Final Report Summary - NEMOPUR (New Molecular Purification Technology for Pharmaceutical Production)
Project context and objectives
NEMOPUR is a European Commission FP7-funded Marie Curie Initial Training Network of nine partner organisations from industry and academia co-ordinated by Professor Andrew Livingston (Imperial College London), which has sought to exploit membrane separation technology in active pharmaceutical ingredient (API) pharmaceutical processes. During a four-year period, NEMOPUR successfully developed novel methods to remove organic impurities from API production using technologies based on organic solvent nanofiltration (OSN), molecularly imprinted polymers (MIPs) and synergistic combinations of these two. In doing this, the NEMOPUR project has taken significant steps towards reduced energy consumption, improved process capability, low maintenance, increased automation, modularity and reduced footprint in the purification of APIs. NEMOPUR has made a key impact on the current level of OSN and MIP activity across Europe by delivering new innovations for end-users and executing extensive application research and delivering advanced training across different industry sectors raising end-user membrane technology competence levels.
Purification of APIs, which is mostly based on distillation techniques, often consumes the bulk of the processing time and costs within the pharmaceutical manufacturing process. Driven by the challenges of waste disposal and fresh supply costs, poor mass- and energy-efficiency, high operating temperatures (which prove problematic for temperature sensitive material) and significant yield losses, pharmaceutical manufacturers are demanding novel technologies, as an alternative to molecular purification technology. Faced with competitive pressure (namely from India and USA) pharmaceutical companies require a cost-effective and efficient process intensification to control these process-related impurities at each step of manufacturing and find new ways to achieve solvent recovery.
NEMOPUR's major innovative contributions and breakthroughs in molecular purification techniques include a number of industrially important applications based on OSN and MIP technologies, which provide efficient, cost-effective and reliable solutions for critical separation challenges and have demonstrated superior performance across a broad range of applications, versus alternative technologies such as distillation, absorption, pressure swing adsorption, direct compression-condensation, and cryogenics. Tailored membrane products developed within the project demonstrated improved chemical stability in a wide range of solvents, better controlled cut-off properties and better defined separating properties, thereby allowing more effective use of both energy and material inputs to a given production process. Membranes were developed through the application of templating, crosslinking and functionalisation with universal solvent stability and controlled pore size distribution. Novel MIP materials have been created that can be used in industrial processes, particularly new reactive monomers, new methods for coating and grafting MIP onto support matrices, such as nanoporous and nanofibrous materials. MIP film composite membranes which show good stability in organic solvents as well as aqueous solutions have also been created. OSN and MIP technologies have been effectively combined for API purification, and new technologies using MIPs and OSN to remove organic impurities from API in continuous mode have successfully been developed. Further optimisation of the operating conditions of the process, through a better understanding of how to apply the membrane products, will allow the energy and process material inputs to be even further reduced. This will enhance the rate of uptake of this resource-efficient separation technology, leading to further revenue generation and employment opportunities in the EU, as well as helping to reduce the carbon footprint of the chemical companies adopting this technology.
NEMOPUR technical focus
Organic solvent nanofiltration
Polymeric membranes, including OSN membranes, is an emerging molecular separation technology in many industries such as chemical, petroleum, food, pharmaceutical and bio-pharmaceutical. Research within NEMOPUR focused on API manufacturing processes and developing new membranes with improved chemical stability in a wide range of solvents, and better controlled cut-off properties by templating, crosslinking and functionalisation. Crosslinked PI (polyimides) and PEEK (Polytheretherketone) ultrafiltration (UF) membranes were used as supports for the formation of organic solvent nanofiltration thin film composite (TFC) membranes by interfacial polymerisation. Promising results were obtained by varying different parameters on the formation of the top-layer, enhancing solvent flux without compromising rejection in solvents, including DMF (Dimethylforamide), THF (Tetrahydrofuran), alcohols, acetone, ethyl acetate and Toluene. They are the first OSN TFC membranes prepared via interfacial polymerisation to be resistant in DMF. In order to increase flux we have impregnated the UF supports with PEG400, and post-treated the TFC membranes with an activating solution. Finally, to further improve flux for more hydrophobic solvents, different chemistries have been used, successfully enhancing hydrophobic solvent permeabilities in ethyl acetate, toluene and heptane. We have also developed a high flux membrane containing intrinsic microporosity by interfacial polymerisation, resulting in both a very thin selective layer and high microporosity.
