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Title: Organic solvent nanofiltration in the peptide industry
Author: Marchetti, Patrizia
ISNI:       0000 0004 2741 8853
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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In recent years the application of membrane technology to molecular separation processes has stimulated interest and showed great potential in a number of industrial fields. Ultrafiltration membranes have been successfully applied to downstream separation of therapeutically active peptides, to overcome some of the limitations of the conventional techniques in terms of costs, scale-up, selectivity and solvent recovery. In this research project, Organic Solvent Nanofiltration of peptide solutions is studied, and this understanding is applied to the development of innovative membrane-based purification strategies for industrial case studies. Basic understanding of transport mechanisms was approached by investigating solvent transport through ceramic nano- and ultrafiltration membranes, and developing a predictive phenomenological model for the transport of solvents and solvent mixtures. Effects of solvent-membrane interactions strongly affected the solvent permeation through nanofiltration membranes, while they were found to be negligible in the ultrafiltration range. The effect of the organic solvent on the permeation of neutral and charged solutes (monovalent salts, a small molecule and peptides) in organic/water mixtures was studied, with particular attention to the role of preferential solvation in the solvent mixture. It was found that the solvent composition and the complex association of counter-ions and buffers highly affect membrane permeation and rejection of organic molecules. It is proposed that all these components change the relative solute-membrane affinity. Since permeation of peptides in organic/water mixtures is affected by complicated matrices of input parameters, a Design of Experiment approach was proposed to efficiently investigate the nanofiltration of model peptides in acetonitrile/water solutions. Statistical models for solvent flux, peptide and ion rejection were obtained by Analysis of Variance and interpreted from a phenomenological point of view. The statistical models were used to asisst process development for two industrial case studies: (1) concentration and salt/solvent exchange of a first therapeutic peptide were optimised, based on the integration of the statistical DoE models with the process simulation for concentration and diafiltration; (2) the nanofiltration-assisted synthesis of a second therapeutic peptide, based on the coupling between nanofiltration and reaction in one unique process, was developed and compared to the established process by techno-economical analysis. The so-called "Reactive Peptide Nanofiltration" was found to be advantageous in terms of economics, efficacy, impact on the market, and on the environment. In conclusion, nano ltration was found to be a solid and competitive technique for application to peptide processes. On the basis of the results of this research, Lonza decided to invest in a new nano ltration plant for the downstream of peptides with ceramic membranes. The advantages of nanofiltration technology, in terms of development of more efficient materials (stable in critical solvents and harsh acid/basic conditions), improvement of membrane performances (selectivity, lifetime) and integration of nanofiltration with other techniques in hybrid processes seem therefore promising in overcoming the hesitancy of industries to modify the established processes and invest in new nano ltration plants, by making the payback period for the return of investment more attractive. It is plausible to think that this technology will shortly become a primary choice for new separation and purification processes.
Supervisor: Butte, Alessandro ; Livingstone, Andrew Sponsor: European Commission
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral