eliminated from calibration because the calibration no longer needs to “learn” what the signal is. There is also no need to artificially upset an industrial process in order to collect in-line calibration standards that vary over a certain “range.” Rather, a smoothly running process with a minimum of analytic variation is sufficient for SBC. The science based calibration is also highly selective since it is based on knowing the response spectra of measured compounds and specificity of response can be proven to regulatory agencies and concerned end-users.
3. To evaluate the effectiveness of the combination of physical imaging and NIR chemical measurements for the characterization of the physical and chemical properties of particles against reference methods and to define the limits of detection of the approach (WP3). Performance Indicators: By M3, a protocol for the analysis of varying granulate structures with various excipient granulates, active granulates and the blended granulates will be defined (Deliverable 3.1) and by M11 a report on the efficacy of using a bench-top test-rig to monitor granulate structure (particle size distribution, sphericity) and chemistry (moisture content) will be delivered (Deliverable 3.2). The limits of detection for the approach will be defined via correlations with reference sieve analysis and NIR based methods. Micro imaging will be employed to visually detail the physical structure of the granule (Deliverable 3.3) Milestones 3 and 5 will have been reached. The prototype will be evaluated in laboratory scale granulators.
- Chemical measurements of granule ingredients / moisture content on typical granulation processes will be made. The sensitivity, SNR, selectivity and other key parameters will be tested.
- Laboratory calibration models will be optimised based on test trials. The performance of the test rig will identify parameters used to design the pre-competitive prototype.
4. To draw up the designs of the precompetitive particle characterization hybrid physical imaging and NIR- chemical measurement system in keeping with the industry specifications defined in WP1, as well as the laboratory parameters defined in WP2 and WP3 and to assemble the system hardware (WP4). Performance Indicator: By M14, the designs of the PARTICLE-PRO system will be complete (Deliverable 4.1). Milestone 7 will be complete.
During this design stage, focus will centre on ensuring that the PARTICLE-PRO system is capable of offering the following features:
- The high spectral sensitivity is obtained either using fixed wavelength band pass filters or by scanning with a tuneable Fabry-Perot filter. Method robustness and Reliability- The system will be based upon knowledge of bench top systems developed by each of the research groups involved which should provide a strong starting point for the envisaged prototype.
- Adheres to industry standards, and meets with regulations and approvals- The system is based upon imaging and light and therefore will be nonintrusive in nature.
- Consideration of integration challenges: installing the technology inside the granulator window and outside the granulator window.
- Versatility- the proposed system is partly based upon IR spectroscopy, a universal tool for chemical identification. The system will be trained against a library of IR spectra for excipients and actives alike. Consequently the system will be versatile for identification of all pharmaceutical ingredients.
- Rapid- detection time depends on spatial and spectral resolution required, escalating with increasing resolution. Improvements in recent years in precision and speed in measurement have arisen as a result of increased computer processing speeds, improved cameras, faster hardware, more accurate and efficient algorithms. Innopharmalabs will employ various data processing strategies to facilitate real time processing.
- Easy to use and interpret- The envisaged system will be calibrated for the selected excipients and actives employed during manufacture. It will map the granulate in terms of identified ingredients and provide a quantification of each ingredient. The approach will not require the current level of training required by validation personnel. Moisture content will be reported as a percentage.
- Cost effective- It is envisaged that the market price of a unit will be in the region of €100,000, which will make the technology highly competitive in the marketplace (Malvern particle characteriser 150K, Sisu-Chem NIR Chemical Imager 150K). Advances in the production of low cost array detectors have meant faster data collection and cheaper Chemical measurement systems . Moreover, predictions that the market for NIR chemical instrumentation will increase in the coming years , especially in the pharmaceutical industry due to the Food and Drug Administration’s Process Analytical Technology initiative are expected to drive down the price of imaging spectrometers, opening their way into routine pharmaceutical analysis. Moreover, the development of an average cost imager by combining microelectro-mechanical systems (electrically programmable diffraction gratings) with spectrometers would obviate the need for costly array detectors3.
5. To develop the general software for the operation of the PARTICLE-PRO system, including the synchronized control of the different subsystems, the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP3, in order to characterize the physical and chemical properties of the particles under analysis and readily display the results via an ergonomic User Interface (WP5). Performance Indicator: By M15 PARTICLE-PRO Control Software (Deliverable 5.1) will be ready and the PARTICLE-PRO User Interface and database (Deliverable 5.2) will be delivered. Milestone 8 will be complete.
6. To integrate the system hardware, software and User Interface in order to provide a pre-competitive prototype that can be validated in industry and to carry out pre-validation tests with the system to ensure its proper functioning before shipping to industry test-sites. (WP5). Performance Indicator: By M16 the prototype will be fully integrated (Deliverable 5.3) and Milestone 9 will have been achieved.
7. To test and evaluate the PARTICLE-PRO system in commercial pharmaceutical manufacturing sites in order to assess the efficacy of the developed system to effectively characterize the physical and chemical properties of particles during processing in a production environment. Design issues arising from the industrial tests will be fed back into WP4 (WP6). Performance Indicator: Between M18-M24, the prototype will be tested and validated at SIGMOID or TAKEDA in Ireland and SERVIPLAST in Spain. By M17, a comprehensive installation and user manual will be edited (Deliverable 4.1) and by M24 a report on the industrial trials will be delivered (Deliverable 4.2). This will contribute to the fulfilment of Milestones 10.
8. To carry out optimisation work on the prototype based on feedback from the field trails, and to carefully outline scaling-up rules and development work for full production (WP5). Performance Indicator: By M24, a report on the optimisation work carried out on the basis of the results of the industrial trials will be delivered; including recommendations for future scale-up (Deliverable 5.4) will be delivered to the participating SMEs. Milestone 12 of the project will have been fully accomplished.
9. To facilitate the uptake of the PARTICLE-PRO results by the participating SMEs as well as a wider audience by carrying out a comprehensive series of knowledge transfer and training activities to on the one hand show the validity for the system for reliable, in-line particle characterisation in commercial pharmaceutical production facilities, and on the other hand to capacitate end-users about its usability and to outline its benefits for facilitating quality control of the granulation process, reducing plant down-time, reducing costs and trained operator intervention, as well as increasing the reliability and safety of the final product, etc. (WP7). Performance Indicator: Between M18-M24 it is envisaged that at least 3 knowledge transfer and training sessions will be organised at the facilities where the prototypes are being installed and validated in WP6. A report on these knowledge transfer and training activities and materials used, including evaluations and conclusions will be drawn up (Deliverable 7.2) and Milestone 11 will have been met.
Project Results:
Research and technological development activities will form the core of this project, and will for the most part be carried out by the 3 RTD performers, VTT, DTI and IRIS. The RTD Performers will be guided and supported by the participating SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA) to ensure that the research performed complies with their expectations. To this end, the participating SMEs will provide inputs and contributions to the research activities when possible and in keeping with their ability and expertise. The following Work Packages fall within the scope of research and technological development activities:
Industrial Specifications (WP1) –
Objectives
• To ensure a clear understanding of the technological needs of European pharmaceutical manufacturers in terms of granulation control.
• To review the existing state-of-the-art and patents, to ensure that the R&D work is up to date on its starting point (in view of the time lapse between project preparation and project implementation)
• To a review and analysis of regulatory guidelines
• To use the results of the research to drive the definition of the industrial specifications for the PARTICLE-PRO technology
This WP was led by INNOPHARMA, and they will be heavily supported by the SME participant, SIGMOID, as well as assisted by IRIS, VTT and DIT. All the SMEs and OTHER participants (SERVIPLAST, RIKOLA, and TAKEDA) will collaborate actively in order to ensure that they communicate their industrial needs in order to drive the future R&D effort.
Task 1.1: In-depth industry consultations
Subtask 1.1.1- Questionnaire based European-wide survey
A comprehensive questionnaire will be prepared by INNOPHAMA with assistance from IRIS, and it will be validated among the consortium. It will then be set up on an on-line surveying tool (SURVEY-MONKEY) and electronically distributed to a wide number of European pharmaceutical manufacturers, etc. including Pfizer, Genzyme, Alkermes and GSK. The following information, among others, will be gathered by the questionnaires, analysed and conclusions will be drawn on the results:
• Existing granulation controlling methods;
• Limitations and short-fallings of these methods and technologies;
• Existing knowledge and capability levels of operators;
• Granule physical and chemical properties during and after granulation
• Price sensitivity;
• Any existing and upcoming norms, standards and legislation pertaining to Process control and the quality of the final product;
• Quality aspirations/perceptions of consumers in terms of quality and safety.
A minimum threshold of completed questionnaires will be gathered and the data will then be evaluated. The results and conclusions will be included in a dedicated section of the Report on PARTICLE-PRO Market Requirements (Deliverable 1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications). INNOPHARMA will lead this work together with IRIS, and all other partners will participate, especially the other participating SMEs and OTHER (SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA), each bringing their respective industrial and market expertise and knowledge, as well as mobilising their clients and networks to collaborate.
Subtask 1.1.2- On-site visits and in-depth consultations
A series of consultation sessions or in-depth interviews will be conducted with a selected group of pharmaceutical manufacturers, including Pfizer, Genzyme, Alkermes and GSK. This will also involve carrying out a series of on-site visits to manufacturing sites so that the RTD performers can become familiar with the industrial setting as early on in the project as possible, view the granulation equipment, and discuss existing controlling techniques with site technicians. At least 6 on-site visits will be made. In order to ensure that all partners benefit in as much as possible from potential visits, during the KO meeting that will be held in Ireland, a visit will be made to the facilities of SIGMOID or TAKEDA. The results and conclusions arising from these on-site visits and interviews will also be included in Deliverable 1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications. IRIS will lead this subtask, and VTT and DIT will also carry out in-depth consultations and on-site visits. To enable additional field research to be carried out, as well as to gain an insight into the latest technological developments and have the opportunity to interact with large numbers of pharmaceutical manufacturers, equipment manufacturers and other stakeholders, the partners will attend an international exhibition or trade fair, such as EXPOPHARM- International Pharmaceuticals Fair (Germany), POWTECH (Germany every 18 months), FOODPHARMATECH- Denmark (every 2 years), SIPEC Pharmaceutical Trade Show (France), etc., which they will aim to coincide with the M3 meeting if this is possible.
Subtask 1.1.3- Review and analysis of regulatory guidelines
During this task a review of all European and national regulatory guidelines will be carried out in order to ensure that the PARTICLE-PRO system adheres to them. To this end the results of this task will feed into task 1.3 below. INNOPHARMA will lead this subtask with the assistance of SIGMOID and IRIS, as well as the other SMEs.
Task 1.2: In-depth review of the Literature
A thorough review of the literature and patents (especially in the field of granulation) will be carried out in order to ensure that all relevant research in the area is identified. This task will serve to complement and update the State-of-the-Art section of this project, Section B.1.2. This is an important task in view of the timeline that will have passed between the review carried out during project preparation and project implementation. In addition, the results of this task will feed into Task 8.1 Knowledge Management and IPR protection (and in particular Subtask 8.1.1-Defining the Foreground IPR) whereby the novelty of the proposed approach will need to be validated. This task will be led by DIT, who will be assisted by IRIS and VTT. DIT will prepare a report on the review of the literature to be included in D1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications, forming at the same time the basis for the continuous technology watch during the project.
Task 1.3: Definition of the PARTICLE-PRO specifications
Partners will use the results of previous tasks in order to define the overall desired specifications and performance characteristics of the PARTICLE-PRO technology, in keeping with industrial needs, constraints, considerations, etc. A definition of the overall PARTICLE-PRO architecture will be defined and will be used as a blueprint for guiding the technical work to be carried out during the remainder of the project. The results of this task will be documented D1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications. IRIS will lead this task and will be assisted heavily by VTT and DIT. They will consult extensively with the SMEs and OTHER participants (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA).
In the execution of the activities to accurate specify and determine the requirements for the ParticlePro system several approaches were taken. A series of face to face industry consultations conducted through Innopharmalabs network of pharmaceutical contacts. In addition an industry wide questionnaire completed by some of the leading Global pharmaceutical companies.
There was also an in-depth literature review completed as well as an assessment of the current market leading technologies for both chemical and physical analysis.
The combined output was the ability to clearly document the industry requirements for the hybrid ParticlePro technology.
Laboratory bench top building and trials (WP2) –
Objectives
• To design and build a laboratory test rig of the hybrid physical imaging and NIR chemical measurement set up.
• To design basic software to control the measurements with the test rig.
• To carry out the necessary tests to assess the functionality of the developed system.
VTT led this WP. They were supported in Tasks 2.1 and 2.3 by DIT and IRIS. RIKOLA will also support VTT in task 2.1. The rest of the SMEs (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will be involved to follow and steer the research. IRIS will follow this WP to prepare for work in WP4.
Task 2.1 Setting up NIR-chemical measurement and physical measurement test rig
In order to assess the functionality of the NIR chemical measurements together with the physical measurements, it is essential to build a test rig to study the full potential of NIR chemical measurement. The task will make a complete proof-of-concept, and determine how the prototype must be built in order to meet the requirements. This task will be carried out by VTT and they will be assisted by DIT, IRIS and RIKOLA.
Subtask 2.1.1 Building of the test rig
The test unit will be a bench-top device, will evaluate the additional filter-wheel and fibre-optics needed to add to the tuneable Fabry-Perot interferometer for multipoint quasi-imaging technology as well as its integration with the EYECON technology. Furthermore, the measurement speed in laboratory trials is not an important factor, because its aim is to determine what the speed conditions should be for the prototype. Therefore the shortage in signal – low signal to noise ratio – can be compensated with a longer measurement time.
Subtask 2.1.2 Algorithm development
Calibration models using science based i.e. matched filter calibration as well as algorithms for measurement of physical properties will be created. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. The solution is a spectrometric form of matched filter, i.e. it provides the globally optimum measurement accuracy. Simultaneously, it reduces the cost and time required for calibration drastically.
An important effort will be needed in the optical design of the camera optics. Also, to maximise the usability of the system in the trials, the wavelength range and spatial and wavelength resolution will be made as large as possible. This work will lead to a bench-top unit by M6 and will be reported as part of Deliverable 2.1- Report on the test-rig and the performance and stability tests with Phys/Chem test rig. This subtask will be carried out by VTT, with assistance from RIKOLA, IRIS and DIT.
Task 2.2 Performance tests and trials for quantification of physical and chemical properties
The outline for the initial testing is planned to include experiments to study the technology limitations for a thorough proof of concept. Based on these considerations, the following tests will be included in the proof-of-concept testing procedure of this work:
• Signal-to-noise ratio in optimum conditions with Spectral 99% target
• Linearity of signal axis in spectral images
• Spatial image resolution
• Spectral resolution and stability
• Demonstration of a whole spectral range NIR chemical measurement to demonstrate measurement time when typical measurement parameters are used
Once this initial testing phase has been successfully completed, the system will be tested during development for performance criteria against various concentrations of lactose residues on a smooth stainless steel surface. The impact of hardware selection and system limitations will be evaluated against the limit of detection, in order to determine the needs for the prototype. The required spatial and spectral resolution of an in-line system will be identified. Findings from the bench scale tests (tasks 3.2 and 3.3) will be incorporated over this development stage.
The results obtained during the testing process will be reported and summarized in Deliverables 2.1 (Report on the test-rig and the performance and stability tests with Phys/Chem test rig) and 2.2 (Phys/Chem test rig trials for evaluation of active and excipient granules).
This task will be carried out by VTT.
Task 2.3 Performance analysis and specifications for in-line system
Based on the information from performance and stability tests and application tests the specifications for the on-line instrument will be drawn up by VTT, with assistance from IRIS and DIT, together with a set of guidelines for the design. This information will be reported in deliverable 2.3 (Scale-up parameters for developing precompetitive prototype for industrial-scale in-line granulation monitoring). The SMEs and OTHER participants (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA), will be involved to review the results and to provide input to the specifications in keeping with the industry and market knowledge, as well as in tune with their expectations for the on-line system. In work package 2 the documented requirements from work package 1.
In the execution of the activities associated with work package 2 a laboratory test rig in line with the specifications outlined in work package 1 was built. This was built as two subcomponents a particle characteriser with the increased specification Basler ACE camera and Tamron lens configuration. The system was designed and built to accommodate the integration into the hardware of the fibre optic probe requirements for the Multipoint NIR system. In addition the system was fitted with a manual focus adjustment with movements of less than 0.1mm to allow for the accurate calculation and determination of the focal capability of the system. The system incorporated the LED based illumination solution as exists in the current Eyecon device. The test rig consisted of several mounting options and configurations to allow for the performance testing against optical standards and also with static and dynamic samples.
In addition to the physical imaging test rig a multipoint NIR test rig was built. The system was built with the ability to simultaneously process spectral data from four independent channels. The system capability and performance was comprehensively tested and evaluated, parameters such as wavelength calibration, wavelength verification, dark noise, white noise, channel cross talk, signal to noise ratio, signal stability, white and dark reference.
The system performance figures demonstrate the NIR multichannel systems capability for accurate in line measurement of chemical parameters.
Laboratory testing of the system for physical and chemical analysis of granules (WP3) –
Objectives:
• To produce and characterise granules of defined physical and chemical properties.
• To test the efficacy of the system to measure the physical and chemical parameters of granules under static bench top conditions
• To test the system under various excipient and active blends and moisture contents
• To test the approach during laboratory scale granulation processes
• To define the limits of detection for NIR chemical measurements
This task will develop a protocol for the analysis of varying granulate structures. Various excipient granulates, active granulates and the blended granulates will be manufactured and analysed under bench-top conditions with the laboratory test rig. The efficacy of the approach to cope with granulate structure (particle size distribution, sphericity) and chemistry (moisture content). Results will be correlated against reference sieve analysis and NIR based methods. Micro imaging will be employed to visually detail the physical structure of the granule. The prototype will be evaluated in laboratory scale granulators.
As was discussed, these work packages are highly inter-related. WP2 and WP3 will run in parallel and the work in each will progress and evolve in tandem. The outputs of WP2 will feed into WP4 and the results of WP3 will feed into WP5, signifying that both WP2 and WP3 need to be complete by M11-M10 so as not to create a bottle-neck in the progression of the work plan. As WP2 and WP3 will be implemented by different research teams, it is highly feasible that they can be implemented in parallel, and it is indeed necessary that they do so.
For the purposes of the RP2 (final) report, only those activities associated with the finalising of the report for deliverable D3.3 ”ability to obtain particle information from laboratory scale granulators” will be considered as all other aspects of WP3 have been reported in RP1 interim report.
Task 3.4 PARTICLE-PRO testing in laboratory scale granulators
Performance studies will be carried out using the prototype to monitor granule characteristics during granulation at laboratory and pilot plant scale. Small scale high shear, fluidised bed and extruder granulators will be employed to test the system’s performance during granulation. Variable operational conditions such as air velocity, impeller speed, extruder torque/speed will be employed to test the system’s response to step changes in the process. Results will be correlated against reference off-line or on-line methods where available. Performance criteria including limits of detection, processing speeds, response times, and volumetric analysis will be reported. The ability of the technology to determine granulation end point, in terms of size/shape, moisture and ingredient distributions will be provided for laboratory scale systems. This WP will result in defining the limits of operation for the laboratory prototype which will be summarised in Deliverable 3.3-Ability to obtain particle information from laboratory scale granulators. This task will be carried out by DIT with assistance from the end-users SMEs and OTHER (SIGMOID, SERVIPLAST and TAKEDA). INNOPHARMA will also assist with their knowledge of current measurement techniques. RIKOLA will also follow progress in order to absorb the knowledge.
In the execution of the activities associated with the proof of concept testing, DIT created test rigs and the environment to test the applications for determination of key physical and chemical attributes.
Systematic testing was conducted on both systems with respect to dynamic and static conditions to assess the system’s ability to determine discrete changes in physical or chemical properties of typical granulates and spheres.
All test results were compared against current industry norms and certified standards to ensure the accuracy of the data being generated.
A humidity chamber was created and laser based loss on drying techniques employed to assess and determine the system capability to predict changes in moisture level and further assessment to determine the accuracy and sensitivity of the system to moisture changes. This testing proved quite successful and the modelling process was transferrable to the laboratory and commercial scale granulation processes.
In addition to the physical imaging systems functional capability and sensitivity to particle shape and size a design of experiment also provide evidence that for certain product presentations such as spheronisation the NIR system was also sensitive to changes in the particle size.
Although not part of the system specification experiments were also designed to determine if an algorithm could be developed to provide information with respect to surface finish. This would be especially relevant to Sigmoid Pharma one of the consortium end user SMEs as in their spheronisation process surface finish can have a significant influence on the performance of the therapeutic capability of their product. The experiment design clearly indicates that there is the capability to provide qualitative information with respect to the surface properties of the spheres. While this requires further work and the algorithms have not been embedded in the base ParticlePro software, the design of experiment proved that the concept was viable.
In other areas the ability of the NIR application to track more than one parameter was also challenged. This was achieved through the application of principle component analysis and modelling software to track changes in moisture content while simultaneously tracking material addition to a blend application in a fluidised chamber. Again results of this experiment were quite conclusive in demonstrating multiple marker monitoring capability.
The conditions challenged and determined in the laboratory bench top based experiments also translated successfully to the dynamic laboratory scale granulation applications and later to the industrial scale evaluation trials.
Design and Building of the PARTICLE-PRO system (WP4)-
Objectives:
• To design, build and calibrate the PARTICLE-PRO system, in keeping with the results and parameters from WP2 and WP3 and taking into account the requirements defined by end-users of the system in WP1. It is envisaged that as many commercially available components as possible will be used in order to assemble the precompetitive prototype.
• To design the control interfaces and basic process controls for the PARTICLE-PRO subsystems.
• To carry out the necessary tests to assess the functionality of the developed subsystems.
During this WP the different subsystems of the pre-industrial prototype of the PARTICLE-PRO hardware for the pre-competitive prototype will be designed, built and calibrated in keeping with the parameters defined in WP2 for the industrial scale-up and taking into account the requirements defined by end-users of the system in WP1. It is envisaged that as many commercially available components as possible will be used in order to assemble the precompetitive prototype The control interfaces and basic software controls will also be designed and integrated into the PARTICLE-PRO subsystems. All the necessary tests to assess the functionality of the developed subsystem will be carried out.
Task 4.1: Industrial prototype design
In keeping with the parameters defined from the laboratory work carried out by VTT in WP2, a detailed concept design (block diagram) of the PARTICLE-PRO system and its subsystems will first of all be designed. The optical design will be made according to the established specifications such as resolution in wavelength and size, field of view and focusing requirements of the system. The light sources and electronics for the control, operation and data acquisition of the sensor array will be defined in terms of the sensitivity and acquisition requirements established during WP2 and WP3.
Following these designs, the detailed mechanical drawings will be carried out. These drawings will include information about materials and interconnections between the different components and they will serve as a detailed blueprint and guide for the integration of all the components of the PARTICLE-PRO system.
The different components (such as illumination source, imaging optic, spectral encoder for wavelength selection, detector and acquisition system-usually a frame-grabber board interfaced with a PC) that will be required by the proposed PARTICLE-PRO system for carrying out the selected measurements will then be selected and purchased from among, as much as practically possible, commercially available options.
During this design stage, in order to ensure the exploitability and future commercialisation of the prototype, standardisation procedures and manufacturing costs will be given special attention. In addition, the flexibility and ease of integration of the system will be attributed paramount importance and will be kept at the forefront of research efforts, in order to ensure the future widespread uptake of PARTICLE-PRO (and its family of products) by SMEs from across the European pharmaceutical industry.
This task will be carried out by IRIS in consultation with VTT, especially in view of the novel spectrograph background IPR held by VTT, which is a fundamental driver for the development of the proposed system. The participating SMEs (INNOPHARMA, SIGMOID, SERVIPLAST, and RIKOLA) will all be involved to contribute their guidance and knowledge to the design and to ensure it meets with their expectations.
Deliverable 4.1-Report describing the building of the PARTICLE-PRO prototype, will include the mechanical design in SolidWorks format, as well as the electronic and optical designs and the list of components used in its fabrication.
Task 4.2: Building of the PARTICLE-PRO hardware
During this task, the PARTICLE-PRO prototype will be built using the detailed designs prepared in Task 4.1. The rest of the necessary components and equipment that cannot be used from the test-rig (camera, data display, etc.) will be selected and purchased. Preliminary functionality testing will be performed on the different sub-systems that make up the prototype, in order to check that they are operating correctly. Then they will be integrated together.
The building of the prototype will be reported in Deliverable 4.1-Report describing the building of the PARTICLE-PRO prototype as well as the results of its laboratory evaluation. This task will be carried out by IRIS with input from INNOPHARMA and RIKOLA.
Task 4.3: Process control system
During this task, the controls for the operation and synchronization of the different subsystems will be designed and developed, together with a basic user interface with the basic commands for the operation of the different parts of the prototype, to enable the functionality tests to be performed. IRIS will carry out this task with assistance from INNOPHARMA. It is important to highlight that this task will focus on the electronics of the system, as opposed to the system software that will be developed in WP5.
A User Manual of the PARTICLE-PRO system will be drafted in Deliverable 4.2: PARTICLE-PRO User Manual.
Deliverables
Deliverable 4.1: Report describing the building of the PARTICLE-PRO prototype (including designs) (M16): Documentation of work performed to design and build the prototype and the results of its laboratory evaluation. Full designs of the precompetitive prototype system, including mechanical design in SolidWorks format, electronic and optical designs and list of components used in its fabrication.
Deliverable 4.2: PARTICLE-PRO User Manual (M16): Written document that provides a basic step-by-step guide to the installation of the prototype, including the most important safety issues.
During the execution of the activities of WP4 the ParticlePro system was designed and built in accordance with the specifications defined in WP1 and also from the learnings of Innopharmalabs experiences with respect to particle sizing and NIR applications. The ParticlePro device is an integration of two individual systems. Particle sizing is achieved using a commercially available particle sizing system called Eyecon™ and a NIR multipoint system which at the point of commencement of the ParticlePro project was at TG2 in the product lifecycle. TG2 in the product development lifecycle represents precompetitive prototype stage where laboratory based testing and system viability has been completed, this system is called MultiEye™.
In the design of the particle sizing system it was decided to incorporate an updated camera and lens system to try to improve on the current capabilities of the Eyecon™ system and also to enhance the analytical capabilities of the sizing algorithm.
In the hardware design of the ParticlePro device modularity was also a consideration, this was to allow for the application to be fully or partially integrated. This level of flexibility is necessary to cover a greater range of pharmaceutical or non-pharmaceutical applications. For example in continuous granulation processes it is essential that certain chemical aspects of the process are measured at different points of the process, this would not be achievable with a fully integrated system. Also for roller compaction applications for granulation generation, the physical and chemical aspects are measured at different points in the process.
The hardware design took these requirements in to consideration building fibre connections and collimators in to the Particle sizer body to allow for physical and chemical evaluation at the same point in the process, with the flexibility of being able to disconnect the fibres to connect to alternative parts of the process.
In conjunction with the specification and building of the ParticlePro system a user manual was generated to assist with the physical set up, explain the model interfaces and also fully describe the integrated user interface. This manual was developed and updated accordingly, based on changes required following the different stages of system testing and assessment.
Software Development, System Integration and Optimisation (WP5) –
Objectives:
• To develop the general software for the operation of the PARTICLE-PRO system, including the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP2 and WP3.
• To design and develop the user application according to the requirements established during WP1.
• To integrate the system hardware, software and User Interface
The building of the system software and the User Interface represents an important component of the PARTICLE-PRO architecture. The objective of this work package is to develop the general software for the operation of the PARTICLE-PRO system, including the synchronized control of the different subsystems, the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP3. The User Interface will be developed according to the requirements established during WP1. If a network configuration is desired, a specific web-based application (that will use “open-source” solutions, such as php programming language and MySQL database) will be designed and implemented to generate the results. The hardware and software will then be integrated together and pre-validation trials will be carried out to ensure the integrated system functions properly prior to shipping to industrial test sites. In parallel with the Industrial Validation work that will be carried out at industrial sites during WP6, the RTDs will carry out necessary optimisation work of the prototype in keeping with the results of performance and operational testing, and to enable the necessary development work that will be required in order to arrive at a commercial system will be recommended.
WP4 and WP5 will run in parallel to ensure that the results from both are ready for integration together by M15. As WP4 and WP5 will be implemented by different research teams, it is highly feasible that they can be implemented in parallel, and it is indeed necessary that they do so.
A comprehensive series of demonstration activities will also be carried out in order to prove the viability of the new PARTICLE-PRO technology for its future industrial application and commercialisation.
Task 5.1: Software Development (IRIS)
In keeping with the general input specifications defined in WP1, the software for the full system will be designed in order to enable, as much as possible, the running of the prototype without the need for the intervention of an operator, as well as to enable the chemical identification of the contaminants from the measured spectra. It will integrate the different software packages for each subsystem, acquire the data, process the information with the calibration algorithms and libraries developed in WP2 and WP3, and determine the presence of contaminants. This software will be a combination of the EYECON software with the new developed SBC algorithms for the moisture and chemical characterisation measurements.
The software developed will be documented as part of Deliverable 5.1. PARTICLE-PRO Control Software, User Interface and database.
IRIS will lead this task with assistance from INNOPHARMA, VTT and DIT.
Task 5.2: User Interface Development (IRIS)
During this task, the user interface will be developed in accordance with the requirements established in WP1, so that it can be used in a wide variety of end user groups, and depending on whether the system is to be used on its own or integrated in a network configuration.
The user interface will also be designed so the results are displayed and stored in the most convenient manner, to ensure easy and clear understanding by the user.
Deliverable 5.1. PARTICLE-PRO Control Software, User Interface and database, will summarise the characteristics of the UI and will also include the code developed.
The control software will then be implemented and integrated into the PARTICLE-PRO prototype. IRIS will carry out this task in consultation with all the SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA).
Task 5.3 Integration of Software and UI with Hardware technology (IRIS)
This task will consist of fine-tuning the assembly of the various sub-systems, (pre-assembled during WP4) and on the integration of the subsystems with their control packages in the developed System software and user interface.
Extensive tests will then be carried out to validate the hardware and software compatibility, as well as to fine-tune the control system. As a consequence, software debugging will be done and robustness of the electronics as well as the protection of the whole PARTICLE-PRO system will be done. When housings, plug-ins or other required parts will be needed, they will be designed and manufactured under this task. IRIS will carry out this task with assistance from VTT, Innopharmalabs, and RIKOLA.
Task 5.4 Calibration and functionality testing of the PARTICLE-PRO prototype (DIT)
During this task the PARTICLE-PRO prototype will be calibrated. When this is done, extensive pre-validation functional tests will be performed in order to check that the prototype works according to specifications. The outcome will be a pre-competitive prototype ready for industrial validation. All the SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will follow this work.
Once this is done, the PARTICLE-PRO system will be ready for industrial validation.
Task 5.5: System Optimisation (IRIS)
During this task, the RTDs will follow closely the performance and operational aspects of the pre-competitive prototype during set up and testing in Tasks 6.1 and Task 6.2 respectively. During this task, further modifications and tweaking will be made to the prototype in keeping with the results that merge from the parallel testing of prototype in the field in comparison with conventional methods.
The researchers and industrial partners will draw up a series of recommendations for any future research work or developments that should be carried out by the participating SMEs in the future (post project), in order to ensure that the pre-competitive PARTICLE-PRO prototype can be fully converted into an industrially feasible product which can be successfully taken to market and which can be exploited at industrial scale in the marketplace. All of the participating SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will be involved in this task, which will be a very important task for helping them to define the post project work that will need to be done prior to market entry of the technology. The results of this task will feed into Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization.
Moreover, recommendations that emerge from the demonstration sessions that will be held in WP7 will also be picked up, and tweaking and improvements will be implemented by the RTDs during this task, and additional recommendations will be evaluated for their suitability and feasibility for implementation during the commercialisation stage post project.
Deliverables
Deliverable 5.1: PARTICLE-PRO Control Software, User Interface and database (M15): Written documentation, with a software package and a code package.
In terms of the execution of the activities associated with work package 5, system integration and build was completed successfully. The achievements with respect to work package 5 are documents in the report for deliverable 5.1.
The ParticlePro system was built consisting of a cylindrical design fabricated from stainless steel as opposed to the current moulded plastic casing for the Eyecon™, this will facilitate future ATEX rating for the final ParticlePro system. There were some recommended changes for the design and configuration of the MultiEye™ system but the project scope for ParticlePro did not allow for the inclusion of these changes. They will however be incorporated in to the future design and build of the commercial ParticlePro or MultiEye™ systems. This changes will have no impact on the effectiveness and functionality of the ParticlePro system.
The system was built to allow for the running of both the physical application and the chemical applications on a single laptop.
In the activities in WP2 and WP3 the software was built and designed on a number of platforms, C#, C++ and R for the physical characteristics and Labview and R for the chemical characteristics. The particle sizer UI is built on C# business logic while the Analytical algorithms are built in C++ with the algorithms developed by DIT in WP3 built in R. The chemical analysis algorithms are built in Labview while the application models were built in R by DIT. IRIS as part of the integration process have standardised the coding configurations for ease of integration.
The system was built and configured using a newly designed particle sizing application with DIT designing an enhancement of the analytical algorithms. This work also had to be factored in by IRIS in the integration and running of the particle sizing algorithms.
The system capability for physical measurement was assessed against standards supplied by Innopharmalabs, the sizes of these standards are certified externally using sieve analysis and Malvern Mastersizer. The results achieved against these standards were quite comparable and acceptable for the system and more than sufficient for the conducting of industrial trials.
The chemical capability of the system was assessed against know wavelength and reference standards and as with the particle sizing the results achieved were comparable and acceptable for the commencement of industrial trials.
In terms of speed of analysis the systems process speed was slightly slower than that of the current Eyecon™ and MultiEye™ systems. This is as a result of the increase in the complexity of the analytical algorithms due to the additional parameters being analysed and also the fact that both systems run of a single laptop. Having said that the analysis speed is still less than 20 seconds which in the context of current in process testing and for real time process control is still more than sufficient.
The system has been built and configured in accordance with the requirements determined in work package 1. The ongoing development of the system during the execution of WP4 and WP5 incorporated the results and findings at each stage of industrial evaluation of the ParticlePro system, in order to optimise the specification for a commercially viable system.
Industrial Validation of the PARTICLE-PRO System (WP6) –
Objectives:
• To set-up the PARTICLE-PRO system in the test sites at the end-user facilities of SIGMOID or TAKEDA in Ireland and SERVIPLAST in Spain.
• To extensively test the prototype in order to validate its performance in the field, comparing it to conventional particle characterisation methods, and to make the necessary modifications to improve the prototype
• To assist the participating SMEs in fully defining the specifications and future development work that needs to be carried out post project, in order to arrive at a fully commercial product
This WP will assess the efficacy of the developed system to deal with various granulation processes within a process facility. Correlations against reference particle characterization methods will be made. Design issues arising from the industrial tests will be fed back into WP5 to enable improvements to be made to the system, and to enable recommendations for future development work towards commercialization to be drafted.
This work plan also includes a comprehensive series of other activities in order to transfer knowledge from the RTD to the SMEs and to facilitate the take-up of results by the SME participants, as well as by a wider audience of companies from the wider industry:
This WP will be led by DIT who will be supported by IRIS and INNOPHARMA. SIGMOID or TAKEDA and SERVIPLAST will be involved as the test sites. RIKOLA will be involved to support the set up and to ensure the smooth running of the system during trials. INNOPHARMA will share their knowledge of pharmaceutical manufacture and the state-of-the-art in alternative control technologies so that comparisons can be made. They will also provide a test site if this is required.
Task 6.1: Set-up of PARTICLE-PRO in end-user facilities (IRIS, DIT)
During this task, IRIS will set-up the PARTICLE-PRO instrument in the partner facilities (SIGMOID or TAKEDA and SERVIPLAST). Again the effective and early planning of the industrial specifications of the PARTICLE-PRO technology during WP1 should greatly facilitate this task. At this point, initial minimal training or instruction on the proper use of the instrument will need to be delivered to these end-user SMEs, in order to ensure that they are each performing the analytical study correctly.
Task 6.2: Industrial trials and evaluation of results (DIT)
Once the PARTICLE-PRO system has been set up in the sites of SIGMOID or TAKEDA and SERVIPLAST partner facilities, the system will be extensively tested to validate its performance under real industrial operation environments. Tests will be carried out in bench-top and in-line modes over a series of products and operating conditions. Granulation unit operation of high shear, fluidised bed and extrusion will be tested. The tests will be very carefully planned together with these end-user partners, in order to ensure the coherent and successful validation of the effectiveness of the proposed system for the in-line physical and chemical characterisation of particles. The performance criteria as outlined in Task 3.4 will be repeated at production level, with correlations developed with reference off-line measurements. This activity will be detailed in a protocol and subsequent report format.
Exhaustive testing of the instrument at the partner facilities will be carried out. This testing will involve parallel trials using PARTICLE-PRO and current ‘best-in-class’ in-line and off-line analytical methods – NIR, Loss on Drying, Laser and sieve analysis. In this way we can get a meaningful comparison of its effectiveness as a monitoring tool (Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization).
The ability of the PARTICLE-PRO to determine granulation end point, in terms of size/shape, moisture and ingredient distributions will be provided for industrial scale systems.
Deliverables
Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization (M24): A written report that documents the key findings, outputs and conclusions following the field trials that will have been carried out with the PARTICLE-PRO system, as well as the main development work that will need to be carried out post-project in order to take the PARTICLE-PRO prototype from pre-competitive status to a fully commercial system.
The system was tested extensively on a number of platforms during the course of the industrial trials and evaluations.