The NEMOPUR project has progressed significantly with the development of new TFC membranes that are robust and are able to separate genotoxins from drug compounds; in parallel to this research, characterisation of membranes and membrane processes has been carried in order to understand mechanisms governing the membrane formation and the molecular separation. We developed a new technique that is able in situ to measure the pore size under transmission electron microscopy (TEM) and to elucidate the macromolecular structures formed during the membrane formation. The morphology of these structures is believed to be responsible for solute transport behaviour and separation properties of the OSN membranes. Since the characterisation methods are in situ, information on relationship between membrane nanostructure and functional performance can be determined. The technique is based on in situ nanoprobing of the pores with the high contrast osmium dioxide (OsO2) nanoparticles allowing for mapping the porous phases and measuring the pore size in P84 co-polyimide integrally skinned asymmetric OSN membranes with custom-made nanostructure showed by controllable solute rejection and flux. A good correlation between the pore size and rejection for the P84 co-polyimide membranes has been found, and thus this achievement has led to apply the nanoprobing porosimetry to wider range of OSN membranes such as commercial asymmetric membranes and lab-bench fabricated thin film composite membranes.
Molecularly imprinted polymers
NEMOPUR has successfully developed novel MIP materials and techniques to isolate and purify API intermediate molecules from the model system mixtures. Experimental work has resulted in new molecularly imprinted film-macroporous membranes using newly designed reactive monomers for stoichiometric non-covalent imprinting which are stable in organic solvents. These have been used to develop a new, low mass transfer resistance system for fast equilibration and removal of impurities in organic solvents. Researchers tested forming and then crosslinking the macroporous membranes prior to coating with the MIP film and then forming the macroporous membrane, coating it with a MIP film, and then crosslinking both the underlying membrane and the MIP film simultaneously, giving promising results.
MIP based polishing phases for genotoxic impurities have been developed, as well as a capturing phase capable of binding a cyclic peptide while excluding oligomeric or acyclic impurities and to use the polymers to promote cyclisation. NEMOPUR has developed 1,3-diisopropylurea selective MIPs, methyl tosylate MIPs selective MIPs endotoxin selective MIPs. Rebinding tests shows high capacity and selectivity. These MIPs offer readily scalable production chemistries. Having taken key steps towards generating innovative and original solutions to the impurity challenge, researchers have began to implement processes using continuous and batch platforms and develop models for predicting performance of these platforms for API intermediate purification which can be used as design tools. Both imprinted polymers and reactive scavengers were shown to be useful materials for removal of undesired genotoxic impurities in reaction solvents containing the active pharmaceutical ingredient. The materials were able to solve these demanding clean-up tasks. We achieved clean-up levels that were close to complete removal of those toxic contaminants. Furthermore, the chromatographic separation is commercially feasible (see chromatogram below). The improved safety of pharmaceutical ingredients is of course beneficial for patients and therefore for society.
The research conducted within the NEMOPUR project has benefited from a highly coordinated and integrated approach by a multidisciplinary, inter-sectorial academic-industrial research team leading to effective technology transfer between different sectors using membrane technology. The membrane industry encompasses a broad field of science, engineering and technology and operates at the intersection of multiple disciplines, including material science, chemistry, chemical engineering, mechanical engineering, electrical engineering, life sciences and nanotechnology. NEMOPUR brought together leading companies and academic institutions from these different science and engineering fields through a multidisciplinary framework and successfully employed the research skills and expertise available within three universities / research institutes, two technology SMEs (small and medium-sized enterprises) and four pharmaceutical manufacturers. Together they represent a vertically integrated consortium, with knowledge stretching from the basic research to the design and marketing of products. Advanced research achieved through an intense cooperation between the academic and industry sectors on different aspects and components of purification advances enabled breakthroughs in research and development. This in turn has led to a variety of benefits including increased support for academic research by industry, increased and accelerated technology transfer, enhanced competitiveness, and ultimately, economic development within the European Community.