The system was set up on a number of platforms and pharmaceutical processes. In the cases of Takeda and Serviplast access to their processes was difficult due to commercial production requirements and the issues with respect to interfering with a validated GMP process. Both Takeda and Serviplast use predominantly fluid bed granulation/drying platforms supplied by Glatt. In order to meet their requirements with respect to assessing the systems capability, the consortium reached an agreement with Glatt GmbH in Binzen Germany to conduct the systems evaluation on both their laboratory scale and commercial scale granulation systems. In addition as a consideration to Glatt the consortium provided them with the opportunity to evaluate the systems capability on their new continuous manufacturing platform, which would require system monitoring using PAT at several different points on the process.
In addition to the collaboration with Glatt the consortium also collaborated with the University of Sheffield in the UK and University College Cork in Ireland. These collaboration allows the consortium to evaluate the systems capability of two different commercial roller compaction processes. This is an alternative granulation process facilitating the compaction of dry ingredients, not suitable for high shear blending, into ribbons for milling into compressible granulate. In addition to the testing of the systems capabilities these collaborations also provided addition avenues for the dissemination of results to a wider audience.
The system was tested a various stages of development on roller compaction, fluid bed granulation/drying, extrusion, drying and coating processes. These tests were completed at University College Cork, Glatt GmbH IN Binzen Germany and Sigmoid Pharma in Dublin Ireland.
The overall result of the testing are detailed in the report for deliverable 6.1.
During roller compaction trials the system was used to determine if ParticlePro was capable of detection changes in ribbon density due to changes in critical process parameters. To assess the NIR results against current density analysis tools. In addition to determine if there is correlation between the changes in the critical quality attributes of the compacted ribbon and the final particle size distribution of the granules produced during the milling stage.
The results achieved showed significant levels of correlation and a clear ability of the system to be utilised for the monitoring of roller compaction processes. The modular nature of the ParticlePro design facilitates the use of any combination of NIR probes from a single probe to all four probes in different configurations, linear or square orientation. In fact the MultiEye™ proved more effective than the current laboratory based FT-IR method. Similarly the particle sizer compared well to typical analysis systems such as sieve and Camsizer.
During granulation trials at Glatt a similar result was achieved. The NIR application were used in the determination of moisture content and from a blend simulation point of view the use of principle component analysis to observe the addition of PVP in solution to an unblended combination of Avicel and Lactose.
The ParticlePro system demonstrated a clear capability to monitor typical granulation processes for both the chemical and physical attributes of the processes. In addition to typical batch granulation processes the system also demonstrated a clear ability to monitor and track different points in the new continuous manufacturing platforms.
As with the results of the roller compaction process there was good correlation between the ParticlePro system and other typical process analytical tools, such as LOD testing, sieve analysis, and a competitor in line laser diffraction probe. Again the ParticlePro system demonstrated better correlation than the in-line competitor system did to sieve analysis.
The process at Sigmoid Pharma is quite unique and has been developed to facilitate the delivery of therapeutic doses using actives that don’t readily bind and release in typical dry or wet granulation processes. The system is subject to IPR protection so cannot currently be fully described in the project. However it is a unique method for the generation of spheres with subsequent critical drying and coating processes. The efficiency of the drying and coating processes has a significant impact on the delivery of the therapeutic dose.
The primary objective was to determine if the ParticlePro system was capable of detecting changes in the physical and chemical characteristics of the spheres at different stages of the process and to determine if an appropriate model could be built in order to facilitate the determination of the end point of each step of the process. There were a number of challenges associated with monitoring this unique process. Firstly the limited number of samples that could be taken during the drum drying process, secondly the limitations for interfacing the NIR probes of the ParticlePro system.
Despite these challenges the system again demonstrated a clear ability to monitor and track the process, which in the case of the drum drying process was in excess of 20 hours. Again there was good correlation between final results and typical analytical technologies.
During the testing there were some issues with regard to system interruptions due to the processing platform on the laptop, however these issues were resolved satisfactorily as were demonstrated during the 22 hour long monitoring of the drying process at Sigmoid.
In general the industrial trials proved quite successful and were well received by the consortium SMEs and end users. These results were also well received by other end users outside the consortium and also by Glatt who want to pursue further evaluation with the potential to recommend the system as an option for supply with their batch and continuous processes.
Potential Impact:
Expected final results and potential impact.
The pharmaceutical industry represents one of the fastest growing industry sectors in the world today. While the process of drug discovery has been fundamental to the development of new therapies, increasingly pharmaceutical companies are relying on the development of novel product formulations to maintain market share. Within this, particle characterization is key to developing an understanding of the functionality of new products, formulations and delivery systems. Moreover, pharmaceutical companies are adopting more complex and promising approaches with dosage forms, including controlled release tablets, multi-coated tablets and granule coatings. For European players to tap into these emerging markets, they need timely and affordable access to innovative process controlling technologies to help them stay ahead of global competition.
INNOPHARMA, a technology provider that specializes in providing breakthrough technologies to the pharmaceutical sector, has identified a clear technological need for improving granulation control and for better positioning themselves in a highly competitive market. INNOPHARMA wants to build on their existing EYECON system that characterises 3D particle images providing information on size and shape in real time and integrate novel NIR chemical measurement approaches that would allow for spatial measurement of granule moisture and ingredient profiles. INNOPHARMA lacks the research capability to developed such a combined system and, to this end, they plan to subcontract work to 3 RTD performers (VTT, DIT and IRIS) through the “Research for SMEs” scheme, so that they can access technology that they can take into the market with the help of the interferometers, optoelectronics suppliers (RIKOLA) in order to serve strong European and indeed global demand.
Indeed industry demand for the technology is expected to be strong in view of the multiple benefits that will be realised through the use of the system in pharmaceutical manufacture: increased granulation process control, increased process quality, increased batch yields, reduced down-time, reduced investigations as a result of deviation investigations, reduced risk of non-supply of products, greater assurance for regulatory bodies, greater patient safety assurance and the feasibility of continuous process validation and real time release of medicinal products. Moreover, financial savings realised through analytical headcount reduction, elimination of analysis time / instrumentation and reduced manufacturing cycle time could be greater than €400,000 for a typical pharmaceutical manufacturing facility with circa 30 batches manufactured per annum.
Already at this early stage, industry interest is significant, and the supply SMEs are joined in the consortium by a group of end-user SMEs who are keen to be early adopters of the technology at discounted rates (SIGMOID, SERVIPLAST). In addition, the presence of a large pharmaceutical manufacturer (TADEKA) is indeed a major endorsement for project and its proposed results.
By owning the Intellectual Property to develop a commercial system that would deliver such a plethora of benefits to the lucrative pharmaceutical sector and at a cost effective price, opens up a highly promising business opportunity for the supply SMEs (INNOPHARMA and RIKOLA) who will work together to service this market, which would be worth € 15 M in the first 5 years of market entry, and an additional € 8 M through the application of the platform technology for other industries where characterisation of particles is a critical quality attribute such as: powdered milk, nutritional products, baby formula, whey products, etc.
As drug delivery systems become more sophisticated, the complex components involved need to be checked more carefully during formulation development and quality control than traditional delivery systems. Innovation and the uptake of new technologies will prove of paramount importance and developments such as PARTICLE-PRO will go a long way towards assisting to strengthen Europe’s reputation as a consistent supplier of high quality and safe pharmaceuticals and biopharmaceuticals. Against such a backdrop, the SME participants are committed, via their active participation in this Research for SMEs proposal, to guiding the RTD performers in the development of a hybrid of imaging-based physical characterization and NIR-Chemical measurement technologies that will provide real-time physical and chemical granule characterisation for a manufacturing process. The SMEs will actively participate in the work plan in terms of mobilising a bottom-up approach whereby they will guide and support the RTD performers in delivering usable results that they will validate and exploit. The SMEs will take on ownership of the beneficial results of this project and the responsibility for their full exploitation at European-wide level.
Contribution to advancement of knowledge / technological progress
The results of this project will represent a significant advance of the state-of-the-art in analytical technology to characterise the physical and chemical properties of particles and indeed the developed hybrid physical imaging and NIR chemical measurement device will be a worldwide breakthrough for the pharmaceutical, and indeed food granulation sectors. It is envisaged that by overcoming the limitations of the existing state-of-the-art in granulation control that a number of key innovations and technological progress will emerge from the research.
The current mechanism for determination of granulation of end point is typically based on a pre-validated time period with fixed air flow rates, air temperatures and liquid feed rates. This defined process is on occasion supported by in-line fixed point NIR analysis to monitor moisture content but more usually by off-line moisture Loss on Drying instruments and off-line physical analysis using sieve analysis or laser based analytical instruments. The paradigm shift towards in-line determination of granulation endpoint through characterisation of physical and chemical parameters and enabling advanced process understanding will ensure greater process robustness, leaner manufacturing processes (saving time, energy and money) and ultimately patient safety. The pharmaceutical user will gather significant understanding of the granulation process during clinical trial manufacture. This understanding of the physical and chemical properties will enable a significantly reduced scale-up time during the commercialisation phase of the pharmaceutical product thereby introducing products to the market in a timelier manner (compared with a typical 3 to 5 years currently).
In terms of a contribution to the technology progress, as an emerging technique, Chemical measurement integrates conventional imaging and spectroscopy to attain both spatial and spectral information from an object. As was discussed above, the combination of the chemical selectivity of vibrational spectroscopy with the power of image visualisation, enables this technique to deliver a more complete description of ingredient concentration and distribution in heterogeneous solids, semi-solids and powders.
VTT has several robust cost efficient and miniaturized spectrograph technology platforms for spectroscopic measurements.
1. VTT patented miniature piezo-actuated Fabry-Perot tunable filter technology gives more freedom for wavelength selection and still offers good wavelength resolution, low drift and high measurement speed, this technology is commercialized by RIKOLA. The benefits of these new devices compared to for example Acousto-Optic Tunable filter (AOTF) or Liquid Crystal Tunable Filter (LCTF) devices are their small size and weight, speed of wavelength tuning, high optical throughput, independence of polarization state of incoming light and the capability to record three wavelengths simultaneously.
2. By combining multi-channel detector technology with tunable Fabry-Perot filter VTT has developed and patented a quasi-imaging technique, to simultaneously increase the number of wavelength channels from multi-channel systems and still get the highest possible measurement speed. Advantages of quasi imaging, known wavelength channels, include fast data acquisition, flexibility of measurement, robustness, small size and low cost.
In all cases robustness of the measurement is extremely critical and wavelength drift must be minimized with hermetically sealed detector solution integrated to the Particle-Pro device in WP2 and WP4.
VTT has already developed and utilised the innovative Fabry-Perot interferometer (FPI) concept in UAV (Unmanned aerial vehicle) sensing applications and visible range chemical imager and color measurements. Preliminary results have demonstrated the first generation research based on FPI spectrometer module for laboratory chemical mapping applications. The measurement speed and high SNR achieved by the proposed novel FPI concept are even more critical for in-line real-time NIR chemical measurements applications, such as wet granulation control. Due to the small-size of preliminary FPI spectrometer technology, it can be seen as an enabling technology for new in-line Chemical monitoring development.
Another limiting factor of NIR chemical measurements is the need to calibration models of every component to be measured. These sets of calibrations are sold with the devices as part of the software (or separately at an extra cost). These libraries are very time consuming to build and with the standard chemometric models there is always a need to be validated against reference methods and the calibration models vary from one device to device. The so-called science-based method (SBC) has recently provided a solution to the calibration problem. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. In SBC, with response defined a-priori by spectroscopic expertise and application knowledge, spectroscopy is no longer a “secondary” method that needs calibration against a “primary” reference method. Instead, it becomes a “primary” method, firmly rooted in physics and chemistry. Significant practical benefits become available from this change whenever the shape of the response spectrum is “manually” defined. One great advantage is that specificity of response can be proven to regulatory agencies and concerned end-users, which in today’s increasingly regulated and controlled environment this is a major competitive benefit for reassuring consumers and the market and heightening confidence. The last two decades have seen the development of commercial systems for the application of NIR chemical imaging and physical imaging in the pharmaceutical sector. However, to date there is no commercial system in the market that can provide real time on-.line measurements of both physical and chemical parameters. Such an ability, which the PARTICLE-PRO system will possess, makes for a system that is more flexible and suited for responding to the increase need to follow Process Analytical Technology (PAT) and pharmaceutical quality by designed required by the FDA.
The European pharmaceutical industry has an important role to play in ensuring that the people of Europe enjoy a good standard of health . The European Union strives, therefore, to guarantee broad access to medicinal products, to provide the public with high quality information, and to ensure that the medicinal products manufactured are safe and effective21. The single market for pharmaceutical products makes it possible to achieve these aims by increasing the competitiveness of the industry through promoting research and innovation for the benefit of the public21.
Process Analytical Technology (PAT) is now the buzzword in the pharmaceutical industry. It is the new framework for better understanding in pharmaceutical processes of which granulation is a very big part. Central to PAT is improving final product quality by process design through knowledge of the fundamental scientific principles behind it, and continuous online control of a process. The challenge is to do this whilst maintaining or improving the current level of product quality6.
Without doubt, the impact of providing the industry with a novel hybrid physical imaging and NIR chemical measurement technology to characterise the physical and chemical properties of particles holds enormous benefits adding value to and increasing the competitiveness of the European pharmaceutical sectors, for improved pharmaceutical product quality and safety, as well as for patient health and safety. Moreover, as the novel hybrid PARTICLE-PRO analytical technology will be designed, manufactured, supplied and serviced from Europe, this will have a positive impact for jobs, growth and innovation.
How the results of the project will improve the competitiveness of the SME participants
The project will result in a hybrid physical imaging and NIR chemical measurement technology that will be branded and marketed as PARTICLE-PRO, and will enable the rapid and reliable on-line characterisation of the physical and chemical properties of particles during processing. It is envisaged that the ownership of the rights to exploit the proposed results will afford the participating SMEs with a real business opportunity with a clear economic impact. To this end, they aim to protect the knowledge generated during the project, in order to enable the generation of income and competitive benefits to be derived through the exploitation of the IPR, which will bring a clear strategic and competitive impact for the participating SMEs.
In terms of the benefits to the end-users of the system (SIGMOID, SERVIPLAST, TAKEDA), they will be equipped to:
• Increase granulation process control- by having access to information about particle size, shape and moisture content, as well as the active content uniformity of the final product in real-time from the same device.
• Increase process quality- real-time information from the PARTICLE-PRO device will enable better control over characteristics that influence compression processes, product stability (negatively leading to hydration of the active ingredient), and the active content uniformity of the final product that ensures that each patient receives the correct dosage quantity.
• Increase batch yields- through reduced product rejections, which can be as high as 20% as a result of process problems, by improving response times to process upsets
• Reduce down-time- by replacing time-consuming off-line methods with real-time characterisation. PARTICLE-PRO will eliminating sampling and the time delays inherent in taking and transporting a sample to an off-line laboratory
• Reduce investigations as a result of deviation investigations
• Reduce risk of non-supply of products
• Obtain greater assurance for regulatory bodies- though the use of a technology that is in line with “Process Analytical Technology”, the new framework for better understanding in pharmaceutical processes of which granulation is a very big part
• Reduced scale-up times from Clinical to Commercial manufacture
• Obtain financial savings realised through analytical headcount reduction, elimination of analysis time / instrumentation and reduced manufacturing cycle time. Per annum savings would be greater than €400,000 for a typical pharmaceutical manufacturing facility with circa 30 batches manufactured per year.
The effective communication of these benefits to the market should draw on technology push, as well as stimulate market demand for the proposed PARTICLE-PRO system among the European (and indeed global) pharmaceutical industry. Beyond the product-related benefits, further drivers that should fuel demand include the increasingly stringent regulatory requirements (EU Guide to Good Manufacturing Practice; the U.S. Food and Drug Administration, FDA) and the increasing cost pressures. This opens up an enormous business opportunity for the SMEs from the PARTICLE-PRO supply chain (INNOPHARMA and RIKOLA) to tap into this market, especially as the system will be very competitively prices compared to the competition. They will thereby benefit from increased sales and income from the supply of the Fabry Perot Interferometer (RIKOLA), as well as the manufacture and sale of the complete solution (INNOPHARMA), including the system software. They expect to access new international markets and open up distribution networks across Europe, and indeed beyond, as a result of the commercialisation of the novel PARTICLE-PRO phys./CI particle characterisation system.
In order to quantify these competitive benefits for each SME, the direct economic impacts have been calculated (Table 6), along with the subsequent new jobs that could be created as a result. These initial estimations are based on an analysis of the type of exploitation that each beneficiary will make of the results in keeping with their positioning on the user and supply chain, their existing turnover and employees and their capacity to exploit the results of the project, and the resulting competitive benefits. New jobs created are based on average capital intensity in the industrial sector of € 120,000 per job per annum .
Contribution to improving industrial competitiveness across the European Union
Beyond strengthening the competitiveness of the participating SMEs, this PARTICLE-PRO project will also contribute to improving industrial competitiveness across the European Union through the commercialisation of the system in EU-27.
Figures published in 2008 by the European Commission (Eurostat) show that the pharmaceutical industry is the industrial sector which invests most in research & development with 15.3% of total EU private R&D expenditure. Of the 635,000 people it employs in Europe, 117,000 work in R&D . To this end, the research-based pharmaceutical industry is one of Europe’s leading high-technology industrial employers. In fact, recent studies in some countries showed that the research-based pharmaceutical industry generates three to four times more employment indirectly - upstream and downstream - than it does directly, a significant proportion being high value added jobs (e.g. clinical science, universities, etc.)23. The pharmaceutical industry is also the sector with the highest ratio of R&D investment to net sales. It amounts to approximately 3.5% of total EU manufacturing value-added and 19.2% of the total worldwide business R&D expenditure. The research-based pharmaceutical industry is a key asset of the European economy representing about 19.2% of global business R&D investments and about 3.5% of the total EU manufactured exports23.
The savings realized through reduced scale up times and greater process robustness will enable even greater percentages of investment to be made in pharmaceutical R&D.
European demand for pharmaceuticals is expanding due to an ageing population, earlier diagnosis of disease and wider use of pharmaceuticals. However, despite this growing domestic demand, since the early 1990s, Europe has been losing competitiveness with respect to its main competitors, in particular the US. Data for 2007 and preliminary figures for 2008 confirm the vulnerability of Europe’s research-based pharmaceutical industry. Benchmarking and performance indicators show Europe's relative lack of attractiveness for pharmaceutical R&D investments. Between 1990 and 2008, R&D investment in United States grew by 5.6 times whilst in Europe it only grew by 3.5 times. Today there is rapid growth in the research environment in emerging economies such as China and India, resulting in closures of R&D sites in Europe and openings of new sites on the Asian continent. To this end, improving the performance of European manufacturers is of paramount for safeguarding the competitiveness of the European players in this sector.
Particle physics governs process variables such as flow, blending, granulation, compression and coating. These variables can have a significant effect on final product behaviour such as blend homogeneity, drug absorption rates, product robustness, etc. The identified key physical parameters include particle/granule size and shape. Similarly the chemistry variation within the products has a critical effect on product quality. The development of a technology capable of monitoring physical and chemical parameters of a process on-line will significantly increase process understanding and control thereby assuring product quality, lean operational costs, as well as patient safety.
Equipping the European pharmaceutical industry with a technology that will enable them to safeguard product quality and safety, reduce costs, increase production throughput, meet with international good manufacturing practices, and facilitate quicker new product development, will undoubtedly contribute to increasing the competitiveness of these sectors at European level, as well as to safeguarding the futures of the 635,000 employed in the pharmaceutical and biopharmaceutical industries, as well as their related supply and value chains in Europe. Moreover, we envisage the creation of at least 800-1000 new jobs by 2020 (within 5 years of commercial availability of the system in the market) through increased pharmaceutical production in the EU, as a result of increased product throughput and capacity in existing plants, as well as knock-on jobs along the value chain, and in the manufacture of the PARTICLE-PRO system itself to serve the European (and global) market. This would be based on a 0.02-0.03 % annual increase in jobs in the pharmaceutical sector in Europe through increased competitiveness via the uptake of a PAT technology to improve the efficiency of their granulation process and to improve the quality and safety of the final product, which are key drivers for growth and job creation.
However, particles and granules play a key role in process efficacy and final product quality for numerous industries beyond the pharmaceutical sector, such as food and nutritionals. To this end, by rolling out the technology to the food and nutrition sector for the physical and chemical characteristics of particles during food granulation processing (through further development work, validation and demonstration, which is a firm intention of the participating supply SMEs by 2015), the benefits for 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. These benefits will be particularly felt in the case of the production of infant formula, powdered milk, nutritional product, whey product manufacture, whereby the uniform presence of various sugar/fat components within the granule as well as its size and structure is critical to the performance of the product.
The extent to which the proposed project will lead to new and improved products, processes or services with clear market potential
Successful granulation and active homogeneity are critical to assuring product quality. Once PARTICLE-PRO is ready to launch in the market, it is envisaged that the ownership of the rights to exploit the proposed technology will afford the industry partners with a real business opportunity through the uptake and commercialisation of a novel particle characterisation device with very promising market potential at EU, and indeed global, level.
In fact, the worldwide pharmaceutical market is very lucrative for pharmaceutical producers and also for equipment suppliers, service providers and consultants . The world pharmaceutical market more than doubled in size between 1998 and 2006 . In 2009 global pharmaceutical sales were worth approximately 750 billion-760 billion U.S. dollars . The US, however, is the world market leader with a 39.3% share of world production, followed by Europe and Japan. Seven emerging markets- Brazil, China, India, Mexico, Russia, South Korea, and Turkey- contribute nearly 25% of growth worldwide and were expected to grow 12–13% in 2008 to $85–90 billion .
To satisfy demand, a large number of capital projects have been initiated and completed worldwide, creating what appears to be the ideal growth market for companies that specialise in the design and delivery of pharmaceutical plants and equipment, and especially suppliers of specialised equipment24. Figure 8 shows the envisaged ease with which PARTICLE-PRO would be integrated into current granulating equipment designs. The flexibility of design will be such that it could be retrofitted non-invasively to current fluidized bed, high shear or extruder granulator designs. Equally as a selling point for granulation equipment, suppliers could use the technology as an advanced control strategy of their process.
The strategy for dissemination of the results, findings and benefits of the ParticlePro project will need to follow an agreed pre-determined communication plan. The unique and proprietary nature of the technologies involved in the design and building of the detection device will need to be protected until the full exploitation.
To ensure protection of the early research results, external communication will be focused on the project website and industry visits and consultations with a specific focus on those pharmaceutical companies who have embraced the move to PAT in the pharmaceutical and related industries.
The project leaflet and poster will be preliminary designed with the printing of the leaflet targeted to include some images and non-proprietary results for WP4, “design and building of the ParticlePro system.
Note: As the project moves through each of the development phases associated with the construction and testing of a pre-competitive prototype portable test rig, communication and dissemination of the results and the strategy associated with the communication plan, will need to be agreed by all members of the consortium to protect and maximise the opportunity to exploit the ParticlePro technology.
The following activities have been planned for the 1 – 15 month period of the ParticlePro project.
• Development and upkeep of the ParticlePro website.
• Develop a link to the ParticlePro website on the Innopharmalabs technology website.
• Planned visits and communications to Pharmaceutical, Academic and Development facilities across Europe and the US. This activity commenced with evaluation trials for the individual technologies, involving Sheffield University in the UK and UCC and UL in Ireland. This activity commenced in April 2013 with further activity planned for October 2013 for the physical evaluation of particles. In February 2014 further trials are planned to evaluate the potential of the NIR system to track changes in a typical roller compaction process.
• Innopharmalabs are currently in the process of negotiating partnerships with key equipment manufacturers. Part of this relationship will be the testing and subsequent recommendation of technologies resulting from the FP7 funded R&D activity.
• Power-point presentation template will be developed by the end of February 2014 to facilitate communication of the project results.
• Poster and leaflet layout to be finalised and prepared for the inclusion of non-proprietary results obtained during the completion of WP4, this is targeted for April 2014
• Press release planned to coincide with the kick off for the Pure Formula and Crystal Vis research for SME projects. Press release to be developed for release in January 2014.
• White paper to be completed in February 2014. The white paper will discuss and explore the results achieved to date on the laboratory test rig. The white paper will be distributed through some of the channels identified in section 5.1 of this document.
• Meeting with Patent Attorney in May 2014 to determine the process for protection of the IPR associated with the ParticlePro technology, and how we can leverage the existing patents/patent applications for existing foreground and background activities.
• There were two white papers generated from the combinations of laboratory and industrial based testing. The first of these white papers.is published, the second is in review.
M. A. P. McAuliffe, G. E. O., C. A. Blackshields, J. A. C., D. P. Egan, L. K., E. O’Neill, S. L., & G. M. Walker, A. M. C. (2014, April). The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing. Organic Process Research; Development.
Evaluation of Diffuse Reflectance Near Infrared Fibre Optical Sensors in Measurements for Chemical Identification and Quantification for Binary Granule Blends. D. Togashi, L. Alvarez-Jubete, H. Rifai,R. Cama-Moncunill, P. Cruise, C. Sullivan, P.J. Cullen. Journal of Near Infra Red Spectroscopy. Currently in review for acceptance and open publication.
• Presentation of our results and progress to an ISPE (International Society for Pharmaceutical Engineers), PAT Community of Practice forum to be planned for mid 2014.
• The prototype development phase is completed in month 16 of the project which is the end of April 2014. In the two month leading up to its completion and subsequent testing, the unique features of the technical application and structure of the test rig will be reviewed. This activity is required to facilitate the completion of the exploitation agreement and the preparations for any potential patent applications that are to be filed prior to further publication of the results of the project.
• In the period from August to October of 2014 during the development of the final exploitation agreement, a plan is to be drawn up to present on the final results at IFPAC in January 2015. There are 3 talks scheduled for presentation to industry and academia at IFPAC in Arlington between the 26th and 29th of January 2015. In addition Innopharmalabs will exhibit Eyecon™ and MultiEye™ interfaced on a single test rig at the IFPAC conference.
4.2 To Be Planned Activities
The following activities are to be planned with consortium agreement for the content and mechanisms for the communication and dissemination plan.
• Development of target groups and communities such as ISPE communities of practice, academic forums and networking tools.
• Communication session specifically targeted for regulatory authorities.
• Presentation of project results at Achema in June 2015, this is to be planned in partnership with Glatt GmbH. There will be a further trials process.
• Further process development activity to be complete with Glatt on their new blending process for continuous manufacturing platforms. This work to be completed in the lead up to Achema June 2015.
• Sigmoid process development and process enhancement activity to be planned for Q1 and Q2 2015.
• Paul Cruise of Innopharmalabs will commence a PHD in February of 2015, the subject being “Multi-spectral and imaging technologies for pharmaceutical manufacturing”. This work being conducted in conjunction with academia and the industry will further enforce the application of these technologies for the control and monitoring of pharmaceutical processes.
• Innopharmalabs undertakes to complete chemometric training in PLS and PCA model building and application in our objective to provide a complete solution as opposed to just a piece of technology. This is scheduled for the last week in January 2015.
The exploitation strategy needs to be coupled with a well thought out well defined business plan. The exploitation potential will only become apparent as the development process of the ParticlePro device progresses. At this point in the project timeline the preliminary plan for the exploitation of the ParticlePro technology will be adopted from the DOW dated 2012-09-10.
As can be seen from the above diagram in the PDF attached to this final report, the starting point will centre on a definition of the protected IPR, whereby a verifiable list of all intellectual property rights that have been applied for or registered (such as the application of a European patent) will be provided, as well as a description of all the results that may have commercial or industrial applications. At this stage, Table A5 of Part A outlines the envisaged project results. In addition, an explanation of the access rights to be exchanged between the participating SMEs for the use of knowledge will be outlined, along with the economic conditions established for the granting of such access rights.
The further development work and implied risks involved will also be detailed and based on the findings of Task 6.2: Industrial Trials and evaluation of results, whereby the resulting recommendations will have been documented in a report that will outline all the necessary actions that will need to be taken post-project, along with any potential risks. This report will be analysed by the partners and specific roles and responsibilities will be agreed among the participating SMEs. The RTDs will assist the SMEs in costing this future development work (and there will be no obligation whatsoever for this future development work to be subcontracted to the RTD performers). It is envisaged that the investment in further development work will be shared among the 5 SME participants in proportions to be agreed as the IPR unfolds, as they all hope to benefit from the exploitation of its results. If required, the RTDs will offer assistance and guidance in accessing additional sources of funding for this future development work.
Following on from the discussion with the patent attorney, it is essential that the unique technological applications and designs for the portable test-rig and proposed commercial designs be closely guarded and continually assessed. This is necessary to protect the IPR and the opportunities for patent filing for the technological application for in-line monitoring of physical and chemical characteristics.
In accordance with the DoW and the consortium agreement the end user SMEs will receive preferential rights for the installation of the Particle Pro system in their facilities and thus benefit from the results generated during the project. This will also provide them with the opportunity to assess the suitability of the system for their requirements and allow them to also avail of preferential pricing on the final commercial system.
The other SMEs, Innopharma and Rikola will be responsible for taking the project results to the wider market. Communication of the results and success of the project will be communicated through currently established consortiums and partnerships. The Particle Pro technology is being developed through the integration of currently existing technologies that are already subject to patent and/or trade mark or have patent submissions pending. As a result the channels to market already exist for this type of PAT technology. Innopharmalabs knowledge of the market and the key players and mechanisms for exploiting the potential of the device will be the primary source of commercial exploitation. Rikola will benefit from the results through the supply of system software or key system components and will also be provided with the opportunity to assemble in part or whole with external partners the commercially designed ParticlePro system.
The typical mechanisms for communicating the project success to the wider market will be to distribute project results in the form of white papers and leaflets. There are a number of options open to Innopharmalabs to complete this activity. Innopharmalabs have avenues through AAPS (American Association of Pharmaceutical Scientists), SSPC (Solid State Pharmaceutical Cluster), Engineering Research Centre – Structured Organic Particulate Systems, in conjunction with these outlets results will be communicated to key equipment manufacturers especially those involved in new process technology such as continuous wet and dry processes.
In order to maximise the market opportunities for the ParticlePro project the system will be offered in modular form. This is to avail of opportunities where existing Eyecon™ customers may want add the MultiEye NIR functionality to their existing capabilities. There will therefore be 3 version of system software.
a. Software for the operation of Eyecon as a stand-alone system
b. Software for the operation of MultiEye as a stand-alone system
c. Software for the operation of both systems through a single user interface.
A similar approach will be adopted with respect to hardware integration. The systems can again be supplied in modular fashion.
a. As two stand-alone pieces of process analytical technology
b. Partial integration of physical characterisation and chemical characterisation systems
c. Full integration of both the physical and chemical characterisation applications.
The ownership table and the illustrated strategy of exploitation are attached to the PDF for this final report.
In order to maximise the dissemination opportunities for the ParticlePro system as special demonstration rig has been developed and fabricated to demonstrate the system imaging and analysing moving particles. An image of this system in included in the attached PDF document.
In addition at the time of submission of this document additional changes have been requested to the exploitation agreement so deliverable 8.3 has yet to be submitted, however they are attached to this report for information purposes.
List of Websites:
www.particle-pro.eu
Contacts: SMEs/OTHER
Principal contact Ian Jones Innopharmalabs, jonesi@innopharmalabs.com
Rikola OY: raimo.rikola@rikola.fi
Manufacturas Serviplast: eromero@serviplast.com
Sigmoid Pharma: ivan.coulter@sigmoidpharma.com
Takeda Ireland: Brendan.Donohue@Takeda.com
RTD
Dublin Institute of Technology: pjcullen@dit.ie
IRIS: mpinilla@iris.cat
VTT: Pentti.karioja@vtt.fi
The ParticlePro project was devised and coordinated to develop a hybrid technology for the analysis in-line of both the physical and chemical properties of granulate in typical pharmaceutical applications and process platforms. The structure and size distribution of granulate and indeed spheres or beads is critical to the functionality of the finished solid dose product. Particle structure, API distribution, moisture content and particle or sphere size can all influence the therapeutic effect of pharmaceutical products. No single physical or chemical property will be wholly responsible for the lack of efficacy of a solid dosage form. It will be a combination of factors influenced by both the physical and chemical makeup of the formulation. To this end securing the knowledge to understand the process and the formulation is key to ensuring consistency and reproducibility in manufacture and continuity of supply. To address this much required need the ParticlePro consortium have strived to develop a hybrid device constructed through the integration of two background IP systems, the Eyecon particle characteriser and the MultiEye NIR spectrometer. the combination of these two systems provides the opportunity to secure both physical and chemical attributes from the same in-line sample in real time so that informed decisions can be made as to the actions to be taken during the processing steps.
the research and development activity was carried out be a combination of 3 RTDs, VTT in Oulu, Finland providing the background IP knowledge for both the physical and chemical characterise design and construction. DIT in Dublin Ireland, providing the resources to complete proof of concept studies in both a laboratory and an industrial capacity and IRIS in Barcelona, Spain to complete the final pre-competitive prototype design, build and integration.
The consortium consulted with both project and industry end users to ensure appropriate system specification and application identification. The consortium successfully designed built and tested the application of the technology in both laboratory and industrial applications and on a range of platforms including, spheronisation, fluid bed coating and granulation, continuous roller compaction and twin screw wet granulation platforms. The system proved technically capable of monitoring and tracking process changes in real-time on both the industrial and laboratory scale processes.
The Consortium cooperation was excellent through out the course of the project and the level of communication and interaction was significant in the final successful outcome of the project.
Exploitation and dissemination activities have been clearly defined and even at this early stage in the process of moving to a commercially viable system by mid 2015 there is already a significant level of interest from both pharmaceutical and non pharmaceutical entities in the results and the technical solution. These range from food and fertiliser applications within Europe, a major fine chemical application in the USA, to pharmaceutical applications within the European and Indian markets.
Project objectives were achieved on schedule and within the budget allocations of the project.
Project Context and Objectives:
The technological problem or need
In the face of the gravest economic times in living memory, Europe needs to position itself as an attractive manufacturing location; this is fundamental for job creation and growth. However, in order to help our SME sector to survive and grow, and indeed to anchor down multinationals and prevent them from migrating to cheaper manufacturing bases, Europe needs to brand itself as a region of innovation and outstanding product quality. The category of cheap manufacturing location belongs firmly to other regions in the world. Europe must stake a claim as the “region of innovation”. Undoubtedly, innovation could play a major role in retaining and strengthening Europe’s pharmaceutical industry.
70% of pharmaceutical drugs are consumed as powders in the form of tablets or capsules. 50 billion aspirin tablets alone are consumed worldwide each year. As tablets are the most common drug dosage form today, granulation, which allows primary powder particles to adhere and form granules, is one of the most important unit operations in drug manufacturing . Batch rejects that result from process problems can be higher than 20%, the root cause being a lack of process understanding and control. Batch rejects can be a major issue as some APIs can be worth as much as €1million / kg.
As products become increasingly complex, understanding pharmaceutical processing is growing more difficult. Regulatory bodies are encouraging the drug lifecycle concept which links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. The FDA guidance document, Process Validation: General Principles and Practices , promotes modern manufacturing principles, process improvement, innovation, and sound science.
Key to better understanding is knowledge, and access to real-time on-line measurements is fundamental. Indeed, the concept of “Process Analytical Technology” (PAT) is the new framework for better understanding in pharmaceutical processes of which granulation is a very big part. Central to PAT is improving final product quality by process design through knowledge of the fundamental scientific principles behind it, and continuous online control of a process.
Particles and granules play a key role in process efficacy and final product quality of pharmaceuticals. Particle physics governs process variables such as powder flow, blending, granulation, compression and coating. The identified key physical parameters include granule size/shape and the key chemical parameters include moisture content and ingredient identity (active versus excipient concentration). The size/shape and moisture variables can have a significant effect on final product behaviour including content uniformity, drug absorption rates and product robustness. Similarly, the ingredient distribution within granules and between granules has a critical effect on product acceptance and patience safety.
In the pharmaceutical industry, while granulation is frequently employed to obtain a particular blend quality as well as improving the flow and compression properties of the powder mixture, a more recent field of application is the use of such dry granules as independent forms of a drug, which release the active substances as uniformly as possible throughout a prolonged period (8-12 hours). These so-called retardant drug forms benefit the patient by having longer administration intervals and accordingly a reduced administration frequency when compared with conventional drug forms. As there is a mathematical relationship between the rate of active substance release and the surface/volume ratio of the granules, reliable data about the granulation process is of paramount importance.
A significant portion of pipeline products are intended for manufacture using granulation, roller compaction and milling manufacturing platforms. There is also a trend towards continuous manufacture of pharmaceutical products. In short, the development of a technology capable of monitoring physical and chemical parameters of a process in-line would significantly increase process understanding and control thereby assuring product quality, patient safety, and lean operational costs.
The current method of determining the end-point of pharmaceutical processes such as granulation is typically a combination of (1) off-line analysis of size and shape characteristics, (2) off-line analysis of moisture content and (3) end product analysis of active content uniformity. The size and shape characteristics are important as they can significantly impact on the compression process. The moisture content is important as it can impact on compression and product stability (negatively leading to hydration of the active ingredient). The active content uniformity is important to ensure that each patient receives the correct active dosage.
The development of one hybrid technology that is capable of assessing these four characteristics (granule size, shape, moisture content and ingredient distribution) in real time would significantly advance pharmaceutical manufacturing control leading to greater product quality and patient safety. In fact this would represent a global breakthrough with a technology, which could provide the physical and chemical nature of granules as they form within the process environment. The ability to identify the chemical signature of particles spatially will allow profiling of ingredient distribution and ultimately content uniformity. The output of this project will be an advance control strategy for end point determination of the highly variable process of pharmaceutical granulation. Such innovative technologies are in line with the recently published FDA guideline on process validation where the use of process controlling technologies to support the continued verification of manufacturing process is recommended. Miniaturization of novel spectrograph approaches, new calibration strategies and the rapid development of computational processing speeds have facilitated the feasibility of such advanced technologies.