NEMOPUR placed enormous emphasis on the training and development needs of the recruited researchers with each ESR benefiting from cross-disciplinary research and comprehensive multi-level training in membrane technologies and applications focused on targeted areas. After a rigorous recruitment process to select highly motivated and talented researchers, detailed personal development plans were created for each of the 12 ESRs and 4 ERs to ensure that they received a comprehensive and structured training programme customised to their training needs. NEMOPUR's unique interdisciplinary PhD programme and career development platform ensured that NEMOPUR trained skilled graduates not only have knowledge of recent scientific research but also an ability to solve complex problems, perform advanced research, apply new concepts and develop new scientific methodologies. The training platform cut across different industry sectors, which has led to an increase in end-user membrane technology competence levels. The NEMOPUR network was industry focussed with a clear emphasis on applications which is capable of facilitating industry-driven pilot plant activity. Half the ESRs were employed within industry whilst also benefitting from academic facilities and training including state-of-the-art laboratory facilities for synthesis, characterisation and evaluation of membranes. Secondments, visits and training organised by industrial partners ensured that all ESRs gained experience of industrial practice thereby gaining education that included more generic and long-lasting skills. Formal training in technical and professional skills topics were complemented by training in business development from business partners; and secondments and exchanges between Partners have helped to ensure the transfer of knowledge and best practice within the network. ESRs benefited from a close collaborative international network which stimulated social interaction; increased the capacity for scientific and technological problem-solving and prepared them for an international research career either in academia or in industry.
Dissemination was an essential part of NEMOPUR, not only to communicate the achievements and successes of the project to the outside world, but also to develop essential communication skills of researchers. Attendance at and contributions to a range of technical events (conferences, seminars, workshops) and international conferences will lead to a wide range of experience at presenting and explaining research, preparing the researchers to work and communicate across disciplines and sectors.
Project website: http://www.imperial.ac.uk/molecularpurification
NEMOPUR is a European Commission FP7-funded Marie Curie Initial Training Network of nine partner organisations from industry and academia co-ordinated by Professor Andrew Livingston (Imperial College London), which has sought to exploit membrane separation technology in active pharmaceutical ingredient (API) pharmaceutical processes. During a four-year period, NEMOPUR successfully developed novel methods to remove organic impurities from API production using technologies based on organic solvent nanofiltration (OSN), molecularly imprinted polymers (MIPs) and synergistic combinations of these two. In doing this, the NEMOPUR project has taken significant steps towards reduced energy consumption, improved process capability, low maintenance, increased automation, modularity and reduced footprint in the purification of APIs. NEMOPUR has made a key impact on the current level of OSN and MIP activity across Europe by delivering new innovations for end-users and executing extensive application research and delivering advanced training across different industry sectors raising end-user membrane technology competence levels.
Purification of APIs, which is mostly based on distillation techniques, often consumes the bulk of the processing time and costs within the pharmaceutical manufacturing process. Driven by the challenges of waste disposal and fresh supply costs, poor mass- and energy-efficiency, high operating temperatures (which prove problematic for temperature sensitive material) and significant yield losses, pharmaceutical manufacturers are demanding novel technologies, as an alternative to molecular purification technology. Faced with competitive pressure (namely from India and USA) pharmaceutical companies require a cost-effective and efficient process intensification to control these process-related impurities at each step of manufacturing and find new ways to achieve solvent recovery.