One important reason why many companies shy away from developing NIR-based sensors is the need for multivariate calibration. The absorbance bands of NIR spectra are small and typically heavily overlapped. Quantitative analysis therefore requires multivariate data analysis, i.e. involves absorbance values at multiple wavelengths. The so-called science-based method (SBC) has recently provided a solution to the calibration problem. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. In SBC, with response defined a-priori by spectroscopic expertise and application knowledge, spectroscopy is no longer a “secondary” method that needs calibration against a “primary” reference method. Instead, it becomes a “primary” method, firmly rooted in physics and chemistry. Significant practical benefits become available from this change whenever a responsible application scientist is able to define the shape of the response spectrum “manually”. One great advantage is that specificity of response can be proven to regulatory agencies and concerned end-users, which in today’s increasingly regulated and controlled environment this is a major competitive benefit for reassuring consumers and the market and heightening confidence. The calibration process itself becomes fully transparent and “communicate-able,” or in the words of the pharmaceutical industry, science-based. This fact in itself creates a multitude of opportunities for adapting calibrations to given measurement situations, always keeping the result under user control.
To this end, the proposed PARTICLE-PRO project aims to develop a technology that is a hybrid of established imaging platforms. Physical characterization of size and shape will be determined with the EYECON technology (that provides 3D images of particles) owned by INNOPHARMA. To this technology, NIR chemical measurement technologies, based upon novel miniaturized spectrograph advances, will be integrated, to provide chemical and moisture information of the sample. This combined approach will be carried out in real-time to provide on-line granule characterization.
The overall objective of this project will centre on the development of a hybrid device based on collimated 3D imaging of particles’ physical parameters (EYECON technology) and novel miniaturized NIR multipoint or quasi chemical imaging technologies that provide spatial measurements of moisture and ingredient identity from the forming granule. The R&D effort will centre on engineering design, software/algorithm design, user interface design; and integration and validation within pharmaceutical manufacturing equipment.
In this project a device, which can measure physical and chemical properties of pharmaceutical granules, will be designed, realized and tested. Technology challenges relate to building a cost efficient, robust, user friendly device which produces multi point or quasi imaging of chemical information (such as moisture distribution, or ingredient concentration) coupled with 3D physical information (particle size and shape) by one single instrument. Spectral information will be generated with a multichannel detector using Fibre-optic coupled multi-point Fabry-Perot technology. With this technology quasi-images or measure in several spatial points by fibre-optics can be obtained. This technology is available to the consortium and has successfully been developed into other devices such as unmanned remote sensing aircraft. Patented calibration methods specially designed for in-line analysers will also be employed. Physical information will be produced with camera and LED illumination based device (EYECON). Novel 3D algorithms are utilized in calculation of physical information. The technology platform will be selected in tune with industry requirements, as this is a marker-driven approach.
In order to realise this, the scientific and technological objectives, and corresponding Performance Indicators, that will be fulfilled during the PARTICLE-PRO project are provided below. Every effort has been made to ensure that these objectives are S.M.A.R.T. (Specific, Measurable, Achievable, Realistic and Timely) and clearly linked to the WPs and linked to deliverables and milestones in Part A:
1. To implement a ‘bottom-up’ approach whereby the needs and specifications of companies from the pharmaceutical industry will be consulted, as will regulatory aspects, the findings from which will be used to guide the definition of the specifications for the PARTICLE-PRO system. (WP1). Performance Indicator: By M3 a public report on the findings of the bottom-up research will be delivered (Deliverable 1.1) and by M4 a confidential report outlining the industrial specifications for the PARTICLE-PRO system (Deliverable 1.2) will be available for project use in order to guide the evolution of the R&D work to ensure that the PARTICLE-PRO system meets with market needs. At this stage Milestone 1 will have been achieved.
2. To build a laboratory scale test rig to integrating physical imaging and multipoint NIR chemical measurement technology for the physical and chemical characterization of particles (WP2). Performance Indicator: By M6, a PARTICLE-PRO test rig will be designed, built and integrated. The device enables to gather physical and chemical information to be obtained with one single setup. Based on the user requirements and performance criteria a number of approaches to wavelength selection will be evaluated for the multipoint quasi-imaging technology (Fig. 1). Finally, by M11, the scale-up parameters for developing a precompetitive PARTICLE-PRO prototype for industrial-scale granulation monitoring purposes will have been defined (Deliverable 2.4). Milestones 2 and 4 will have been achieved.
- Setting up of phys/NIR chemical imaging test rig: VTT will design and build the laboratory test rig. This test rig will be used for laboratory trials in which the physical and chemical information will be measured with a single unit. The rig will allow the best parameters for the combination of the technologies into the PARTICLE-PRO system to be defined and will therefore contain some of the main parts as the final system. Also the design phase will involve a series of subtasks: software design, design of light sources, control electronics, optics and mechanics and selection of camera. To maximise the usability of the system in the trials, the wavelength scale and spatial resolution will be made as flexible as possible.
- Innovative patented science based calibration methods (SBC) will be used in development and testing of NIR chemical test rig and prototype. These calibration methods have specially been developed for in-line instruments, where large sets of calibration samples needed for PLS or other calibration methods are required are hard to get. In SBC the need for lab-reference values is virtually eliminated from calibration because the calibration no longer needs to “learn” what the signal is. There is also no need to artificially upset an industrial process in order to collect in-line calibration standards that vary over a certain “range.” Rather, a smoothly running process with a minimum of analytic variation is sufficient for SBC. The science based calibration is also highly selective since it is based on knowing the response spectra of measured compounds and specificity of response can be proven to regulatory agencies and concerned end-users.
3. To evaluate the effectiveness of the combination of physical imaging and NIR chemical measurements for the characterization of the physical and chemical properties of particles against reference methods and to define the limits of detection of the approach (WP3). Performance Indicators: By M3, a protocol for the analysis of varying granulate structures with various excipient granulates, active granulates and the blended granulates will be defined (Deliverable 3.1) and by M11 a report on the efficacy of using a bench-top test-rig to monitor granulate structure (particle size distribution, sphericity) and chemistry (moisture content) will be delivered (Deliverable 3.2). The limits of detection for the approach will be defined via correlations with reference sieve analysis and NIR based methods. Micro imaging will be employed to visually detail the physical structure of the granule (Deliverable 3.3) Milestones 3 and 5 will have been reached. The prototype will be evaluated in laboratory scale granulators.
- Chemical measurements of granule ingredients / moisture content on typical granulation processes will be made. The sensitivity, SNR, selectivity and other key parameters will be tested.
- Laboratory calibration models will be optimised based on test trials. The performance of the test rig will identify parameters used to design the pre-competitive prototype.
4. To draw up the designs of the precompetitive particle characterization hybrid physical imaging and NIR- chemical measurement system in keeping with the industry specifications defined in WP1, as well as the laboratory parameters defined in WP2 and WP3 and to assemble the system hardware (WP4). Performance Indicator: By M14, the designs of the PARTICLE-PRO system will be complete (Deliverable 4.1). Milestone 7 will be complete.
During this design stage, focus will centre on ensuring that the PARTICLE-PRO system is capable of offering the following features:
- The high spectral sensitivity is obtained either using fixed wavelength band pass filters or by scanning with a tuneable Fabry-Perot filter. Method robustness and Reliability- The system will be based upon knowledge of bench top systems developed by each of the research groups involved which should provide a strong starting point for the envisaged prototype.
- Adheres to industry standards, and meets with regulations and approvals- The system is based upon imaging and light and therefore will be nonintrusive in nature.
- Consideration of integration challenges: installing the technology inside the granulator window and outside the granulator window.
- Versatility- the proposed system is partly based upon IR spectroscopy, a universal tool for chemical identification. The system will be trained against a library of IR spectra for excipients and actives alike. Consequently the system will be versatile for identification of all pharmaceutical ingredients.
- Rapid- detection time depends on spatial and spectral resolution required, escalating with increasing resolution. Improvements in recent years in precision and speed in measurement have arisen as a result of increased computer processing speeds, improved cameras, faster hardware, more accurate and efficient algorithms. Innopharmalabs will employ various data processing strategies to facilitate real time processing.
- Easy to use and interpret- The envisaged system will be calibrated for the selected excipients and actives employed during manufacture. It will map the granulate in terms of identified ingredients and provide a quantification of each ingredient. The approach will not require the current level of training required by validation personnel. Moisture content will be reported as a percentage.
- Cost effective- It is envisaged that the market price of a unit will be in the region of €100,000, which will make the technology highly competitive in the marketplace (Malvern particle characteriser 150K, Sisu-Chem NIR Chemical Imager 150K). Advances in the production of low cost array detectors have meant faster data collection and cheaper Chemical measurement systems . Moreover, predictions that the market for NIR chemical instrumentation will increase in the coming years , especially in the pharmaceutical industry due to the Food and Drug Administration’s Process Analytical Technology initiative are expected to drive down the price of imaging spectrometers, opening their way into routine pharmaceutical analysis. Moreover, the development of an average cost imager by combining microelectro-mechanical systems (electrically programmable diffraction gratings) with spectrometers would obviate the need for costly array detectors3.
5. To develop the general software for the operation of the PARTICLE-PRO system, including the synchronized control of the different subsystems, the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP3, in order to characterize the physical and chemical properties of the particles under analysis and readily display the results via an ergonomic User Interface (WP5). Performance Indicator: By M15 PARTICLE-PRO Control Software (Deliverable 5.1) will be ready and the PARTICLE-PRO User Interface and database (Deliverable 5.2) will be delivered. Milestone 8 will be complete.
6. To integrate the system hardware, software and User Interface in order to provide a pre-competitive prototype that can be validated in industry and to carry out pre-validation tests with the system to ensure its proper functioning before shipping to industry test-sites. (WP5). Performance Indicator: By M16 the prototype will be fully integrated (Deliverable 5.3) and Milestone 9 will have been achieved.
7. To test and evaluate the PARTICLE-PRO system in commercial pharmaceutical manufacturing sites in order to assess the efficacy of the developed system to effectively characterize the physical and chemical properties of particles during processing in a production environment. Design issues arising from the industrial tests will be fed back into WP4 (WP6). Performance Indicator: Between M18-M24, the prototype will be tested and validated at SIGMOID or TAKEDA in Ireland and SERVIPLAST in Spain. By M17, a comprehensive installation and user manual will be edited (Deliverable 4.1) and by M24 a report on the industrial trials will be delivered (Deliverable 4.2). This will contribute to the fulfilment of Milestones 10.
8. To carry out optimisation work on the prototype based on feedback from the field trails, and to carefully outline scaling-up rules and development work for full production (WP5). Performance Indicator: By M24, a report on the optimisation work carried out on the basis of the results of the industrial trials will be delivered; including recommendations for future scale-up (Deliverable 5.4) will be delivered to the participating SMEs. Milestone 12 of the project will have been fully accomplished.
9. To facilitate the uptake of the PARTICLE-PRO results by the participating SMEs as well as a wider audience by carrying out a comprehensive series of knowledge transfer and training activities to on the one hand show the validity for the system for reliable, in-line particle characterisation in commercial pharmaceutical production facilities, and on the other hand to capacitate end-users about its usability and to outline its benefits for facilitating quality control of the granulation process, reducing plant down-time, reducing costs and trained operator intervention, as well as increasing the reliability and safety of the final product, etc. (WP7). Performance Indicator: Between M18-M24 it is envisaged that at least 3 knowledge transfer and training sessions will be organised at the facilities where the prototypes are being installed and validated in WP6. A report on these knowledge transfer and training activities and materials used, including evaluations and conclusions will be drawn up (Deliverable 7.2) and Milestone 11 will have been met.
Project Results:
Research and technological development activities will form the core of this project, and will for the most part be carried out by the 3 RTD performers, VTT, DTI and IRIS. The RTD Performers will be guided and supported by the participating SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA) to ensure that the research performed complies with their expectations. To this end, the participating SMEs will provide inputs and contributions to the research activities when possible and in keeping with their ability and expertise. The following Work Packages fall within the scope of research and technological development activities:
Industrial Specifications (WP1) –
Objectives
• To ensure a clear understanding of the technological needs of European pharmaceutical manufacturers in terms of granulation control.
• To review the existing state-of-the-art and patents, to ensure that the R&D work is up to date on its starting point (in view of the time lapse between project preparation and project implementation)
• To a review and analysis of regulatory guidelines
• To use the results of the research to drive the definition of the industrial specifications for the PARTICLE-PRO technology
This WP was led by INNOPHARMA, and they will be heavily supported by the SME participant, SIGMOID, as well as assisted by IRIS, VTT and DIT. All the SMEs and OTHER participants (SERVIPLAST, RIKOLA, and TAKEDA) will collaborate actively in order to ensure that they communicate their industrial needs in order to drive the future R&D effort.
Task 1.1: In-depth industry consultations
Subtask 1.1.1- Questionnaire based European-wide survey
A comprehensive questionnaire will be prepared by INNOPHAMA with assistance from IRIS, and it will be validated among the consortium. It will then be set up on an on-line surveying tool (SURVEY-MONKEY) and electronically distributed to a wide number of European pharmaceutical manufacturers, etc. including Pfizer, Genzyme, Alkermes and GSK. The following information, among others, will be gathered by the questionnaires, analysed and conclusions will be drawn on the results:
• Existing granulation controlling methods;
• Limitations and short-fallings of these methods and technologies;
• Existing knowledge and capability levels of operators;
• Granule physical and chemical properties during and after granulation
• Price sensitivity;
• Any existing and upcoming norms, standards and legislation pertaining to Process control and the quality of the final product;
• Quality aspirations/perceptions of consumers in terms of quality and safety.
A minimum threshold of completed questionnaires will be gathered and the data will then be evaluated. The results and conclusions will be included in a dedicated section of the Report on PARTICLE-PRO Market Requirements (Deliverable 1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications). INNOPHARMA will lead this work together with IRIS, and all other partners will participate, especially the other participating SMEs and OTHER (SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA), each bringing their respective industrial and market expertise and knowledge, as well as mobilising their clients and networks to collaborate.
Subtask 1.1.2- On-site visits and in-depth consultations
A series of consultation sessions or in-depth interviews will be conducted with a selected group of pharmaceutical manufacturers, including Pfizer, Genzyme, Alkermes and GSK. This will also involve carrying out a series of on-site visits to manufacturing sites so that the RTD performers can become familiar with the industrial setting as early on in the project as possible, view the granulation equipment, and discuss existing controlling techniques with site technicians. At least 6 on-site visits will be made. In order to ensure that all partners benefit in as much as possible from potential visits, during the KO meeting that will be held in Ireland, a visit will be made to the facilities of SIGMOID or TAKEDA. The results and conclusions arising from these on-site visits and interviews will also be included in Deliverable 1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications. IRIS will lead this subtask, and VTT and DIT will also carry out in-depth consultations and on-site visits. To enable additional field research to be carried out, as well as to gain an insight into the latest technological developments and have the opportunity to interact with large numbers of pharmaceutical manufacturers, equipment manufacturers and other stakeholders, the partners will attend an international exhibition or trade fair, such as EXPOPHARM- International Pharmaceuticals Fair (Germany), POWTECH (Germany every 18 months), FOODPHARMATECH- Denmark (every 2 years), SIPEC Pharmaceutical Trade Show (France), etc., which they will aim to coincide with the M3 meeting if this is possible.
Subtask 1.1.3- Review and analysis of regulatory guidelines
During this task a review of all European and national regulatory guidelines will be carried out in order to ensure that the PARTICLE-PRO system adheres to them. To this end the results of this task will feed into task 1.3 below. INNOPHARMA will lead this subtask with the assistance of SIGMOID and IRIS, as well as the other SMEs.
Task 1.2: In-depth review of the Literature
A thorough review of the literature and patents (especially in the field of granulation) will be carried out in order to ensure that all relevant research in the area is identified. This task will serve to complement and update the State-of-the-Art section of this project, Section B.1.2. This is an important task in view of the timeline that will have passed between the review carried out during project preparation and project implementation. In addition, the results of this task will feed into Task 8.1 Knowledge Management and IPR protection (and in particular Subtask 8.1.1-Defining the Foreground IPR) whereby the novelty of the proposed approach will need to be validated. This task will be led by DIT, who will be assisted by IRIS and VTT. DIT will prepare a report on the review of the literature to be included in D1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications, forming at the same time the basis for the continuous technology watch during the project.
Task 1.3: Definition of the PARTICLE-PRO specifications
Partners will use the results of previous tasks in order to define the overall desired specifications and performance characteristics of the PARTICLE-PRO technology, in keeping with industrial needs, constraints, considerations, etc. A definition of the overall PARTICLE-PRO architecture will be defined and will be used as a blueprint for guiding the technical work to be carried out during the remainder of the project. The results of this task will be documented D1.1- Report on Market Requirements and PARTICLE-PRO Industrial Specifications. IRIS will lead this task and will be assisted heavily by VTT and DIT. They will consult extensively with the SMEs and OTHER participants (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA).
In the execution of the activities to accurate specify and determine the requirements for the ParticlePro system several approaches were taken. A series of face to face industry consultations conducted through Innopharmalabs network of pharmaceutical contacts. In addition an industry wide questionnaire completed by some of the leading Global pharmaceutical companies.
There was also an in-depth literature review completed as well as an assessment of the current market leading technologies for both chemical and physical analysis.
The combined output was the ability to clearly document the industry requirements for the hybrid ParticlePro technology.
Laboratory bench top building and trials (WP2) –
Objectives
• To design and build a laboratory test rig of the hybrid physical imaging and NIR chemical measurement set up.
• To design basic software to control the measurements with the test rig.
• To carry out the necessary tests to assess the functionality of the developed system.
VTT led this WP. They were supported in Tasks 2.1 and 2.3 by DIT and IRIS. RIKOLA will also support VTT in task 2.1. The rest of the SMEs (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will be involved to follow and steer the research. IRIS will follow this WP to prepare for work in WP4.
Task 2.1 Setting up NIR-chemical measurement and physical measurement test rig
In order to assess the functionality of the NIR chemical measurements together with the physical measurements, it is essential to build a test rig to study the full potential of NIR chemical measurement. The task will make a complete proof-of-concept, and determine how the prototype must be built in order to meet the requirements. This task will be carried out by VTT and they will be assisted by DIT, IRIS and RIKOLA.
Subtask 2.1.1 Building of the test rig
The test unit will be a bench-top device, will evaluate the additional filter-wheel and fibre-optics needed to add to the tuneable Fabry-Perot interferometer for multipoint quasi-imaging technology as well as its integration with the EYECON technology. Furthermore, the measurement speed in laboratory trials is not an important factor, because its aim is to determine what the speed conditions should be for the prototype. Therefore the shortage in signal – low signal to noise ratio – can be compensated with a longer measurement time.
Subtask 2.1.2 Algorithm development
Calibration models using science based i.e. matched filter calibration as well as algorithms for measurement of physical properties will be created. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. The solution is a spectrometric form of matched filter, i.e. it provides the globally optimum measurement accuracy. Simultaneously, it reduces the cost and time required for calibration drastically.
An important effort will be needed in the optical design of the camera optics. Also, to maximise the usability of the system in the trials, the wavelength range and spatial and wavelength resolution will be made as large as possible. This work will lead to a bench-top unit by M6 and will be reported as part of Deliverable 2.1- Report on the test-rig and the performance and stability tests with Phys/Chem test rig. This subtask will be carried out by VTT, with assistance from RIKOLA, IRIS and DIT.
Task 2.2 Performance tests and trials for quantification of physical and chemical properties
The outline for the initial testing is planned to include experiments to study the technology limitations for a thorough proof of concept. Based on these considerations, the following tests will be included in the proof-of-concept testing procedure of this work:
• Signal-to-noise ratio in optimum conditions with Spectral 99% target
• Linearity of signal axis in spectral images
• Spatial image resolution
• Spectral resolution and stability
• Demonstration of a whole spectral range NIR chemical measurement to demonstrate measurement time when typical measurement parameters are used
Once this initial testing phase has been successfully completed, the system will be tested during development for performance criteria against various concentrations of lactose residues on a smooth stainless steel surface. The impact of hardware selection and system limitations will be evaluated against the limit of detection, in order to determine the needs for the prototype. The required spatial and spectral resolution of an in-line system will be identified. Findings from the bench scale tests (tasks 3.2 and 3.3) will be incorporated over this development stage.
The results obtained during the testing process will be reported and summarized in Deliverables 2.1 (Report on the test-rig and the performance and stability tests with Phys/Chem test rig) and 2.2 (Phys/Chem test rig trials for evaluation of active and excipient granules).
This task will be carried out by VTT.
Task 2.3 Performance analysis and specifications for in-line system
Based on the information from performance and stability tests and application tests the specifications for the on-line instrument will be drawn up by VTT, with assistance from IRIS and DIT, together with a set of guidelines for the design. This information will be reported in deliverable 2.3 (Scale-up parameters for developing precompetitive prototype for industrial-scale in-line granulation monitoring). The SMEs and OTHER participants (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA, and TAKEDA), will be involved to review the results and to provide input to the specifications in keeping with the industry and market knowledge, as well as in tune with their expectations for the on-line system. In work package 2 the documented requirements from work package 1.
In the execution of the activities associated with work package 2 a laboratory test rig in line with the specifications outlined in work package 1 was built. This was built as two subcomponents a particle characteriser with the increased specification Basler ACE camera and Tamron lens configuration. The system was designed and built to accommodate the integration into the hardware of the fibre optic probe requirements for the Multipoint NIR system. In addition the system was fitted with a manual focus adjustment with movements of less than 0.1mm to allow for the accurate calculation and determination of the focal capability of the system. The system incorporated the LED based illumination solution as exists in the current Eyecon device. The test rig consisted of several mounting options and configurations to allow for the performance testing against optical standards and also with static and dynamic samples.
In addition to the physical imaging test rig a multipoint NIR test rig was built. The system was built with the ability to simultaneously process spectral data from four independent channels. The system capability and performance was comprehensively tested and evaluated, parameters such as wavelength calibration, wavelength verification, dark noise, white noise, channel cross talk, signal to noise ratio, signal stability, white and dark reference.
The system performance figures demonstrate the NIR multichannel systems capability for accurate in line measurement of chemical parameters.
Laboratory testing of the system for physical and chemical analysis of granules (WP3) –
Objectives:
• To produce and characterise granules of defined physical and chemical properties.
• To test the efficacy of the system to measure the physical and chemical parameters of granules under static bench top conditions
• To test the system under various excipient and active blends and moisture contents
• To test the approach during laboratory scale granulation processes
• To define the limits of detection for NIR chemical measurements
This task will develop a protocol for the analysis of varying granulate structures. Various excipient granulates, active granulates and the blended granulates will be manufactured and analysed under bench-top conditions with the laboratory test rig. The efficacy of the approach to cope with granulate structure (particle size distribution, sphericity) and chemistry (moisture content). Results will be correlated against reference sieve analysis and NIR based methods. Micro imaging will be employed to visually detail the physical structure of the granule. The prototype will be evaluated in laboratory scale granulators.
As was discussed, these work packages are highly inter-related. WP2 and WP3 will run in parallel and the work in each will progress and evolve in tandem. The outputs of WP2 will feed into WP4 and the results of WP3 will feed into WP5, signifying that both WP2 and WP3 need to be complete by M11-M10 so as not to create a bottle-neck in the progression of the work plan. As WP2 and WP3 will be implemented by different research teams, it is highly feasible that they can be implemented in parallel, and it is indeed necessary that they do so.
For the purposes of the RP2 (final) report, only those activities associated with the finalising of the report for deliverable D3.3 ”ability to obtain particle information from laboratory scale granulators” will be considered as all other aspects of WP3 have been reported in RP1 interim report.
Task 3.4 PARTICLE-PRO testing in laboratory scale granulators
Performance studies will be carried out using the prototype to monitor granule characteristics during granulation at laboratory and pilot plant scale. Small scale high shear, fluidised bed and extruder granulators will be employed to test the system’s performance during granulation. Variable operational conditions such as air velocity, impeller speed, extruder torque/speed will be employed to test the system’s response to step changes in the process. Results will be correlated against reference off-line or on-line methods where available. Performance criteria including limits of detection, processing speeds, response times, and volumetric analysis will be reported. The ability of the technology to determine granulation end point, in terms of size/shape, moisture and ingredient distributions will be provided for laboratory scale systems. This WP will result in defining the limits of operation for the laboratory prototype which will be summarised in Deliverable 3.3-Ability to obtain particle information from laboratory scale granulators. This task will be carried out by DIT with assistance from the end-users SMEs and OTHER (SIGMOID, SERVIPLAST and TAKEDA). INNOPHARMA will also assist with their knowledge of current measurement techniques. RIKOLA will also follow progress in order to absorb the knowledge.
In the execution of the activities associated with the proof of concept testing, DIT created test rigs and the environment to test the applications for determination of key physical and chemical attributes.
Systematic testing was conducted on both systems with respect to dynamic and static conditions to assess the system’s ability to determine discrete changes in physical or chemical properties of typical granulates and spheres.
All test results were compared against current industry norms and certified standards to ensure the accuracy of the data being generated.
A humidity chamber was created and laser based loss on drying techniques employed to assess and determine the system capability to predict changes in moisture level and further assessment to determine the accuracy and sensitivity of the system to moisture changes. This testing proved quite successful and the modelling process was transferrable to the laboratory and commercial scale granulation processes.
In addition to the physical imaging systems functional capability and sensitivity to particle shape and size a design of experiment also provide evidence that for certain product presentations such as spheronisation the NIR system was also sensitive to changes in the particle size.
Although not part of the system specification experiments were also designed to determine if an algorithm could be developed to provide information with respect to surface finish. This would be especially relevant to Sigmoid Pharma one of the consortium end user SMEs as in their spheronisation process surface finish can have a significant influence on the performance of the therapeutic capability of their product. The experiment design clearly indicates that there is the capability to provide qualitative information with respect to the surface properties of the spheres. While this requires further work and the algorithms have not been embedded in the base ParticlePro software, the design of experiment proved that the concept was viable.
In other areas the ability of the NIR application to track more than one parameter was also challenged. This was achieved through the application of principle component analysis and modelling software to track changes in moisture content while simultaneously tracking material addition to a blend application in a fluidised chamber. Again results of this experiment were quite conclusive in demonstrating multiple marker monitoring capability.
The conditions challenged and determined in the laboratory bench top based experiments also translated successfully to the dynamic laboratory scale granulation applications and later to the industrial scale evaluation trials.
Design and Building of the PARTICLE-PRO system (WP4)-
Objectives:
• To design, build and calibrate the PARTICLE-PRO system, in keeping with the results and parameters from WP2 and WP3 and taking into account the requirements defined by end-users of the system in WP1. It is envisaged that as many commercially available components as possible will be used in order to assemble the precompetitive prototype.
• To design the control interfaces and basic process controls for the PARTICLE-PRO subsystems.
• To carry out the necessary tests to assess the functionality of the developed subsystems.
During this WP the different subsystems of the pre-industrial prototype of the PARTICLE-PRO hardware for the pre-competitive prototype will be designed, built and calibrated in keeping with the parameters defined in WP2 for the industrial scale-up and taking into account the requirements defined by end-users of the system in WP1. It is envisaged that as many commercially available components as possible will be used in order to assemble the precompetitive prototype The control interfaces and basic software controls will also be designed and integrated into the PARTICLE-PRO subsystems. All the necessary tests to assess the functionality of the developed subsystem will be carried out.
Task 4.1: Industrial prototype design
In keeping with the parameters defined from the laboratory work carried out by VTT in WP2, a detailed concept design (block diagram) of the PARTICLE-PRO system and its subsystems will first of all be designed. The optical design will be made according to the established specifications such as resolution in wavelength and size, field of view and focusing requirements of the system. The light sources and electronics for the control, operation and data acquisition of the sensor array will be defined in terms of the sensitivity and acquisition requirements established during WP2 and WP3.
Following these designs, the detailed mechanical drawings will be carried out. These drawings will include information about materials and interconnections between the different components and they will serve as a detailed blueprint and guide for the integration of all the components of the PARTICLE-PRO system.
The different components (such as illumination source, imaging optic, spectral encoder for wavelength selection, detector and acquisition system-usually a frame-grabber board interfaced with a PC) that will be required by the proposed PARTICLE-PRO system for carrying out the selected measurements will then be selected and purchased from among, as much as practically possible, commercially available options.
During this design stage, in order to ensure the exploitability and future commercialisation of the prototype, standardisation procedures and manufacturing costs will be given special attention. In addition, the flexibility and ease of integration of the system will be attributed paramount importance and will be kept at the forefront of research efforts, in order to ensure the future widespread uptake of PARTICLE-PRO (and its family of products) by SMEs from across the European pharmaceutical industry.
This task will be carried out by IRIS in consultation with VTT, especially in view of the novel spectrograph background IPR held by VTT, which is a fundamental driver for the development of the proposed system. The participating SMEs (INNOPHARMA, SIGMOID, SERVIPLAST, and RIKOLA) will all be involved to contribute their guidance and knowledge to the design and to ensure it meets with their expectations.
Deliverable 4.1-Report describing the building of the PARTICLE-PRO prototype, will include the mechanical design in SolidWorks format, as well as the electronic and optical designs and the list of components used in its fabrication.
Task 4.2: Building of the PARTICLE-PRO hardware
During this task, the PARTICLE-PRO prototype will be built using the detailed designs prepared in Task 4.1. The rest of the necessary components and equipment that cannot be used from the test-rig (camera, data display, etc.) will be selected and purchased. Preliminary functionality testing will be performed on the different sub-systems that make up the prototype, in order to check that they are operating correctly. Then they will be integrated together.
The building of the prototype will be reported in Deliverable 4.1-Report describing the building of the PARTICLE-PRO prototype as well as the results of its laboratory evaluation. This task will be carried out by IRIS with input from INNOPHARMA and RIKOLA.
Task 4.3: Process control system
During this task, the controls for the operation and synchronization of the different subsystems will be designed and developed, together with a basic user interface with the basic commands for the operation of the different parts of the prototype, to enable the functionality tests to be performed. IRIS will carry out this task with assistance from INNOPHARMA. It is important to highlight that this task will focus on the electronics of the system, as opposed to the system software that will be developed in WP5.
A User Manual of the PARTICLE-PRO system will be drafted in Deliverable 4.2: PARTICLE-PRO User Manual.
Deliverables
Deliverable 4.1: Report describing the building of the PARTICLE-PRO prototype (including designs) (M16): Documentation of work performed to design and build the prototype and the results of its laboratory evaluation. Full designs of the precompetitive prototype system, including mechanical design in SolidWorks format, electronic and optical designs and list of components used in its fabrication.
Deliverable 4.2: PARTICLE-PRO User Manual (M16): Written document that provides a basic step-by-step guide to the installation of the prototype, including the most important safety issues.
During the execution of the activities of WP4 the ParticlePro system was designed and built in accordance with the specifications defined in WP1 and also from the learnings of Innopharmalabs experiences with respect to particle sizing and NIR applications. The ParticlePro device is an integration of two individual systems. Particle sizing is achieved using a commercially available particle sizing system called Eyecon™ and a NIR multipoint system which at the point of commencement of the ParticlePro project was at TG2 in the product lifecycle. TG2 in the product development lifecycle represents precompetitive prototype stage where laboratory based testing and system viability has been completed, this system is called MultiEye™.
In the design of the particle sizing system it was decided to incorporate an updated camera and lens system to try to improve on the current capabilities of the Eyecon™ system and also to enhance the analytical capabilities of the sizing algorithm.
In the hardware design of the ParticlePro device modularity was also a consideration, this was to allow for the application to be fully or partially integrated. This level of flexibility is necessary to cover a greater range of pharmaceutical or non-pharmaceutical applications. For example in continuous granulation processes it is essential that certain chemical aspects of the process are measured at different points of the process, this would not be achievable with a fully integrated system. Also for roller compaction applications for granulation generation, the physical and chemical aspects are measured at different points in the process.
The hardware design took these requirements in to consideration building fibre connections and collimators in to the Particle sizer body to allow for physical and chemical evaluation at the same point in the process, with the flexibility of being able to disconnect the fibres to connect to alternative parts of the process.
In conjunction with the specification and building of the ParticlePro system a user manual was generated to assist with the physical set up, explain the model interfaces and also fully describe the integrated user interface. This manual was developed and updated accordingly, based on changes required following the different stages of system testing and assessment.
Software Development, System Integration and Optimisation (WP5) –
Objectives:
• To develop the general software for the operation of the PARTICLE-PRO system, including the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP2 and WP3.
• To design and develop the user application according to the requirements established during WP1.
• To integrate the system hardware, software and User Interface
The building of the system software and the User Interface represents an important component of the PARTICLE-PRO architecture. The objective of this work package is to develop the general software for the operation of the PARTICLE-PRO system, including the synchronized control of the different subsystems, the user application and the analytical software that will process the data obtained by the system. This analytical software will use the algorithms and spectral databases developed during WP3. The User Interface will be developed according to the requirements established during WP1. If a network configuration is desired, a specific web-based application (that will use “open-source” solutions, such as php programming language and MySQL database) will be designed and implemented to generate the results. The hardware and software will then be integrated together and pre-validation trials will be carried out to ensure the integrated system functions properly prior to shipping to industrial test sites. In parallel with the Industrial Validation work that will be carried out at industrial sites during WP6, the RTDs will carry out necessary optimisation work of the prototype in keeping with the results of performance and operational testing, and to enable the necessary development work that will be required in order to arrive at a commercial system will be recommended.
WP4 and WP5 will run in parallel to ensure that the results from both are ready for integration together by M15. As WP4 and WP5 will be implemented by different research teams, it is highly feasible that they can be implemented in parallel, and it is indeed necessary that they do so.
A comprehensive series of demonstration activities will also be carried out in order to prove the viability of the new PARTICLE-PRO technology for its future industrial application and commercialisation.
Task 5.1: Software Development (IRIS)
In keeping with the general input specifications defined in WP1, the software for the full system will be designed in order to enable, as much as possible, the running of the prototype without the need for the intervention of an operator, as well as to enable the chemical identification of the contaminants from the measured spectra. It will integrate the different software packages for each subsystem, acquire the data, process the information with the calibration algorithms and libraries developed in WP2 and WP3, and determine the presence of contaminants. This software will be a combination of the EYECON software with the new developed SBC algorithms for the moisture and chemical characterisation measurements.
The software developed will be documented as part of Deliverable 5.1. PARTICLE-PRO Control Software, User Interface and database.
IRIS will lead this task with assistance from INNOPHARMA, VTT and DIT.
Task 5.2: User Interface Development (IRIS)
During this task, the user interface will be developed in accordance with the requirements established in WP1, so that it can be used in a wide variety of end user groups, and depending on whether the system is to be used on its own or integrated in a network configuration.
The user interface will also be designed so the results are displayed and stored in the most convenient manner, to ensure easy and clear understanding by the user.
Deliverable 5.1. PARTICLE-PRO Control Software, User Interface and database, will summarise the characteristics of the UI and will also include the code developed.
The control software will then be implemented and integrated into the PARTICLE-PRO prototype. IRIS will carry out this task in consultation with all the SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA).
Task 5.3 Integration of Software and UI with Hardware technology (IRIS)
This task will consist of fine-tuning the assembly of the various sub-systems, (pre-assembled during WP4) and on the integration of the subsystems with their control packages in the developed System software and user interface.
Extensive tests will then be carried out to validate the hardware and software compatibility, as well as to fine-tune the control system. As a consequence, software debugging will be done and robustness of the electronics as well as the protection of the whole PARTICLE-PRO system will be done. When housings, plug-ins or other required parts will be needed, they will be designed and manufactured under this task. IRIS will carry out this task with assistance from VTT, Innopharmalabs, and RIKOLA.
Task 5.4 Calibration and functionality testing of the PARTICLE-PRO prototype (DIT)
During this task the PARTICLE-PRO prototype will be calibrated. When this is done, extensive pre-validation functional tests will be performed in order to check that the prototype works according to specifications. The outcome will be a pre-competitive prototype ready for industrial validation. All the SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will follow this work.
Once this is done, the PARTICLE-PRO system will be ready for industrial validation.
Task 5.5: System Optimisation (IRIS)
During this task, the RTDs will follow closely the performance and operational aspects of the pre-competitive prototype during set up and testing in Tasks 6.1 and Task 6.2 respectively. During this task, further modifications and tweaking will be made to the prototype in keeping with the results that merge from the parallel testing of prototype in the field in comparison with conventional methods.
The researchers and industrial partners will draw up a series of recommendations for any future research work or developments that should be carried out by the participating SMEs in the future (post project), in order to ensure that the pre-competitive PARTICLE-PRO prototype can be fully converted into an industrially feasible product which can be successfully taken to market and which can be exploited at industrial scale in the marketplace. All of the participating SMEs and OTHER (INNOPHARMA, SIGMOID, SERVIPLAST, RIKOLA and TAKEDA), will be involved in this task, which will be a very important task for helping them to define the post project work that will need to be done prior to market entry of the technology. The results of this task will feed into Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization.
Moreover, recommendations that emerge from the demonstration sessions that will be held in WP7 will also be picked up, and tweaking and improvements will be implemented by the RTDs during this task, and additional recommendations will be evaluated for their suitability and feasibility for implementation during the commercialisation stage post project.