NEMOPUR's major innovative contributions and breakthroughs in molecular purification techniques include a number of industrially important applications based on OSN and MIP technologies, which provide efficient, cost-effective and reliable solutions for critical separation challenges and have demonstrated superior performance across a broad range of applications, versus alternative technologies such as distillation, absorption, pressure swing adsorption, direct compression-condensation, and cryogenics. Tailored membrane products developed within the project demonstrated improved chemical stability in a wide range of solvents, better controlled cut-off properties and better defined separating properties, thereby allowing more effective use of both energy and material inputs to a given production process. Membranes were developed through the application of templating, crosslinking and functionalisation with universal solvent stability and controlled pore size distribution. Novel MIP materials have been created that can be used in industrial processes, particularly new reactive monomers, new methods for coating and grafting MIP onto support matrices, such as nanoporous and nanofibrous materials. MIP film composite membranes which show good stability in organic solvents as well as aqueous solutions have also been created. OSN and MIP technologies have been effectively combined for API purification, and new technologies using MIPs and OSN to remove organic impurities from API in continuous mode have successfully been developed. Further optimisation of the operating conditions of the process, through a better understanding of how to apply the membrane products, will allow the energy and process material inputs to be even further reduced. This will enhance the rate of uptake of this resource-efficient separation technology, leading to further revenue generation and employment opportunities in the EU, as well as helping to reduce the carbon footprint of the chemical companies adopting this technology.
NEMOPUR technical focus
Organic solvent nanofiltration
Polymeric membranes, including OSN membranes, is an emerging molecular separation technology in many industries such as chemical, petroleum, food, pharmaceutical and bio-pharmaceutical. Research within NEMOPUR focused on API manufacturing processes and developing new membranes with improved chemical stability in a wide range of solvents, and better controlled cut-off properties by templating, crosslinking and functionalisation. Crosslinked PI (polyimides) and PEEK (Polytheretherketone) ultrafiltration (UF) membranes were used as supports for the formation of organic solvent nanofiltration thin film composite (TFC) membranes by interfacial polymerisation. Promising results were obtained by varying different parameters on the formation of the top-layer, enhancing solvent flux without compromising rejection in solvents, including DMF (Dimethylforamide), THF (Tetrahydrofuran), alcohols, acetone, ethyl acetate and Toluene. They are the first OSN TFC membranes prepared via interfacial polymerisation to be resistant in DMF. In order to increase flux we have impregnated the UF supports with PEG400, and post-treated the TFC membranes with an activating solution. Finally, to further improve flux for more hydrophobic solvents, different chemistries have been used, successfully enhancing hydrophobic solvent permeabilities in ethyl acetate, toluene and heptane. We have also developed a high flux membrane containing intrinsic microporosity by interfacial polymerisation, resulting in both a very thin selective layer and high microporosity.
The NEMOPUR project has progressed significantly with the development of new TFC membranes that are robust and are able to separate genotoxins from drug compounds; in parallel to this research, characterisation of membranes and membrane processes has been carried in order to understand mechanisms governing the membrane formation and the molecular separation. We developed a new technique that is able in situ to measure the pore size under transmission electron microscopy (TEM) and to elucidate the macromolecular structures formed during the membrane formation. The morphology of these structures is believed to be responsible for solute transport behaviour and separation properties of the OSN membranes. Since the characterisation methods are in situ, information on relationship between membrane nanostructure and functional performance can be determined. The technique is based on in situ nanoprobing of the pores with the high contrast osmium dioxide (OsO2) nanoparticles allowing for mapping the porous phases and measuring the pore size in P84 co-polyimide integrally skinned asymmetric OSN membranes with custom-made nanostructure showed by controllable solute rejection and flux. A good correlation between the pore size and rejection for the P84 co-polyimide membranes has been found, and thus this achievement has led to apply the nanoprobing porosimetry to wider range of OSN membranes such as commercial asymmetric membranes and lab-bench fabricated thin film composite membranes.
Molecularly imprinted polymers
NEMOPUR has successfully developed novel MIP materials and techniques to isolate and purify API intermediate molecules from the model system mixtures. Experimental work has resulted in new molecularly imprinted film-macroporous membranes using newly designed reactive monomers for stoichiometric non-covalent imprinting which are stable in organic solvents. These have been used to develop a new, low mass transfer resistance system for fast equilibration and removal of impurities in organic solvents. Researchers tested forming and then crosslinking the macroporous membranes prior to coating with the MIP film and then forming the macroporous membrane, coating it with a MIP film, and then crosslinking both the underlying membrane and the MIP film simultaneously, giving promising results.