Deliverables
Deliverable 5.1: PARTICLE-PRO Control Software, User Interface and database (M15): Written documentation, with a software package and a code package.
In terms of the execution of the activities associated with work package 5, system integration and build was completed successfully. The achievements with respect to work package 5 are documents in the report for deliverable 5.1.
The ParticlePro system was built consisting of a cylindrical design fabricated from stainless steel as opposed to the current moulded plastic casing for the Eyecon™, this will facilitate future ATEX rating for the final ParticlePro system. There were some recommended changes for the design and configuration of the MultiEye™ system but the project scope for ParticlePro did not allow for the inclusion of these changes. They will however be incorporated in to the future design and build of the commercial ParticlePro or MultiEye™ systems. This changes will have no impact on the effectiveness and functionality of the ParticlePro system.
The system was built to allow for the running of both the physical application and the chemical applications on a single laptop.
In the activities in WP2 and WP3 the software was built and designed on a number of platforms, C#, C++ and R for the physical characteristics and Labview and R for the chemical characteristics. The particle sizer UI is built on C# business logic while the Analytical algorithms are built in C++ with the algorithms developed by DIT in WP3 built in R. The chemical analysis algorithms are built in Labview while the application models were built in R by DIT. IRIS as part of the integration process have standardised the coding configurations for ease of integration.
The system was built and configured using a newly designed particle sizing application with DIT designing an enhancement of the analytical algorithms. This work also had to be factored in by IRIS in the integration and running of the particle sizing algorithms.
The system capability for physical measurement was assessed against standards supplied by Innopharmalabs, the sizes of these standards are certified externally using sieve analysis and Malvern Mastersizer. The results achieved against these standards were quite comparable and acceptable for the system and more than sufficient for the conducting of industrial trials.
The chemical capability of the system was assessed against know wavelength and reference standards and as with the particle sizing the results achieved were comparable and acceptable for the commencement of industrial trials.
In terms of speed of analysis the systems process speed was slightly slower than that of the current Eyecon™ and MultiEye™ systems. This is as a result of the increase in the complexity of the analytical algorithms due to the additional parameters being analysed and also the fact that both systems run of a single laptop. Having said that the analysis speed is still less than 20 seconds which in the context of current in process testing and for real time process control is still more than sufficient.
The system has been built and configured in accordance with the requirements determined in work package 1. The ongoing development of the system during the execution of WP4 and WP5 incorporated the results and findings at each stage of industrial evaluation of the ParticlePro system, in order to optimise the specification for a commercially viable system.
Industrial Validation of the PARTICLE-PRO System (WP6) –
Objectives:
• To set-up the PARTICLE-PRO system in the test sites at the end-user facilities of SIGMOID or TAKEDA in Ireland and SERVIPLAST in Spain.
• To extensively test the prototype in order to validate its performance in the field, comparing it to conventional particle characterisation methods, and to make the necessary modifications to improve the prototype
• To assist the participating SMEs in fully defining the specifications and future development work that needs to be carried out post project, in order to arrive at a fully commercial product
This WP will assess the efficacy of the developed system to deal with various granulation processes within a process facility. Correlations against reference particle characterization methods will be made. Design issues arising from the industrial tests will be fed back into WP5 to enable improvements to be made to the system, and to enable recommendations for future development work towards commercialization to be drafted.
This work plan also includes a comprehensive series of other activities in order to transfer knowledge from the RTD to the SMEs and to facilitate the take-up of results by the SME participants, as well as by a wider audience of companies from the wider industry:
This WP will be led by DIT who will be supported by IRIS and INNOPHARMA. SIGMOID or TAKEDA and SERVIPLAST will be involved as the test sites. RIKOLA will be involved to support the set up and to ensure the smooth running of the system during trials. INNOPHARMA will share their knowledge of pharmaceutical manufacture and the state-of-the-art in alternative control technologies so that comparisons can be made. They will also provide a test site if this is required.
Task 6.1: Set-up of PARTICLE-PRO in end-user facilities (IRIS, DIT)
During this task, IRIS will set-up the PARTICLE-PRO instrument in the partner facilities (SIGMOID or TAKEDA and SERVIPLAST). Again the effective and early planning of the industrial specifications of the PARTICLE-PRO technology during WP1 should greatly facilitate this task. At this point, initial minimal training or instruction on the proper use of the instrument will need to be delivered to these end-user SMEs, in order to ensure that they are each performing the analytical study correctly.
Task 6.2: Industrial trials and evaluation of results (DIT)
Once the PARTICLE-PRO system has been set up in the sites of SIGMOID or TAKEDA and SERVIPLAST partner facilities, the system will be extensively tested to validate its performance under real industrial operation environments. Tests will be carried out in bench-top and in-line modes over a series of products and operating conditions. Granulation unit operation of high shear, fluidised bed and extrusion will be tested. The tests will be very carefully planned together with these end-user partners, in order to ensure the coherent and successful validation of the effectiveness of the proposed system for the in-line physical and chemical characterisation of particles. The performance criteria as outlined in Task 3.4 will be repeated at production level, with correlations developed with reference off-line measurements. This activity will be detailed in a protocol and subsequent report format.
Exhaustive testing of the instrument at the partner facilities will be carried out. This testing will involve parallel trials using PARTICLE-PRO and current ‘best-in-class’ in-line and off-line analytical methods – NIR, Loss on Drying, Laser and sieve analysis. In this way we can get a meaningful comparison of its effectiveness as a monitoring tool (Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization).
The ability of the PARTICLE-PRO to determine granulation end point, in terms of size/shape, moisture and ingredient distributions will be provided for industrial scale systems.
Deliverables
Deliverable 6.1: Evaluation of Industrial Trials and recommendations for future commercialization (M24): A written report that documents the key findings, outputs and conclusions following the field trials that will have been carried out with the PARTICLE-PRO system, as well as the main development work that will need to be carried out post-project in order to take the PARTICLE-PRO prototype from pre-competitive status to a fully commercial system.
The system was tested extensively on a number of platforms during the course of the industrial trials and evaluations.
The system was set up on a number of platforms and pharmaceutical processes. In the cases of Takeda and Serviplast access to their processes was difficult due to commercial production requirements and the issues with respect to interfering with a validated GMP process. Both Takeda and Serviplast use predominantly fluid bed granulation/drying platforms supplied by Glatt. In order to meet their requirements with respect to assessing the systems capability, the consortium reached an agreement with Glatt GmbH in Binzen Germany to conduct the systems evaluation on both their laboratory scale and commercial scale granulation systems. In addition as a consideration to Glatt the consortium provided them with the opportunity to evaluate the systems capability on their new continuous manufacturing platform, which would require system monitoring using PAT at several different points on the process.
In addition to the collaboration with Glatt the consortium also collaborated with the University of Sheffield in the UK and University College Cork in Ireland. These collaboration allows the consortium to evaluate the systems capability of two different commercial roller compaction processes. This is an alternative granulation process facilitating the compaction of dry ingredients, not suitable for high shear blending, into ribbons for milling into compressible granulate. In addition to the testing of the systems capabilities these collaborations also provided addition avenues for the dissemination of results to a wider audience.
The system was tested a various stages of development on roller compaction, fluid bed granulation/drying, extrusion, drying and coating processes. These tests were completed at University College Cork, Glatt GmbH IN Binzen Germany and Sigmoid Pharma in Dublin Ireland.
The overall result of the testing are detailed in the report for deliverable 6.1.
During roller compaction trials the system was used to determine if ParticlePro was capable of detection changes in ribbon density due to changes in critical process parameters. To assess the NIR results against current density analysis tools. In addition to determine if there is correlation between the changes in the critical quality attributes of the compacted ribbon and the final particle size distribution of the granules produced during the milling stage.
The results achieved showed significant levels of correlation and a clear ability of the system to be utilised for the monitoring of roller compaction processes. The modular nature of the ParticlePro design facilitates the use of any combination of NIR probes from a single probe to all four probes in different configurations, linear or square orientation. In fact the MultiEye™ proved more effective than the current laboratory based FT-IR method. Similarly the particle sizer compared well to typical analysis systems such as sieve and Camsizer.
During granulation trials at Glatt a similar result was achieved. The NIR application were used in the determination of moisture content and from a blend simulation point of view the use of principle component analysis to observe the addition of PVP in solution to an unblended combination of Avicel and Lactose.
The ParticlePro system demonstrated a clear capability to monitor typical granulation processes for both the chemical and physical attributes of the processes. In addition to typical batch granulation processes the system also demonstrated a clear ability to monitor and track different points in the new continuous manufacturing platforms.
As with the results of the roller compaction process there was good correlation between the ParticlePro system and other typical process analytical tools, such as LOD testing, sieve analysis, and a competitor in line laser diffraction probe. Again the ParticlePro system demonstrated better correlation than the in-line competitor system did to sieve analysis.
The process at Sigmoid Pharma is quite unique and has been developed to facilitate the delivery of therapeutic doses using actives that don’t readily bind and release in typical dry or wet granulation processes. The system is subject to IPR protection so cannot currently be fully described in the project. However it is a unique method for the generation of spheres with subsequent critical drying and coating processes. The efficiency of the drying and coating processes has a significant impact on the delivery of the therapeutic dose.
The primary objective was to determine if the ParticlePro system was capable of detecting changes in the physical and chemical characteristics of the spheres at different stages of the process and to determine if an appropriate model could be built in order to facilitate the determination of the end point of each step of the process. There were a number of challenges associated with monitoring this unique process. Firstly the limited number of samples that could be taken during the drum drying process, secondly the limitations for interfacing the NIR probes of the ParticlePro system.
Despite these challenges the system again demonstrated a clear ability to monitor and track the process, which in the case of the drum drying process was in excess of 20 hours. Again there was good correlation between final results and typical analytical technologies.
During the testing there were some issues with regard to system interruptions due to the processing platform on the laptop, however these issues were resolved satisfactorily as were demonstrated during the 22 hour long monitoring of the drying process at Sigmoid.
In general the industrial trials proved quite successful and were well received by the consortium SMEs and end users. These results were also well received by other end users outside the consortium and also by Glatt who want to pursue further evaluation with the potential to recommend the system as an option for supply with their batch and continuous processes.
Potential Impact:
Expected final results and potential impact.
The pharmaceutical industry represents one of the fastest growing industry sectors in the world today. While the process of drug discovery has been fundamental to the development of new therapies, increasingly pharmaceutical companies are relying on the development of novel product formulations to maintain market share. Within this, particle characterization is key to developing an understanding of the functionality of new products, formulations and delivery systems. Moreover, pharmaceutical companies are adopting more complex and promising approaches with dosage forms, including controlled release tablets, multi-coated tablets and granule coatings. For European players to tap into these emerging markets, they need timely and affordable access to innovative process controlling technologies to help them stay ahead of global competition.
INNOPHARMA, a technology provider that specializes in providing breakthrough technologies to the pharmaceutical sector, has identified a clear technological need for improving granulation control and for better positioning themselves in a highly competitive market. INNOPHARMA wants to build on their existing EYECON system that characterises 3D particle images providing information on size and shape in real time and integrate novel NIR chemical measurement approaches that would allow for spatial measurement of granule moisture and ingredient profiles. INNOPHARMA lacks the research capability to developed such a combined system and, to this end, they plan to subcontract work to 3 RTD performers (VTT, DIT and IRIS) through the “Research for SMEs” scheme, so that they can access technology that they can take into the market with the help of the interferometers, optoelectronics suppliers (RIKOLA) in order to serve strong European and indeed global demand.
Indeed industry demand for the technology is expected to be strong in view of the multiple benefits that will be realised through the use of the system in pharmaceutical manufacture: increased granulation process control, increased process quality, increased batch yields, reduced down-time, reduced investigations as a result of deviation investigations, reduced risk of non-supply of products, greater assurance for regulatory bodies, greater patient safety assurance and the feasibility of continuous process validation and real time release of medicinal products. Moreover, financial savings realised through analytical headcount reduction, elimination of analysis time / instrumentation and reduced manufacturing cycle time could be greater than €400,000 for a typical pharmaceutical manufacturing facility with circa 30 batches manufactured per annum.
Already at this early stage, industry interest is significant, and the supply SMEs are joined in the consortium by a group of end-user SMEs who are keen to be early adopters of the technology at discounted rates (SIGMOID, SERVIPLAST). In addition, the presence of a large pharmaceutical manufacturer (TADEKA) is indeed a major endorsement for project and its proposed results.
By owning the Intellectual Property to develop a commercial system that would deliver such a plethora of benefits to the lucrative pharmaceutical sector and at a cost effective price, opens up a highly promising business opportunity for the supply SMEs (INNOPHARMA and RIKOLA) who will work together to service this market, which would be worth € 15 M in the first 5 years of market entry, and an additional € 8 M through the application of the platform technology for other industries where characterisation of particles is a critical quality attribute such as: powdered milk, nutritional products, baby formula, whey products, etc.
As drug delivery systems become more sophisticated, the complex components involved need to be checked more carefully during formulation development and quality control than traditional delivery systems. Innovation and the uptake of new technologies will prove of paramount importance and developments such as PARTICLE-PRO will go a long way towards assisting to strengthen Europe’s reputation as a consistent supplier of high quality and safe pharmaceuticals and biopharmaceuticals. Against such a backdrop, the SME participants are committed, via their active participation in this Research for SMEs proposal, to guiding the RTD performers in the development of a hybrid of imaging-based physical characterization and NIR-Chemical measurement technologies that will provide real-time physical and chemical granule characterisation for a manufacturing process. The SMEs will actively participate in the work plan in terms of mobilising a bottom-up approach whereby they will guide and support the RTD performers in delivering usable results that they will validate and exploit. The SMEs will take on ownership of the beneficial results of this project and the responsibility for their full exploitation at European-wide level.
Contribution to advancement of knowledge / technological progress
The results of this project will represent a significant advance of the state-of-the-art in analytical technology to characterise the physical and chemical properties of particles and indeed the developed hybrid physical imaging and NIR chemical measurement device will be a worldwide breakthrough for the pharmaceutical, and indeed food granulation sectors. It is envisaged that by overcoming the limitations of the existing state-of-the-art in granulation control that a number of key innovations and technological progress will emerge from the research.
The current mechanism for determination of granulation of end point is typically based on a pre-validated time period with fixed air flow rates, air temperatures and liquid feed rates. This defined process is on occasion supported by in-line fixed point NIR analysis to monitor moisture content but more usually by off-line moisture Loss on Drying instruments and off-line physical analysis using sieve analysis or laser based analytical instruments. The paradigm shift towards in-line determination of granulation endpoint through characterisation of physical and chemical parameters and enabling advanced process understanding will ensure greater process robustness, leaner manufacturing processes (saving time, energy and money) and ultimately patient safety. The pharmaceutical user will gather significant understanding of the granulation process during clinical trial manufacture. This understanding of the physical and chemical properties will enable a significantly reduced scale-up time during the commercialisation phase of the pharmaceutical product thereby introducing products to the market in a timelier manner (compared with a typical 3 to 5 years currently).
In terms of a contribution to the technology progress, as an emerging technique, Chemical measurement integrates conventional imaging and spectroscopy to attain both spatial and spectral information from an object. As was discussed above, the combination of the chemical selectivity of vibrational spectroscopy with the power of image visualisation, enables this technique to deliver a more complete description of ingredient concentration and distribution in heterogeneous solids, semi-solids and powders.
VTT has several robust cost efficient and miniaturized spectrograph technology platforms for spectroscopic measurements.
1. VTT patented miniature piezo-actuated Fabry-Perot tunable filter technology gives more freedom for wavelength selection and still offers good wavelength resolution, low drift and high measurement speed, this technology is commercialized by RIKOLA. The benefits of these new devices compared to for example Acousto-Optic Tunable filter (AOTF) or Liquid Crystal Tunable Filter (LCTF) devices are their small size and weight, speed of wavelength tuning, high optical throughput, independence of polarization state of incoming light and the capability to record three wavelengths simultaneously.
2. By combining multi-channel detector technology with tunable Fabry-Perot filter VTT has developed and patented a quasi-imaging technique, to simultaneously increase the number of wavelength channels from multi-channel systems and still get the highest possible measurement speed. Advantages of quasi imaging, known wavelength channels, include fast data acquisition, flexibility of measurement, robustness, small size and low cost.
In all cases robustness of the measurement is extremely critical and wavelength drift must be minimized with hermetically sealed detector solution integrated to the Particle-Pro device in WP2 and WP4.
VTT has already developed and utilised the innovative Fabry-Perot interferometer (FPI) concept in UAV (Unmanned aerial vehicle) sensing applications and visible range chemical imager and color measurements. Preliminary results have demonstrated the first generation research based on FPI spectrometer module for laboratory chemical mapping applications. The measurement speed and high SNR achieved by the proposed novel FPI concept are even more critical for in-line real-time NIR chemical measurements applications, such as wet granulation control. Due to the small-size of preliminary FPI spectrometer technology, it can be seen as an enabling technology for new in-line Chemical monitoring development.
Another limiting factor of NIR chemical measurements is the need to calibration models of every component to be measured. These sets of calibrations are sold with the devices as part of the software (or separately at an extra cost). These libraries are very time consuming to build and with the standard chemometric models there is always a need to be validated against reference methods and the calibration models vary from one device to device. The so-called science-based method (SBC) has recently provided a solution to the calibration problem. The SBC method transfers the principles of time signal processing to spectrometry and derives the optimal calibration solution alias “optimal filter” in a closed-form mathematical formula. In SBC, with response defined a-priori by spectroscopic expertise and application knowledge, spectroscopy is no longer a “secondary” method that needs calibration against a “primary” reference method. Instead, it becomes a “primary” method, firmly rooted in physics and chemistry. Significant practical benefits become available from this change whenever the shape of the response spectrum is “manually” defined. One great advantage is that specificity of response can be proven to regulatory agencies and concerned end-users, which in today’s increasingly regulated and controlled environment this is a major competitive benefit for reassuring consumers and the market and heightening confidence. The last two decades have seen the development of commercial systems for the application of NIR chemical imaging and physical imaging in the pharmaceutical sector. However, to date there is no commercial system in the market that can provide real time on-.line measurements of both physical and chemical parameters. Such an ability, which the PARTICLE-PRO system will possess, makes for a system that is more flexible and suited for responding to the increase need to follow Process Analytical Technology (PAT) and pharmaceutical quality by designed required by the FDA.
The European pharmaceutical industry has an important role to play in ensuring that the people of Europe enjoy a good standard of health . The European Union strives, therefore, to guarantee broad access to medicinal products, to provide the public with high quality information, and to ensure that the medicinal products manufactured are safe and effective21. The single market for pharmaceutical products makes it possible to achieve these aims by increasing the competitiveness of the industry through promoting research and innovation for the benefit of the public21.
Process Analytical Technology (PAT) is now the buzzword in the pharmaceutical industry. It is the new framework for better understanding in pharmaceutical processes of which granulation is a very big part. Central to PAT is improving final product quality by process design through knowledge of the fundamental scientific principles behind it, and continuous online control of a process. The challenge is to do this whilst maintaining or improving the current level of product quality6.
Without doubt, the impact of providing the industry with a novel hybrid physical imaging and NIR chemical measurement technology to characterise the physical and chemical properties of particles holds enormous benefits adding value to and increasing the competitiveness of the European pharmaceutical sectors, for improved pharmaceutical product quality and safety, as well as for patient health and safety. Moreover, as the novel hybrid PARTICLE-PRO analytical technology will be designed, manufactured, supplied and serviced from Europe, this will have a positive impact for jobs, growth and innovation.
How the results of the project will improve the competitiveness of the SME participants
The project will result in a hybrid physical imaging and NIR chemical measurement technology that will be branded and marketed as PARTICLE-PRO, and will enable the rapid and reliable on-line characterisation of the physical and chemical properties of particles during processing. It is envisaged that the ownership of the rights to exploit the proposed results will afford the participating SMEs with a real business opportunity with a clear economic impact. To this end, they aim to protect the knowledge generated during the project, in order to enable the generation of income and competitive benefits to be derived through the exploitation of the IPR, which will bring a clear strategic and competitive impact for the participating SMEs.
In terms of the benefits to the end-users of the system (SIGMOID, SERVIPLAST, TAKEDA), they will be equipped to:
• Increase granulation process control- by having access to information about particle size, shape and moisture content, as well as the active content uniformity of the final product in real-time from the same device.
• Increase process quality- real-time information from the PARTICLE-PRO device will enable better control over characteristics that influence compression processes, product stability (negatively leading to hydration of the active ingredient), and the active content uniformity of the final product that ensures that each patient receives the correct dosage quantity.
• Increase batch yields- through reduced product rejections, which can be as high as 20% as a result of process problems, by improving response times to process upsets
• Reduce down-time- by replacing time-consuming off-line methods with real-time characterisation. PARTICLE-PRO will eliminating sampling and the time delays inherent in taking and transporting a sample to an off-line laboratory
• Reduce investigations as a result of deviation investigations
• Reduce risk of non-supply of products
• Obtain greater assurance for regulatory bodies- though the use of a technology that is in line with “Process Analytical Technology”, the new framework for better understanding in pharmaceutical processes of which granulation is a very big part
• Reduced scale-up times from Clinical to Commercial manufacture
• Obtain financial savings realised through analytical headcount reduction, elimination of analysis time / instrumentation and reduced manufacturing cycle time. Per annum savings would be greater than €400,000 for a typical pharmaceutical manufacturing facility with circa 30 batches manufactured per year.
The effective communication of these benefits to the market should draw on technology push, as well as stimulate market demand for the proposed PARTICLE-PRO system among the European (and indeed global) pharmaceutical industry. Beyond the product-related benefits, further drivers that should fuel demand include the increasingly stringent regulatory requirements (EU Guide to Good Manufacturing Practice; the U.S. Food and Drug Administration, FDA) and the increasing cost pressures. This opens up an enormous business opportunity for the SMEs from the PARTICLE-PRO supply chain (INNOPHARMA and RIKOLA) to tap into this market, especially as the system will be very competitively prices compared to the competition. They will thereby benefit from increased sales and income from the supply of the Fabry Perot Interferometer (RIKOLA), as well as the manufacture and sale of the complete solution (INNOPHARMA), including the system software. They expect to access new international markets and open up distribution networks across Europe, and indeed beyond, as a result of the commercialisation of the novel PARTICLE-PRO phys./CI particle characterisation system.
In order to quantify these competitive benefits for each SME, the direct economic impacts have been calculated (Table 6), along with the subsequent new jobs that could be created as a result. These initial estimations are based on an analysis of the type of exploitation that each beneficiary will make of the results in keeping with their positioning on the user and supply chain, their existing turnover and employees and their capacity to exploit the results of the project, and the resulting competitive benefits. New jobs created are based on average capital intensity in the industrial sector of € 120,000 per job per annum .
Contribution to improving industrial competitiveness across the European Union
Beyond strengthening the competitiveness of the participating SMEs, this PARTICLE-PRO project will also contribute to improving industrial competitiveness across the European Union through the commercialisation of the system in EU-27.
Figures published in 2008 by the European Commission (Eurostat) show that the pharmaceutical industry is the industrial sector which invests most in research & development with 15.3% of total EU private R&D expenditure. Of the 635,000 people it employs in Europe, 117,000 work in R&D . To this end, the research-based pharmaceutical industry is one of Europe’s leading high-technology industrial employers. In fact, recent studies in some countries showed that the research-based pharmaceutical industry generates three to four times more employment indirectly - upstream and downstream - than it does directly, a significant proportion being high value added jobs (e.g. clinical science, universities, etc.)23. The pharmaceutical industry is also the sector with the highest ratio of R&D investment to net sales. It amounts to approximately 3.5% of total EU manufacturing value-added and 19.2% of the total worldwide business R&D expenditure. The research-based pharmaceutical industry is a key asset of the European economy representing about 19.2% of global business R&D investments and about 3.5% of the total EU manufactured exports23.
The savings realized through reduced scale up times and greater process robustness will enable even greater percentages of investment to be made in pharmaceutical R&D.
European demand for pharmaceuticals is expanding due to an ageing population, earlier diagnosis of disease and wider use of pharmaceuticals. However, despite this growing domestic demand, since the early 1990s, Europe has been losing competitiveness with respect to its main competitors, in particular the US. Data for 2007 and preliminary figures for 2008 confirm the vulnerability of Europe’s research-based pharmaceutical industry. Benchmarking and performance indicators show Europe's relative lack of attractiveness for pharmaceutical R&D investments. Between 1990 and 2008, R&D investment in United States grew by 5.6 times whilst in Europe it only grew by 3.5 times. Today there is rapid growth in the research environment in emerging economies such as China and India, resulting in closures of R&D sites in Europe and openings of new sites on the Asian continent. To this end, improving the performance of European manufacturers is of paramount for safeguarding the competitiveness of the European players in this sector.
Particle physics governs process variables such as flow, blending, granulation, compression and coating. These variables can have a significant effect on final product behaviour such as blend homogeneity, drug absorption rates, product robustness, etc. The identified key physical parameters include particle/granule size and shape. Similarly the chemistry variation within the products has a critical effect on product quality. The development of a technology capable of monitoring physical and chemical parameters of a process on-line will significantly increase process understanding and control thereby assuring product quality, lean operational costs, as well as patient safety.
Equipping the European pharmaceutical industry with a technology that will enable them to safeguard product quality and safety, reduce costs, increase production throughput, meet with international good manufacturing practices, and facilitate quicker new product development, will undoubtedly contribute to increasing the competitiveness of these sectors at European level, as well as to safeguarding the futures of the 635,000 employed in the pharmaceutical and biopharmaceutical industries, as well as their related supply and value chains in Europe. Moreover, we envisage the creation of at least 800-1000 new jobs by 2020 (within 5 years of commercial availability of the system in the market) through increased pharmaceutical production in the EU, as a result of increased product throughput and capacity in existing plants, as well as knock-on jobs along the value chain, and in the manufacture of the PARTICLE-PRO system itself to serve the European (and global) market. This would be based on a 0.02-0.03 % annual increase in jobs in the pharmaceutical sector in Europe through increased competitiveness via the uptake of a PAT technology to improve the efficiency of their granulation process and to improve the quality and safety of the final product, which are key drivers for growth and job creation.
However, particles and granules play a key role in process efficacy and final product quality for numerous industries beyond the pharmaceutical sector, such as food and nutritionals. To this end, by rolling out the technology to the food and nutrition sector for the physical and chemical characteristics of particles during food granulation processing (through further development work, validation and demonstration, which is a firm intention of the participating supply SMEs by 2015), the benefits for 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. These benefits will be particularly felt in the case of the production of infant formula, powdered milk, nutritional product, whey product manufacture, whereby the uniform presence of various sugar/fat components within the granule as well as its size and structure is critical to the performance of the product.
The extent to which the proposed project will lead to new and improved products, processes or services with clear market potential
Successful granulation and active homogeneity are critical to assuring product quality. Once PARTICLE-PRO is ready to launch in the market, it is envisaged that the ownership of the rights to exploit the proposed technology will afford the industry partners with a real business opportunity through the uptake and commercialisation of a novel particle characterisation device with very promising market potential at EU, and indeed global, level.
In fact, the worldwide pharmaceutical market is very lucrative for pharmaceutical producers and also for equipment suppliers, service providers and consultants . The world pharmaceutical market more than doubled in size between 1998 and 2006 . In 2009 global pharmaceutical sales were worth approximately 750 billion-760 billion U.S. dollars . The US, however, is the world market leader with a 39.3% share of world production, followed by Europe and Japan. Seven emerging markets- Brazil, China, India, Mexico, Russia, South Korea, and Turkey- contribute nearly 25% of growth worldwide and were expected to grow 12–13% in 2008 to $85–90 billion .
To satisfy demand, a large number of capital projects have been initiated and completed worldwide, creating what appears to be the ideal growth market for companies that specialise in the design and delivery of pharmaceutical plants and equipment, and especially suppliers of specialised equipment24. Figure 8 shows the envisaged ease with which PARTICLE-PRO would be integrated into current granulating equipment designs. The flexibility of design will be such that it could be retrofitted non-invasively to current fluidized bed, high shear or extruder granulator designs. Equally as a selling point for granulation equipment, suppliers could use the technology as an advanced control strategy of their process.
The strategy for dissemination of the results, findings and benefits of the ParticlePro project will need to follow an agreed pre-determined communication plan. The unique and proprietary nature of the technologies involved in the design and building of the detection device will need to be protected until the full exploitation.
To ensure protection of the early research results, external communication will be focused on the project website and industry visits and consultations with a specific focus on those pharmaceutical companies who have embraced the move to PAT in the pharmaceutical and related industries.
The project leaflet and poster will be preliminary designed with the printing of the leaflet targeted to include some images and non-proprietary results for WP4, “design and building of the ParticlePro system.
Note: As the project moves through each of the development phases associated with the construction and testing of a pre-competitive prototype portable test rig, communication and dissemination of the results and the strategy associated with the communication plan, will need to be agreed by all members of the consortium to protect and maximise the opportunity to exploit the ParticlePro technology.
The following activities have been planned for the 1 – 15 month period of the ParticlePro project.
• Development and upkeep of the ParticlePro website.
• Develop a link to the ParticlePro website on the Innopharmalabs technology website.
• Planned visits and communications to Pharmaceutical, Academic and Development facilities across Europe and the US. This activity commenced with evaluation trials for the individual technologies, involving Sheffield University in the UK and UCC and UL in Ireland. This activity commenced in April 2013 with further activity planned for October 2013 for the physical evaluation of particles. In February 2014 further trials are planned to evaluate the potential of the NIR system to track changes in a typical roller compaction process.
• Innopharmalabs are currently in the process of negotiating partnerships with key equipment manufacturers. Part of this relationship will be the testing and subsequent recommendation of technologies resulting from the FP7 funded R&D activity.
• Power-point presentation template will be developed by the end of February 2014 to facilitate communication of the project results.
• Poster and leaflet layout to be finalised and prepared for the inclusion of non-proprietary results obtained during the completion of WP4, this is targeted for April 2014
• Press release planned to coincide with the kick off for the Pure Formula and Crystal Vis research for SME projects. Press release to be developed for release in January 2014.
• White paper to be completed in February 2014. The white paper will discuss and explore the results achieved to date on the laboratory test rig. The white paper will be distributed through some of the channels identified in section 5.1 of this document.
• Meeting with Patent Attorney in May 2014 to determine the process for protection of the IPR associated with the ParticlePro technology, and how we can leverage the existing patents/patent applications for existing foreground and background activities.
• There were two white papers generated from the combinations of laboratory and industrial based testing. The first of these white papers.is published, the second is in review.
M. A. P. McAuliffe, G. E. O., C. A. Blackshields, J. A. C., D. P. Egan, L. K., E. O’Neill, S. L., & G. M. Walker, A. M. C. (2014, April). The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing. Organic Process Research; Development.
Evaluation of Diffuse Reflectance Near Infrared Fibre Optical Sensors in Measurements for Chemical Identification and Quantification for Binary Granule Blends. D. Togashi, L. Alvarez-Jubete, H. Rifai,R. Cama-Moncunill, P. Cruise, C. Sullivan, P.J. Cullen. Journal of Near Infra Red Spectroscopy. Currently in review for acceptance and open publication.
• Presentation of our results and progress to an ISPE (International Society for Pharmaceutical Engineers), PAT Community of Practice forum to be planned for mid 2014.
• The prototype development phase is completed in month 16 of the project which is the end of April 2014. In the two month leading up to its completion and subsequent testing, the unique features of the technical application and structure of the test rig will be reviewed. This activity is required to facilitate the completion of the exploitation agreement and the preparations for any potential patent applications that are to be filed prior to further publication of the results of the project.
• In the period from August to October of 2014 during the development of the final exploitation agreement, a plan is to be drawn up to present on the final results at IFPAC in January 2015. There are 3 talks scheduled for presentation to industry and academia at IFPAC in Arlington between the 26th and 29th of January 2015. In addition Innopharmalabs will exhibit Eyecon™ and MultiEye™ interfaced on a single test rig at the IFPAC conference.
4.2 To Be Planned Activities
The following activities are to be planned with consortium agreement for the content and mechanisms for the communication and dissemination plan.
• Development of target groups and communities such as ISPE communities of practice, academic forums and networking tools.
• Communication session specifically targeted for regulatory authorities.
• Presentation of project results at Achema in June 2015, this is to be planned in partnership with Glatt GmbH. There will be a further trials process.
• Further process development activity to be complete with Glatt on their new blending process for continuous manufacturing platforms. This work to be completed in the lead up to Achema June 2015.
• Sigmoid process development and process enhancement activity to be planned for Q1 and Q2 2015.
• Paul Cruise of Innopharmalabs will commence a PHD in February of 2015, the subject being “Multi-spectral and imaging technologies for pharmaceutical manufacturing”. This work being conducted in conjunction with academia and the industry will further enforce the application of these technologies for the control and monitoring of pharmaceutical processes.
• Innopharmalabs undertakes to complete chemometric training in PLS and PCA model building and application in our objective to provide a complete solution as opposed to just a piece of technology. This is scheduled for the last week in January 2015.
The exploitation strategy needs to be coupled with a well thought out well defined business plan. The exploitation potential will only become apparent as the development process of the ParticlePro device progresses. At this point in the project timeline the preliminary plan for the exploitation of the ParticlePro technology will be adopted from the DOW dated 2012-09-10.
As can be seen from the above diagram in the PDF attached to this final report, the starting point will centre on a definition of the protected IPR, whereby a verifiable list of all intellectual property rights that have been applied for or registered (such as the application of a European patent) will be provided, as well as a description of all the results that may have commercial or industrial applications. At this stage, Table A5 of Part A outlines the envisaged project results. In addition, an explanation of the access rights to be exchanged between the participating SMEs for the use of knowledge will be outlined, along with the economic conditions established for the granting of such access rights.
The further development work and implied risks involved will also be detailed and based on the findings of Task 6.2: Industrial Trials and evaluation of results, whereby the resulting recommendations will have been documented in a report that will outline all the necessary actions that will need to be taken post-project, along with any potential risks. This report will be analysed by the partners and specific roles and responsibilities will be agreed among the participating SMEs. The RTDs will assist the SMEs in costing this future development work (and there will be no obligation whatsoever for this future development work to be subcontracted to the RTD performers). It is envisaged that the investment in further development work will be shared among the 5 SME participants in proportions to be agreed as the IPR unfolds, as they all hope to benefit from the exploitation of its results. If required, the RTDs will offer assistance and guidance in accessing additional sources of funding for this future development work.
Following on from the discussion with the patent attorney, it is essential that the unique technological applications and designs for the portable test-rig and proposed commercial designs be closely guarded and continually assessed. This is necessary to protect the IPR and the opportunities for patent filing for the technological application for in-line monitoring of physical and chemical characteristics.
In accordance with the DoW and the consortium agreement the end user SMEs will receive preferential rights for the installation of the Particle Pro system in their facilities and thus benefit from the results generated during the project. This will also provide them with the opportunity to assess the suitability of the system for their requirements and allow them to also avail of preferential pricing on the final commercial system.
The other SMEs, Innopharma and Rikola will be responsible for taking the project results to the wider market. Communication of the results and success of the project will be communicated through currently established consortiums and partnerships. The Particle Pro technology is being developed through the integration of currently existing technologies that are already subject to patent and/or trade mark or have patent submissions pending. As a result the channels to market already exist for this type of PAT technology. Innopharmalabs knowledge of the market and the key players and mechanisms for exploiting the potential of the device will be the primary source of commercial exploitation. Rikola will benefit from the results through the supply of system software or key system components and will also be provided with the opportunity to assemble in part or whole with external partners the commercially designed ParticlePro system.
The typical mechanisms for communicating the project success to the wider market will be to distribute project results in the form of white papers and leaflets. There are a number of options open to Innopharmalabs to complete this activity. Innopharmalabs have avenues through AAPS (American Association of Pharmaceutical Scientists), SSPC (Solid State Pharmaceutical Cluster), Engineering Research Centre – Structured Organic Particulate Systems, in conjunction with these outlets results will be communicated to key equipment manufacturers especially those involved in new process technology such as continuous wet and dry processes.
In order to maximise the market opportunities for the ParticlePro project the system will be offered in modular form. This is to avail of opportunities where existing Eyecon™ customers may want add the MultiEye NIR functionality to their existing capabilities. There will therefore be 3 version of system software.
a. Software for the operation of Eyecon as a stand-alone system
b. Software for the operation of MultiEye as a stand-alone system
c. Software for the operation of both systems through a single user interface.
A similar approach will be adopted with respect to hardware integration. The systems can again be supplied in modular fashion.
a. As two stand-alone pieces of process analytical technology
b. Partial integration of physical characterisation and chemical characterisation systems
c. Full integration of both the physical and chemical characterisation applications.
The ownership table and the illustrated strategy of exploitation are attached to the PDF for this final report.
In order to maximise the dissemination opportunities for the ParticlePro system as special demonstration rig has been developed and fabricated to demonstrate the system imaging and analysing moving particles. An image of this system in included in the attached PDF document.
In addition at the time of submission of this document additional changes have been requested to the exploitation agreement so deliverable 8.3 has yet to be submitted, however they are attached to this report for information purposes.
List of Websites:
www.particle-pro.eu
Contacts: SMEs/OTHER
Principal contact Ian Jones Innopharmalabs, jonesi@innopharmalabs.com
Rikola OY: raimo.rikola@rikola.fi
Manufacturas Serviplast: eromero@serviplast.com
Sigmoid Pharma: ivan.coulter@sigmoidpharma.com
Takeda Ireland: Brendan.Donohue@Takeda.com
RTD
Dublin Institute of Technology: pjcullen@dit.ie
IRIS: mpinilla@iris.cat
VTT: Pentti.karioja@vtt.fi