MIP based polishing phases for genotoxic impurities have been developed, as well as a capturing phase capable of binding a cyclic peptide while excluding oligomeric or acyclic impurities and to use the polymers to promote cyclisation. NEMOPUR has developed 1,3-diisopropylurea selective MIPs, methyl tosylate MIPs selective MIPs endotoxin selective MIPs. Rebinding tests shows high capacity and selectivity. These MIPs offer readily scalable production chemistries. Having taken key steps towards generating innovative and original solutions to the impurity challenge, researchers have began to implement processes using continuous and batch platforms and develop models for predicting performance of these platforms for API intermediate purification which can be used as design tools. Both imprinted polymers and reactive scavengers were shown to be useful materials for removal of undesired genotoxic impurities in reaction solvents containing the active pharmaceutical ingredient. The materials were able to solve these demanding clean-up tasks. We achieved clean-up levels that were close to complete removal of those toxic contaminants. Furthermore, the chromatographic separation is commercially feasible (see chromatogram below). The improved safety of pharmaceutical ingredients is of course beneficial for patients and therefore for society.
The research conducted within the NEMOPUR project has benefited from a highly coordinated and integrated approach by a multidisciplinary, inter-sectorial academic-industrial research team leading to effective technology transfer between different sectors using membrane technology. The membrane industry encompasses a broad field of science, engineering and technology and operates at the intersection of multiple disciplines, including material science, chemistry, chemical engineering, mechanical engineering, electrical engineering, life sciences and nanotechnology. NEMOPUR brought together leading companies and academic institutions from these different science and engineering fields through a multidisciplinary framework and successfully employed the research skills and expertise available within three universities / research institutes, two technology SMEs (small and medium-sized enterprises) and four pharmaceutical manufacturers. Together they represent a vertically integrated consortium, with knowledge stretching from the basic research to the design and marketing of products. Advanced research achieved through an intense cooperation between the academic and industry sectors on different aspects and components of purification advances enabled breakthroughs in research and development. This in turn has led to a variety of benefits including increased support for academic research by industry, increased and accelerated technology transfer, enhanced competitiveness, and ultimately, economic development within the European Community.
NEMOPUR placed enormous emphasis on the training and development needs of the recruited researchers with each ESR benefiting from cross-disciplinary research and comprehensive multi-level training in membrane technologies and applications focused on targeted areas. After a rigorous recruitment process to select highly motivated and talented researchers, detailed personal development plans were created for each of the 12 ESRs and 4 ERs to ensure that they received a comprehensive and structured training programme customised to their training needs. NEMOPUR's unique interdisciplinary PhD programme and career development platform ensured that NEMOPUR trained skilled graduates not only have knowledge of recent scientific research but also an ability to solve complex problems, perform advanced research, apply new concepts and develop new scientific methodologies. The training platform cut across different industry sectors, which has led to an increase in end-user membrane technology competence levels. The NEMOPUR network was industry focussed with a clear emphasis on applications which is capable of facilitating industry-driven pilot plant activity. Half the ESRs were employed within industry whilst also benefitting from academic facilities and training including state-of-the-art laboratory facilities for synthesis, characterisation and evaluation of membranes. Secondments, visits and training organised by industrial partners ensured that all ESRs gained experience of industrial practice thereby gaining education that included more generic and long-lasting skills. Formal training in technical and professional skills topics were complemented by training in business development from business partners; and secondments and exchanges between Partners have helped to ensure the transfer of knowledge and best practice within the network. ESRs benefited from a close collaborative international network which stimulated social interaction; increased the capacity for scientific and technological problem-solving and prepared them for an international research career either in academia or in industry.
Dissemination was an essential part of NEMOPUR, not only to communicate the achievements and successes of the project to the outside world, but also to develop essential communication skills of researchers. Attendance at and contributions to a range of technical events (conferences, seminars, workshops) and international conferences will lead to a wide range of experience at presenting and explaining research, preparing the researchers to work and communicate across disciplines and sectors.
Project website: http://www.imperial.ac.uk/molecularpurification